Download PDF
Review  |  Open Access  |  30 Jul 2023

Amyloid-β-targeted therapies for Alzheimer's disease: currently and in the future

Views: 875 |  Downloads: 181 |  Cited:   1
Ageing Neur Dis 2023;3:13.
10.20517/and.2023.16 |  © The Author(s) 2023.
Author Information
Article Notes
Cite This Article


Alzheimer’s disease (AD) is common and devastating. However, current symptomatic treatments are unable to alter the progression of the disease. Fortunately, many ongoing trials of disease-modifying therapies may provide new insights into the treatment and prevention of AD. Due to the long-held amyloid cascade hypothesis, the development of pharmacotherapies targeting amyloid-β (Aβ) has been a major focus in AD research. The recent positive results and approval of several anti- Aβ monoclonal antibodies seem to be a milestone for AD treatment. In this review, we highlight the rationale and status of different Aβ-targeted therapies for AD, including those now on the market and those in clinical trials. We also discuss the challenges and future perspectives of Aβ-targeted therapies for AD.


Alzheimer’s disease, disease-modifying therapy, amyloid


An estimated 15 million older adults are living with dementia in China, among whom 9.8 million have Alzheimer’s disease (AD)[1]. As the mean life expectancy increases and the aging population grows rapidly, the global cost attributable to dementia will reach US $9.12 trillion in 2050[2]. As such, effective treatment and prevention for AD are eagerly awaited.

Currently, treatment options for AD include both pharmacological and non-pharmacological approaches. Non-pharmacological therapies such as cognition stimulation therapy, occupational therapy, and behavioral interventions aim to enhance cognitive performance and improve the overall quality of life for individuals with AD[3]. Other alternative non-pharmacological therapies, including deep brain stimulation, focused ultrasound, and acoustic/light stimulation at 40 Hz, are under investigation[4]. Pharmacological interventions for AD primarily focus on the underlying pathophysiology of the disease. In 1993, the US Food and Drug Administration (FDA) approved the first drug, tacrine, for AD. Tacrine is an acetylcholinesterase inhibitor (AChEI) but is no longer in use due to hepatotoxicity[5]. An improved second-generation AChEIs and an N-methyl-D-aspartate receptor antagonist entered the market during the decade after tacrine. Although widely used, these drugs only provide symptomatic relief[6]. Therefore, research efforts have focused on developing disease-modifying therapies for the treatment and prevention of AD. Most disease-modifying therapies tested for AD in the past 20 years have targeted amyloid-β (Aβ) peptide and tau protein since they are the two key pathological hallmarks of the disease[6,7]. Meanwhile, remarkable advances in understanding the pathophysiology of AD have led to multiple hypotheses, such as inflammatory hypothesis, metabolism hypothesis, and mitochondrial hypothesis. These emerging hypotheses have sparked clinical development for potential treatments targeting these pathways[7,8], which have been extensively reviewed in other literature[9,10]. Given the recent advancements in Aβ-targeted therapies, this review aims to summarize and provide an updated overview of these therapies, focusing on those that have been approved and those currently in clinical trials.


The impetus for developing Aβ-targeted therapies originates from the prevailing amyloid cascade hypothesis[11]. The production of the Aβ peptide occurs through the cleavage of a type I transmembrane glycoprotein, amyloid precursor protein (APP). In the non-amyloidogenic pathway, cleavage of APP by α-secretase releases a soluble extracellular fragment called sAPPα and retains a membrane-bound C-terminal fragment known as CTFα. CTFα is subsequently processed by γ-secretase, resulting in the generation of a soluble N-terminal fragment called P3 that does not possess aggregating tendencies. Alternatively, when APP is cleaved by β-site APP cleaving enzyme (BACE), it results in the generation of a soluble extracellular fragment called sAPPβ and a 99-residue C-terminal fragment called CTFβ or C99. C99 is further cleaved by γ-secretase, leading to the production of the neurotoxic Aβ peptide (amyloidogenic pathway)[12]. Aβ exists in different lengths, with Aβ40 being the most abundant and Aβ42 being less soluble. Extracellular accumulation of Aβ triggers its aggregation, progressing from monomers, oligomers, and protofibrils and eventually forming insoluble plaques[13], which is a hallmark pathology of AD[14]. Aβ accumulation serves as the initiating event in AD pathogenesis and triggers a series of downstream events such as tau hyperphosphorylation, formation of the neurofibrillary tangle, oxidative stress, inflammatory responses, synaptic dysfunction, and cognitive impairment[15]. Hence, Aβ has been one of the most popular targets in AD drug research. Figure 1 illustrates the mechanism of action of the main Aβ-targeted therapies based on the amyloid cascade hypothesis. Aβ-targeted strategies attempt to antagonize Aβ aggregation (Aβ aggregation inhibitors), reduce Aβ production by inhibiting or modulating BACE and γ-secretase (BACE inhibitors, γ-secretase inhibitors, and γ-secretase modulators), promote clearance of Aβ via active or passive immunotherapies (anti-Aβ vaccines and anti-Aβ monoclonal antibodies) or decrease related protein expression (RNA-based therapies). Figure 2 illustrates the clinical development of Aβ-targeted therapies for AD.

Amyloid-β-targeted therapies for Alzheimer's disease: currently and in the future

Figure 1. Illustration of amyloid cascade hypothesis and targets of anti-amyloid-β (Aβ) therapies for Alzheimer’s disease. This figure illustrates the mechanism of action of the main Aβ-targeted therapies based on the amyloid cascade hypothesis. Blue circles indicate the targets of active and passive immunotherapies. Red circles indicate the targets of Aβ aggregation inhibitors. Aβ: amyloid-β; AICD: amyloid precursor protein intracellular domain; APP: amyloid precursor protein; BACE: β-site amyloid precursor protein cleaving enzyme; C99: a 99-residue C-terminal fragment; sAPPβ: soluble amyloid precursor protein-β.

Amyloid-β-targeted therapies for Alzheimer's disease: currently and in the future

Figure 2. Development of amyloid-β (Aβ)-targeted therapy for Alzheimer’s disease (AD). This figure summarizes the clinical development of Aβ-targeted pharmacotherapies for AD, reported according to the most advanced phase of the study and main therapeutic properties. Data were accessed on July 18, 2023. Agents with “*” indicate that the trials have been discontinued or are inactive. Agents with “†” indicate that the agents have been approved for the treatment of AD. Aβ: amyloid-β; AD: Alzheimer’s disease; APP: amyloid precursor protein; BACE: β-site amyloid precursor protein cleaving enzyme.


Studies have demonstrated that soluble Aβ oligomers, instead of plaques, are a major source of neurotoxicity and cause neuronal damage at the nanomolar level[16]. Hence, Aβ aggregation inhibitors are presumed to be a rational therapeutic strategy for AD. They disrupt the interaction of Aβ peptides, prevent their aggregation into oligomers, and thus limit neurotoxicity. Agents with this mechanism of action include PBT1 and PBT2, scyllo-inositol (ELND005), and tramiprosate.

PBT1(clioquinol) is a small molecule agent functioning as a metal protein attenuating compound[17]. Metal ions, such as copper and zinc, drive Aβ towards fibrillization and amyloid plaque formation and result in a series of redox reactions[18-20]. By binding these metal chaperones, PBT1 disrupts the interaction between Aβ peptides and metals and therefore prevents toxic Aβ oligomerization[17]. PBT1 failed to exhibit significant improvement in cognition or clinical global function in participants with mild cognitive impairment (MCI) to AD but showed a positive effect in those with more severe cognitive impairment (as measured by the Alzheimer’s Disease Assessment Scale-Cognitive [ADAS-cog] Subscale ≥ 25)[21]. The study investigator attributed this finding to the limited statistical power of the study and the nonlinear sensitivity of the ADAS-cog instrument, which hinders the detection of subtle cognitive differences in the less severely affected group. The second-generation clioquinol (PBT2), which has improved pharmacological prosperities and efficacy[22], also failed to show significant effects on cognition or function in MCI or mild to moderate AD[23,24].

Scyllo-inositol is an oral inositol stereoisomer that is thought to neutralize toxic Aβ oligomers and reduce aggregation[25]. This agent showed a dose-dependent reduction in Aβ pathology and ameliorated learning deficits in transgenic mice[25,26]. However, scyllo-inositol failed to show clinical benefits in participants with mild to moderate AD despite encouraging results in preclinical studies[27]. Severe adverse effects, including infections and death, were reported in the higher dosage (2,000 or 4,000 mg/day)[27], while the lower dosage (250 mg/day) appeared to have an acceptable safety profile[28]. Further development of the agent has not progressed in recent years.

Tramiprosate is a small aminosulfonate compound that functions by binding to and stabilizing Aβ42 monomers, thereby preventing oligomerization and plaque formation[29]. Tramiprosate did not show efficacy in mild to moderate AD in a phase III trial[30], but subgroup analyses demonstrated beneficial effects in the high-risk apolipoprotein E (APOE) ε4 carriers[31,32]. Then a prodrug version of tramiprosate, valiltramiprosate (ALZ-801), has developed with enhanced pharmacokinetic properties and tolerance[33]. A phase III trial is ongoing to validate the cognitive efficacy of valiltramiprosate on APOE ε4 homozygotes with early AD[34].


BACE1 is the first and rate-limiting secretase responsible for the proteolysis of APP in the amyloidogenic pathway[12]. The level and activity of BACE1 are higher in AD compared to healthy subjects[35]. BACE1 suppression interferes with the upstream of the amyloid cascade and, therefore, reduces the production of toxic Aβ, which may have important implications in the treatment of AD. Despite numerous studies conducted thus far, no BACE inhibitors have successfully completed phase III clinical trials [Table 1]. The concerning adverse effects observed in these trials include worsening cognitive function and weight loss. These effects may be attributed to the crucial role of BACE1 substrates beyond APP in neurodevelopment, as evidenced by the development of myelination deficits[36], cognitive impairment, and axon guidance defects in BACE1 knockout mice[36-38]. These findings suggest that developing a BACE inhibitor without these side effects could be challenging.

Table 1

Clinical trials of BACE inhibitors, γ-secretase inhibitors and modulators

Target/MechanismSponsorDrugStudy PopulationPhaseStatusClinical trial identifierStart dateEstimated end dateResultsRemarks
BACE inhibitorMerck Verubecestat
Mild to moderate ADII/IIITerminatedNCT01739348November 2012April 2017Lack of efficacy No cognitive or functional
Prodromal ADIIITerminatedNCT01953601November 2013April 2018Toxicity and lack of efficacy Worse cognition and
functional ability; more adverse effects
Eli LillyLY2811376Healthy subjectsICompletedNCT00838084December 2008June 2009Toxicitynonclinical retinal toxicity
Eli LillyLY2886721Mild ADI /IITerminatedNCT01561430March 2012August 2013ToxicityAbnormally elevated liver enzymes
Eli LillyLY3202626Mild ADIITerminatedNCT02791191June 2016July 2018Toxicity and lack of efficacy-
Amgen/NovartisUmibecestat (CNP520) Preclinical AD
II/IIITerminatedNCT03131453August 2017March 2020Toxicity and lack of efficacyWorse cognition; brain atrophy weight loss
Preclinical ADII/IIITerminatedNCT02565511November 2015April 2020
Eisai/BiogenElenbecestat (E2609) Early ADIIITerminatedNCT02956486October 2016January 2020Toxicity and lack of efficacyNo cognitive benefits; more adverse effects
JanssenAtabecestat (JNJ-54861911)Preclinical ADII/IIITerminatedNCT02569398October 2015December 2018Toxicity and lack of efficacyWorse cognition; more adverse effects
Astrazeneca/ Eil LillyLanabecestat (LY3314814, AZD3293)Early AD IIITerminatedNCT02972658March 2017October 2018Toxicity and lack of efficacyWorse cognition; brain atrophy
Mild ADIIITerminatedNCT02783573July 2016September 2018
Boehringer IngelheimBI-1181181 (VTP-37948)Healthy subjectsITerminatedNCT02254161November 2014February 2015ToxicitySkin reactions
Healthy subjectsICompletedNCT02106247April 2014June 2014
Healthy subjectsICompletedNCT02044406January 2014September 2014
PfizerPF-06751979Healthy subjectsICompletedNCT02793232June 2016January 2017Discontinuing research and development in neurology-
Healthy subjectsICompletedNCT03126721April 2017July 2017
Healthy subjectsICompletedNCT02509117July 2015July 2016
Hoffmann-La RocheRG7129 (RO5508887)Healthy subjectsICompletedNCT01664143July 2012September 2012No results have been published-
Healthy subjectsICompletedNCT01592331May 2012October 2012
Healthy subjectsICompletedNCT01461967September 2011December 2011
CoMentisCTS21166Healthy maleICompletedNCT00621010June 2007February 2008No results have been published-
High Point Pharmaceuticals, LLCHPP-854Mild ADITerminatedNCT01482013October 2011March 2012No results have been published-
AstraZenecaAZD3839Healthy subjectsICompletedNCT01348737June 2011November 2011Toxicity-
γ-Secretase inhibitorEli LillySemagacestat (LY450139)Probable ADIIICompletedNCT01035138December 2009April 2011Toxicity and lack of efficacyWorse cognition; risk of skin cancer and infections
Mild to moderate ADIIICompletedNCT00762411September 2008April 2011
Mild to moderate ADIIICompletedNCT00594568March 2008May 2011
Bristol-Myers SquibbAvagacestat (BMS708163)Prodromal ADIITerminatedNCT00890890May 2009July 2013Toxicity and lack of efficacyWorse cognition; gastrointestinal and dermatological side effects
γ-Secretase modulatorMyrexisTarenflurbil (R-flurbiprofen, MPC-7869)Probable ADIIITerminatedNCT00380276September 2006December 2008 Toxicity and lack of efficacy
inadequate ability to penetrate the brain
Mild ADIIITerminatedNCT00322036May 2006December 2008
Mild ADIIICompletedNCT00105547February 2005May 2008
FORUM PharmaceuticalsEVP-0962MCI or early AD, healthy subjectsIICompletedNCT01661673November 2012October 2013Toxicity-
EisaiE2212Healthy subjectsICompletedNCT01221259January 2010November 2012Acceptable safety and promising pharmacodynamic response-
PfizerPF-06648671Healthy subjectsICompletedNCT02407353October 2015March 2016Discontinuing research and development in neurology-
Healthy subjectsICompletedNCT02316756December 2014March 2015
Healthy subjectsICompletedNCT02440100May 2015October 2016

Verubecestat (MK-8931) is an orally administered BACE1 inhibitor characterized by its high cell permeability, excellent water solubility, and remarkable ability to cross the blood-brain barrier[39]. Verubecestat reduced cerebrospinal fluid (CSF) Aβ concentrations by over 90% in rodents and nonhuman primates[39]. Phase I trials[40-42] indicated that verubecestat was well-tolerated and capable of reducing Aβ protein levels in CSF. However, subsequent trials revealed that verubecestat failed to delay cognitive decline in participants with prodromal AD[43]. Moreover, it was associated with a range of treatment-related adverse events, including hippocampal atrophy, suicidal ideation, weight loss, and sleep disorders[44].

LY3202626 is a potent inhibitor of BACE1, known for its ability to cross the blood-brain barrier[45]. Preclinical studies demonstrated that LY3202626 dose-dependently reduced Aβ levels in primary cultured neurons of PDAPP mice[45]. Phase I trials[46-49] indicated that LY3202626 was generally well tolerated. Unfortunately, phase II trials[50] did not show any differences in tau PET, Aβ PET, or cognitive function between the treatment group and the placebo group. Additionally, a reduction in brain volume, particularly in the hippocampus region, was observed. Therefore, the study was discontinued.

Umibecestat (CNP520) exhibits significant selectivity for BACE1 over BACE2 and other proteases[51]. Umibecestat reduced CSF Aβ and Aβ deposition in preclinical models[51]. Animal toxicology studies of umibecestat indicated its safety profile, showing no adverse effects such as hair depigmentation, retinal degeneration, hepatotoxicity, or cardiotoxicity[51]. However, subsequent findings revealed that participants in the treated group experienced cognitive decline, brain atrophy, and weight loss compared to the placebo group, leading to the discontinuation of the study[52,53].

Elenbecestat (E2609) is an orally bioavailable small molecule BACE1 inhibitor[54]. Earlier trials demonstrated that elenbecestat was generally well tolerated and reduced Aβ levels in CSF and plasma, which holds promise for improving cognitive function[54-58]. However, the follow-up study was discontinued due to the lack of effective cognitive improvement in the treatment group[59]. Additionally, some participants in the treatment group experienced adverse effects such as rash, neuropsychiatric symptoms, cognitive impairment, decreased brain volume, a transient decrease in white blood cells, and elevated liver enzymes compared to the placebo group[14,52,60-62].

Atabecestat (JNJ-54861911) exhibits effective penetration into the central nervous system (CNS)[63]. Phase I results reported up to a 95% reduction in Aβ levels in healthy subjects[64]. However, subsequent phase II and III studies were terminated due to abnormally elevated liver enzymes and a potential trend towards cognitive decline in participants[65-67]. Follow-up reports suggest that hepatotoxicity may be linked to the inflammatory response induced by atabecestat and its metabolites[68].

Lanabecestat (LY3314814, AZD3293) showed promising potential in preclinical studies with various animal models[69], leading to its progression into clinical trials. Phase I trial[70] demonstrated the safety of lanabecestat and its ability to significantly reduce Aβ levels in both plasma and CSF. However, the phase III study[71] revealed that lanabecestat treatment did not slow or prevent cognitive decline. Furthermore, some adverse events were reported, including brain atrophy, neuropsychiatric symptoms, weight loss, and hair depigmentation.

BI-1181181 (VTP-37948) is an inhibitor of both BACE1 and BACE2[72]. Results from the phase I trial in stages I and II indicated that a single dose of BI-1181181 was well-tolerated, and its long half-life supported a once-daily oral dosing regimen[73,74]. However, the phase I trial was terminated during stage III due to skin reactions observed in some participants[75].

LY2811376, the first small molecule BACE1 inhibitor entering clinical trials, demonstrated a significant reduction in Aβ levels in both plasma and CSF during the phase I trial[76]. However, subsequent toxicological data revealed retinal toxicity, leading to the discontinuation of further studies[45,77].

LY2886721, a second-generation BACE1 inhibitor developed after LY2811376, exhibits a 10-fold stronger inhibition of BACE1 without affecting other aspartic proteases like histone D, pepsin, and renin[78]. In a PDAPP transgenic mouse model, oral administration of LY2886721 significantly reduced Aβ levels in primary neurons[79]. Phase I trials[80-85] demonstrated the good tolerability of LY2886721 under different dosages and its ability to lower CSF Aβ levels. However, hepatotoxicity was observed in many participants during the phase II trial[86], leading to the discontinuation of the study.

The development of several BACE1 inhibitors has been terminated for various reasons. PF-06751979, developed by Pfizer, showed promising results in preclinical and phase I studies with a reduction in CSF Aβ42 levels[87-92]. However, Pfizer decided to discontinue its development in neurology, leading to the drug not advancing to phase II or III trials[93]. RG7129 (RO5508887) was found to be hepatotoxic, resulting in the discontinuation of the study[94]. Only one registered phase I trial was found for CTS21166[95] and HPP-854[96], but no relevant trial results or records of further clinical studies are available.


γ-Secretase, a transmembrane protein complex, cleaves more than 140 substrates, including APP and Notch[97]. APP is initially cleaved by BACE, producing C99, which is subsequently proteolyzed by γ-secretase at multiple sites to generate Aβ peptides[12,98]. Therefore, targeting γ-secretase is considered a promising strategy for AD. Agents under this rationale include γ-secretase inhibitors and modulators [Table 1].

Semagacestat (LY450139) is the most potent γ-secretase inhibitor tested in humans. A study using stable isotope-labeled amino acid (13C6-leucine) found that semagacestat reduced Aβ production in a dose-dependent manner in the human CNS[99]. However, clinical trials of semagacestat failed due to its non-selective inhibition of substrates, leading to suppressed Notch signaling and accumulation of CTFs. These side effects included an increased risk of skin cancer, infection, gastrointestinal symptoms, and a decline in cognitive performance, which ultimately resulted in the discontinuation of clinical development[100-103].

Avagacestat (BMS708163) was initially considered a potent and selective γ-secretase inhibitor with “Notch-sparing” activity[104]. Preclinical studies indicated that it was 193 times more selective for Aβ processing than Notch and effectively inhibited the formation of Aβ40 and Aβ42, suggesting it may have fewer adverse effects compared to non-selective agents[104]. However, subsequent research revealed that avagacestat exhibited only 3-7 fold selectivity for APP over Notch[105]. Consistent with the latter findings, avagacestat caused Notch-deficient toxicity similar to semagacestat, that is, higher incidence of skin cancer, worsened cognitive function, and higher brain atrophy rate in phase II trials[106,107]. Therefore, the development of avagacestat was terminated.

One reason for the extensive toxicities of γ-secretase inhibitors may be that these proteases regulate many physiological processes within and outside the nervous system[108]. Another explanation for the failure would be too much and too quick suppression of Aβ, as Aβ accumulates and causes neurotoxicity in a chronic manner. Novel strategies aimed at partial suppression of the proteases and gradual reduction of Aβ are under development[109]. γ-Secretase modulators selectively modulate the γ-secretase cleavage site of APP rather than the downstream ε-cleavage site[110]. Consequently, γ-secretase modulators that exert a lesser influence on Notch signaling or other substrates would result in fewer side effects[111].

Nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, indomethacin, and sulindac sulfide, are the first identified γ-secretase modulators based on the epidemiological findings of lower prevalence of AD in NSAID users[112-114]. Short-term administration of NSAIDs reduced Aβ42 levels in the brain of APP transgenic mice and decreased Aβ42 secretion in cultured cells accompanied by an increase in Aβ38 isoforms, suggesting that NSAIDs subtly modulate γ-secretase activity without significantly affecting other APP processing pathways or Notch cleavage. Notably, the effect of NSAIDs on Aβ pathology in the brain is independent of their cyclooxygenase activity[115]. Tarenflurbil is the R-enantiomer of NSAIDs targeting the presenilin component of γ-secretase, which has less effect on cyclooxygenase activity and thus causes fewer gastrointestinal symptoms[115-118]. Tarenflurbil selectively reduced Aβ42 level and rescued the memory deficits of APP transgenic mice at chronic dosage in preclinical studies[116,119]. However, tarenflurbil failed to show significant efficacy in clinical studies, which is ascribed to its suboptimal pharmacodynamics, and the agent was no longer developed[120,121]. CHF507480, an NSAID-derived carboxylic acid analog, is initially considered a γ-secretase modulator but is now reported to act on multiple targets, including tau and neuroinflammation[122,123]. CHF507480 restored hippocampal neurogenesis, decreased brain Aβ burden, and improved memory in mouse models of AD[124,125]. CHF507480 showed clinical improvement in participants with MCI, especially in APOE ε4 carriers[126,127]. However, this differential clinical outcome could be attributed to the higher levels of neuroinflammation in APOE ε4 carriers compared to non-carriers[128], and this agent is being investigated as a microglial modulator[129].

E2012 is a non-NSAID-derived imidazole γ-secretase modulator. A preclinical study showed it dose-dependently reduced Aβ40 and Aβ42 levels in rat CSF, brain, and plasma[130]. It also increased shorter Aβ peptides such as Aβ37 and Aβ38, while maintaining the total amount of Aβ peptides[131]. It demonstrated a 50% efficacy in reducing plasma levels of Aβ42 during the phase I trial[132]. However, a high-dose group in a preclinical safety study exhibited lenticular opacity, leading to the suspension of the clinical trial[133]. E2212, an improved compound of E2012, demonstrated an acceptable safety profile and promising pharmacodynamic response in doses ranging from 10 mg to 250 mg in the phase I trial[134], but no further updates have been reported.


Immunotherapies have emerged as a potential treatment approach to slow down or halt the progression of AD by eliminating Aβ aggregates. The focus is on generating antibodies (active immunization) or using existing antibodies (passive immunization) against Aβ antigens to facilitate the clearance of Aβ[135]. Active immunization allows the production of antibodies over a longer period by administering a few doses of vaccine. However, T-cell-mediated adverse effects may occur after active immunization and limit its use[136]. Figure 3 illustrates the Aβ epitope targeted by representative anti-Aβ vaccines.

Amyloid-β-targeted therapies for Alzheimer's disease: currently and in the future

Figure 3. Amyloid-β (Aβ) epitopes of anti-Aβ vaccines and monoclonal antibodies tested in clinical trials for Alzheimer’s disease. Aβ amino acid sequence is indicated in the one-letter code. Anti-Aβ vaccines and monoclonal antibodies are classified according to the targeting epitope of Aβ. Aβ: amyloid-β.

The first Aβ-targeted active immunotherapy candidate, AN1792, was developed using full-length Aβ42 and formulated with QS21 adjuvant. The inclusion of QS21 adjuvant was aimed at shifting T cell response towards a TH1 phenotype and enhancing the antibody response[137]. In the phase I trial, AN1792 was able to generate an antibody response against Aβ42, leading to a reduction in amyloid plaques in the brain and an improvement in cognitive function among participants[138]. However, the phase II trial was terminated after 6% of participants developed meningoencephalitis mediated by Aβ-specific T-cell inflammatory response[139]. The severe adverse effect is presumably due to the use of full-length Aβ42, which contains T-cell epitopes in the C-terminus. Additionally, AN1792 faced challenges with weak immunogenicity, resulting in low antibody titers and limited therapeutic efficacy[140].

To address the issue of self-reactive T cell response and achieve higher antibody titers, second-generation vaccines were developed to target the B cell epitope of Aβ while avoiding T cell-mediated response[141]. The B cell epitope is primarily found in the Aβ1-15 region, and the fragment Aβ3-10 retains sufficient immunogenicity to elicit strong immune responses while minimizing T cell response. Consequently, the Aβ3-10 fragment is employed as the key component in the peptide vaccine[142-144]. Several second-generation Aβ vaccines have been developed, including amilomotide (CAD106), Vanutide cridificar (ACC-001), Lu AF20513, UB-311, ACI-24, V-950, ABvac40, ALZ-101, AD01, Affitope AD02, and AD03[145,146]. These vaccines have not induced meningoencephalitis in clinical trials, but certain antibody-mediated adverse reactions such as vasogenic edema and microhemorrhages have been reported. Currently, only a few of these vaccines have advanced to late-phase clinical trials, namely amilomotide, ACI-24, UB-311, and ABvac40[146].

Amilomotide is composed of multiple copies of Aβ1-6 coupled to a virus-like particle derived from the bacteriophage Qβ[141]. Active immunization with amilomotide prevented brain amyloid plaque accumulation in a transgenic mouse model of AD, with an 80% reduction in plaque compared to controls[147]. Phase I/II clinical trials of amilomotide conducted thus far have shown a favorable safety profile, acceptable antibody response, and promising effects in slowing down Aβ deposition in humans[141,148]. Notably, no cases of meningoencephalitis, aseptic meningoencephalitis, or vasogenic edema were reported[141]. Given these positive outcomes, amilomotide holds great potential as an effective therapeutic agent for preventing Aβ deposition in high-risk groups. However, further phase II/III trial of amilomotide was terminated prematurely due to unpredicted cognitive changes, brain atrophy, and weight loss[149].

ACI-24 is an Aβ vaccine consisting of a tetra-palmitoylated Aβ1-15 peptide in β conformation, coupled with liposomes containing monophosphorylated lipid A as an adjuvant[150]. Preclinical studies using mouse models of amyloidosis[150] and Down syndrome[151] demonstrated the efficacy of ACI-24 in rescuing memory deficits. Having achieved satisfactory results in the preclinical trial[152], a phase I/II trial[153] was conducted in mild to moderate AD to compare different doses of ACI-24 with placebo and assess its safety, immunogenicity, and efficacy. However, the trial ultimately enrolled only 48 participants, and the planned phase II efficacy stage was canceled due to limited antibody response. A phase II trial[154] with a new formulation was then initiated in participants with mild AD. Results presented in 2021 showed a clear IgM antibody response, and increased CSF Aβ levels, but no observable change in amyloid-PET scans. Another phase I study[155] investigated the safety, tolerability, and immune response of ACI-24 in Down syndrome. The study showed that the ACI-24 vaccine was safe and well tolerated, with no serious adverse events, CNS inflammation, or T-cell activation observed. A dose-dependent IgG response was seen at the higher doses. However, the study had a small sample size of only 16 subjects, and long-term follow-up is necessary to assess the cognitive function of the participants.

UB-311 contains two Aβ1-14-targeting peptides (B-cell epitopes), each linked to a different helper T-cell peptide epitope. These chimeric peptides are formulated to enhance immunogenicity within a Th2-biased delivery system, thereby minimizing T-cell inflammatory reactivity[156]. In a phase I study, UB-311 elicited a strong antibody response against Aβ without stimulating a cytotoxic T-cell response[156]. The safety and good tolerability of UB-311 were further confirmed in a phase II study in participants with mild to moderate AD. Exploratory endpoints of the study demonstrated a slower rate of cognitive decline in AD participants and a reduction in brain Aβ. The extension of the phase II trial was terminated due to treatment assignment error[157,158] and a phase III trial is planned[159].

While the majority of Aβ vaccine research has focused on N-terminal epitopes, alternative approaches are being explored. One such candidate is ABvac40, which consists of multiple repetitions of Aβ33-40, a C-terminal fragment of Aβ40, conjugated to keyhole limpet hemocyanin[160]. Aβ40 is the most common Aβ isoform and the predominant component of cerebral amyloid angiopathy[161]. Furthermore, it can also generate toxic aggregate[162,163] and is associated with the severity of AD[164,165]. The phase I trial demonstrated that ABvac40 was well tolerated and elicited the production of specific antibodies against Aβ40[160]. According to the topline results of the phase II trial presented recently, ABvac40 met its primary safety and efficacy outcome, displayed an excellent safety and tolerability profile, and elicited a robust immune response in participants with MCI or mild AD[166]. More details of the study are pending.

DNA vaccines, also known as genetic vaccines, represent the third generation of vaccines and offer distinct advantages over traditional peptide vaccines. Unlike peptide vaccines, DNA vaccines do not require the addition of adjuvant-like peptides. They are relatively safe, cost-effective, and capable of maintaining a sustained level of antigen expression within host cells[167]. AV-1959D is a DNA vaccine incorporating three copies of Aβ1-11, along with 12 T-cell-activating epitopes derived from various sources such as tetanus toxin, hepatitis B, and influenza viruses. These foreign antigens help enhance antibody responses by activating naïve and memory lymphocytes, which is particularly beneficial for older individuals who typically have weaker responses to vaccines[168,169]. AV-1959D demonstrated a robust cellular immune response and generated potent anti-Aβ antibodies in animal models, without triggering T-cell infiltration[170-173]. Furthermore, the early version of the vaccine effectively inhibited amyloid plaque accumulation, reduced glial activation, and prevented behavior deficits in aged mice[167]. No toxicities or amyloid-related imaging abnormalities (ARIA) were observed in mice susceptible to cerebral amyloid angiopathy[169]. These findings highlight the vaccine's potential as a safe and effective treatment for AD, leading to its advancement to a clinical trial in December 2022. The phase I clinical trial[174] aims to enroll 48 participants with early AD, who will receive different dosages of AV-1959D or placebo to assess its safety and tolerability.


Many active immunotherapies against Aβ were discontinued either because of severe T-cell-mediated meningoencephalitis or for futility[139,148,175]. Consequently, efforts have shifted towards passive immunotherapies to avoid T-cell-mediated responses. Passive anti-Aβ immunotherapies involve humanized monoclonal or polyclonal antibodies targeting Aβ. The anti-Aβ antibodies used in clinical trials have varied in their specificity, targeting different domains of the Aβ peptide [Figure 3]. They have different affinities for various forms of Aβ, including monomers, oligomers, protofibrils, and plaques [Figure 4]. Several monoclonal antibodies have entered phase III trials: aducanumab, lecanemab, donanemab, remternetug, gantenerumab, bapineuzumab, solanezumab, and crenezumab. In addition, three monoclonal antibodies including SHR-1707[176], ACU193[177], and ABBV-916[178] are under phase I and II trials.

Amyloid-β-targeted therapies for Alzheimer's disease: currently and in the future

Figure 4. Different forms of amyloid-β (Aβ) targeted by different monoclonal antibodies. This figure illustrates the different Aβ forms targeted by current anti-Aβ monoclonal antibodies for Alzheimer’s disease. Agents with a “triangle” indicate that the agent preferentially targets the form of Aβ below. Aβ: amyloid-β.

Aducanumab is a recombinant human IgG1 monoclonal antibody targeting N-terminal Aβ3-7[179]. It preferentially directs against soluble Aβ aggregates and insoluble fibrils Aβ. Aducanumab received its first approval for AD in the US in June 2021 based on significant biomarker outcomes in EMERGE and ENGAGE studies[179,180]. Evidence of clinical efficacy is discordant and conflicting in the two identically designed studies[181]. EMERGE study (1,638 MCI or early AD) showed a significant 22% slowing of decline on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) in the high-dose group, while no significant cognitive benefit was observed in either the low- or the high-dose group in ENGAGE study (1,647 MCI or early AD)[180,181]. The approval of aducanumab is controversial, and concerns have been raised about insufficient clinical efficacy and the misuse of statistics[182]. Notably, aducanumab was granted via an accelerated approval mechanism, which means that clinical benefits must be verified in postmarketing trials to obtain continued approval. Aducanumab exerts effects by decreasing amyloid plaques in the brain and, to some extent, phosphorylated tau (p-tau), representing the downstream tau pathology[180]. According to the prescribing information, aducanumab is recommended to be initiated in participants with MCI or mild AD[179]. The most worrisome adverse reactions are ARIA, including ARIA edema (ARIA-E; 35% vs. 3%), ARIA hemosiderin deposition (ARIA-H) microhemorrhage (19% vs. 7%), and ARIA-H superficial siderosis (15% vs. 2%). These adverse reactions are dose-dependent, leading to a greater withdrawal rate in the high-dose group[179,183]. Recipients must be pre-evaluated for susceptibility to these adverse reactions and closely monitored with scheduled magnetic resonance imaging (MRI) scans[184]. The marketing application for aducanumab was rejected by the European Medicines Agency and Japan's Health Ministry in 2021.

To obtain more data on the long-term safety and tolerability of aducanumab, a phase IIIb EMBARK study[185,186] is ongoing. Furthermore, a phase IV confirmatory trial ENVISION[187] began in June 2022. The trial will enroll 1,500 individuals with early AD and last 18 months. The primary outcome is CDR-SB and secondary outcomes include cognitive and functional measures, as well as Aβ and tau PET. Results are expected by 2026.

Lecanemab is a humanized IgG1 version of the mouse monoclonal antibody mAb158, which possesses a specific affinity for soluble Aβ protofibrils[188]. mAb158 exhibited the ability to reduce Aβ protofibrils in the brain and CSF in preclinical studies. Furthermore, mAb158 has the potential to protect neurons by mitigating the toxic effects of Aβ protofibrils by reducing their pathological accumulation in astrocytes[189]. Lecanemab was granted accelerated approval in January 2023 and full approval in July 2023 by the US FDA based on the results from phase II[190,191] and phase III trials (CLARITY AD)[192]. The CLARITY AD trial, a large global clinical study involving 1,795 participants with early AD, demonstrated that lecanemab successfully achieved its primary endpoints. The lecanemab treatment group exhibited a 27% slower clinical deterioration compared to the placebo group after 18 months, which corresponded to a treatment difference of -0.45 in the CDR-SB change in the intent-to-treat population. Additionally, all secondary endpoints, including global cognition and activities of daily living, showed statistically significant improvement compared to placebo. Furthermore, lecanemab effectively reduced Aβ burdens measured by PET scans in a subset of 698 participants. Biomarkers related to tau pathology and neurodegeneration in CSF and plasma also favored lecanemab over placebo. These findings support the positive correlation between the extent of Aβ reduction and the degree of clinical benefit. Lecanemab treatment, like other Aβ-targeted monoclonal antibodies, had side effects including ARIA-E and ARIA-H. ARIA-E incidence was 12.6% (2.8% symptomatic) in the lecanemab group and 1.7% (no symptomatic cases) in the placebo group. ARIA-H incidence was 17.3% (0.7% symptomatic) in the lecanemab group and 8.7% (0.2% symptomatic) in the placebo group. Overall, ARIA events were less frequent with lecanemab compared with other monoclonal antibodies[193]. Fatal brain hemorrhage cases were reported with lecanemab and concomitant anticoagulant treatment[194,195], suggesting caution in treating participants on anticoagulants with anti-Aβ monoclonal antibodies until more safety data are available[196].

The recent approval of lecanemab is encouraging, particularly to clinicians, patients, and caregivers. However, the statistically positive results were considered well below the minimal clinically important difference, which could result from biases due to loss of follow-up or functional unblinding[197]. Therefore, it is too early to conclude since we expect more evidence from postmarketing trials. A phase III study of lecanemab called AHEAD 3-45 began in July 2020[198]. It is a four-year study consisting of two sub-studies, involving a total of 1,400 cognitively normal individuals with elevated brain Aβ. The A3 sub-study (400 participants) focuses on those with Aβ burden below the positivity threshold; they will receive lecanemab at a dose of 5 mg/kg titrated to 10 mg/kg or a placebo every four weeks for 216 weeks with a change in brain Aβ PET as the primary outcome. The A45 sub-study (1,000 participants) enrolls those with positive Aβ PET; they will receive lecanemab titrated to 10 mg/kg every two weeks for 96 weeks, followed by the same dose every four weeks until week 216 with a change in Preclinical Alzheimer Cognitive Composite 5 score as the primary outcome. Notably, blood Aβ42/40 will be used to prescreen participants for elevated brain Aβ before PET imaging.

Donanemab is a humanized IgG1 monoclonal antibody derived from the mouse mE8-IgG2a. It specifically targets N-truncated pyroglutamate Aβ peptide (AβpE), a form of Aβ that aggregates in amyloid plaques[199]. Therefore, donanemab aims to eliminate existing plaques rather than prevent their formation. In a phase II trial (TRAILBLAZER-ALZ) involving 257 participants with early symptomatic AD who had brain tau and deposition, donanemab showed positive effects on delaying the clinical progression, as evidenced by a better composite score for cognition and functional ability (change from baseline in the Integrated Alzheimer’s Disease Rating Scale [iADRS] score at 76 weeks: -6.86 in the treatment group vs. -10.06 in the placebo group)[200]. The slowing in clinical decline was accompanied by a considerable reduction in amyloid plaques, with a mean change difference of 85 centiloids between donanemab and placebo at 76 weeks. This led to approximately two-thirds of the participants receiving donanemab becoming Aβ-PET negative by week 76[200,201]. A subsequent post hoc analysis[201] revealed that individuals with higher baseline Aβ experienced greater plaque reduction in the first six months but were less likely to achieve complete clearance compared to those with lower Aβ levels. The degree of Aβ reduction was correlated with changes on the iADRS clinical endpoint only in APOE ε4 carriers. The slowing of tau accumulation was more prominent in individuals who achieved complete Aβ clearance and in brain regions affected later in the disease progression. The remarkable clearance of amyloid plaques is attributed to the exclusive presence of AβpE within cerebral Aβ plaques[202]. The specific targeting of plaques by the antibody is expected to minimize the risk of ARIA by not affecting normal neurons. However, the occurrence of ARIA was significantly higher in the treatment group compared to the placebo group (ARIA-E:26.7% vs. 0.8%; ARIA-H: 8.4% vs. 3.2%). Furthermore, 7.6% of participants in the treatment group experienced infusion-related reactions, whereas no such reactions were observed in the placebo group. Approximately 90% of the participants treated with donanemab tested positive for antidrug antibodies[200].

Recently, the results for the phase III trial (TRAILBLAZER-ALZ2)[203] of donanemab were released, in which the treatment group demonstrated a significant slowing in cognitive decline (35.1% difference on iADRS measures in the low/medium tau population and 22.3% in the overall population) and showed improvements in all secondary clinical endpoints. The incidence of ARIA in the study was higher in the treatment group (ARIA-E:24.0% donanemab vs. 2.1% placebo and ARIA-H: 31.4% donanemab vs. 13.6% placebo). A series of trials are underway to explore its effect and safety in diverse populations[204-207].

Following donanemab, remternetug (LY3372993) is another monoclonal antibody targeting AβpE[208]. This agent is designed to share similar properties with donanemab while addressing some of the safety concerns related to antidrug antibodies and infusion reactions reported in donanemab[209]. Investigation of the agent started with a phase I trial in 2018 but was prematurely terminated for undisclosed reasons[210]. Another phase I trial[211] was initiated in 2020 involving multiple escalating doses(250-2,800 mg) in healthy subjects and participants with MCI or AD. Interim analysis[209] (41 participants) of the trial showed a dose-dependent reduction in amyloid plaque, with all participants in the 2,800 mg group dropping below the amyloid positivity threshold within three months. Although safety data remained blind, the study reported 10 cases of ARIA-E and 7 cases of ARIA-H, with no apparent connection to the dosage. No antidrug antibodies or systemic infusion reactions were detected. A phase III trial of remternetug (TRAILRUNNER-ALZ 1)[212] is ongoing to evaluate its safety, tolerability, and efficacy on participants with early symptomatic AD and is expected to be completed in 2025. Similarly, another monoclonal antibody, ABBV-916, also targets AβpE and is recently under investigation in a phase II trial[178].

Gantenerumab is a fully human IgG1 monoclonal antibody that targets both the amino-terminal and central regions of Aβ[213]. Gantenerumab preferentially binds to aggregated Aβ, with limited affinity to soluble Aβ. The antibody works by activating microglial phagocytosis and degrading the plaque[213-215]. Despite undergoing development for over a decade and being tested in 9 clinical trials involving 4,135 participants, gantenerumab has not demonstrated significant clinical benefits [214]. In November 2022, the results of the GRADUATE 1 and 2 trials[216-218] were released, revealing that gantenerumab missed its primary endpoint of a 20% reduction in clinical disease progression. The pooled analysis demonstrated an approximately 8% slowing of clinical decline by gantenerumab. Biomarkers of tau pathology and neurodegeneration favored gantenerumab over placebo, suggesting its potential for modifying the disease. However, further results demonstrated that gantenerumab cleared less plaque (46.8-57.6 centiloids at week 116) and had fewer participants achieving Aβ negativity on PET scans compared to previous trials. The incidence of ARIA was relatively high (ARIA-E: 23.9%-25.8% vs. 1.7%-3.8%; ARIA-H: 22.0%-23.7% vs. 12.2%-12.4%). Notably, gantenerumab was assessed in a phase II/III trial conducted by the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU)[219]. The trial aims to prevent dementia in individuals at risk for autosomal-dominant AD. During the trial, gantenerumab dosage was increased by fivefold. However, the completed trial in November 2019 did not achieve its primary endpoint. Given the dismal failure of the agent, studies of gantenerumab have been discontinued.

Several other monoclonal antibodies targeting Aβ did not show promising results. Bapineuzumab was the first passive immunotherapy to be tested in late-phase clinical trials for mild to moderate AD. It binds to Aβ oligomers and monomers with similar affinity[220,221]. While it showed a reduction in Aβ accumulation in AD participants based on PET scans, the clinical trials did not demonstrate significant changes in CSF Aβ levels or meaningful clinical benefits for participants with mild to moderate AD[222-225]. Further, bapineuzumab raised safety concerns due to an increased incidence of ARIA at higher doses[222,226,227]. Consequently, further research on bapineuzumab was discontinued.

Solanezumab is a humanized IgG1 monoclonal antibody that targets the central region of Aβ (Aβ16-24). It works by stabilizing Aβ monomers and preventing the formation of Aβ oligomers, but it does not target fibrils[228,229]. Solanezumab demonstrated a safer profile with a lower frequency of ARIA occurrence[230-235]. However, it did not show significant improvements in cognitive and functional outcomes in phase III trials in mild or mild to moderate AD, including the aforementioned phase II/III trial conducted by DIAN-TU[219,236-238]. Recently updated results from the A4 study showed solanezumab failed to slow cognitive decline in preclinical AD or reduce the risk of progression to symptomatic AD[239,240].

Crenezumab, an IgG4 antibody, targets the mid-region of Aβ and can bind to various forms of Aβ, including monomers, oligomers, fibrils, and plaques, particularly oligomers[241-244]. It reduces the activation of microglia and minimizes adverse effects such as vasogenic edema and brain microhemorrhage[243,245]. Clinical trials showed that crenezumab reduced CSF levels of Aβ oligomers[246] and increased CSF Aβ42[247]. However, larger trials were discontinued as interim analysis indicated that cognitive decline was unlikely to be slowed, and the drug was unlikely to meet its primary endpoint[248]. API Colombian prevention trial[249-251] results, released in June 2022, were negative on the primary and secondary endpoints but showed positive trends for crenezumab. Crenezumab showed a 20% decline slowing in primary outcomes with variability, and some measures including CDR-SB, FDG-PET, CSF and plasma biomarkers had a trend towards improvement but did not reach statistical significance. Therefore, the development of crenezumab has been stopped.


The rationale behind inhibiting APP expression for AD stems from its ability to decrease the amount of available APP for processing, thereby reducing the production of Aβ peptides. This can be achieved through a gene-silencing technique that employs intrathecal injection of small interfering RNA (siRNA) designed to target APP mRNA[252]. ALN-APP, the first siRNA therapy tested for CNS diseases, combines synthetic siRNA with a lipophilic conjugate called 2'-O-hexadecyl (C16), which enhances its ability to penetrate the CNS[253,254]. In nonhuman primate studies, a single intrathecal injection of ALN-APP reduced APP mRNA in the spinal cord and brain, resulting in a 75% decrease in sAPPα and sAPPβ levels. These reductions persisted for 2-3 months, returning to normal after 9 months. In an APP transgenic mouse model for AD, ALN-APP treatment resulted in a 50% decrease in APP mRNA and sAPPα, along with a reduction in Aβ40 deposition and inflammation. Furthermore, it normalized glutamate levels and improved behavioral outcomes[254]. A phase 1 trial of ALN-APP[255] is ongoing on participants with MCI or early-onset AD to evaluate its safety, tolerability, pharmacokinetics, and pharmacodynamics. In April 2023, preliminary results[256] from single-dose data on 20 participants were released, indicating that ALN-APP dose-dependently reduced CSF sAPPα and sAPPβ, with the highest dose achieving a median reduction of over 70% in both biomarkers for at least three months. Adverse events were mild to moderate. Multiple-dose evaluation is on hold in the US but approved in Canada.


In recent years, substantial progress has been made in developing Aβ-targeted therapies for AD. Although previous studies have largely not led to success, valuable experiences have been learned and used to optimize the following research.

Numbers of negative clinical trials with Aβ-targeted therapy for AD have led to the questioning of this long-held hypothesis. Many studies propose that the accumulation of Aβ may be a downstream phenomenon or a compensatory protective mechanism, rather than the central trigger for the onset of the disease[257-259]. AD is a complicated disease with many unanswered questions. Further studies are warranted to uncover the pathophysiology of AD and to find novel effective therapeutic targets for the disease. The development of effective therapies is hampered by a lack of appropriate models. AD is a disease specific to humans, and no animal model can fully recapitulate the manifestations and mechanisms of the disease[260], which may explain why most of the encouraging results in animal models fail to be replicated in clinical trials. One key to bridging the gap is developing more reliable translational animal models to better explicate the disease.

For Aβ-targeted strategies, the correlation between Aβ clearance and clinical benefit is undetermined. Pooled evidence from clinical trials suggests that Aβ reduction strategies do not substantially enhance cognition[261], while some researchers insisted that complete clearance of plaques is necessary for the brain to respond gradually[262,263]. In this context, early initiating treatment might be important for Aβ reduction strategies to be effective[264,265]. Most trials recruit participants with mild to moderate AD, in which the disease could already be too advanced since neuropathological changes of AD have occurred decades before clinical manifestations[266]. Alternatively, recruiting asymptomatic participants with causal mutations of familial AD may be a future trend to meet the full potential of therapies as a preventative treatment, as shown in the DIAN-TU[267].

Many Aβ-targeted therapies with distinct rationales have exhibited enhanced efficacy among APOE ε4 carriers, suggesting that APOE ε4 may play a pivotal role in Aβ-targeted therapies, as evidenced by a pooled analysis[268]. Several hypotheses have been postulated to explain the phenomenon. First, the greater treatment response in carriers could be ascribed to the imbalance in the occurrence of ARIA-E and potential functional unblinding[269]. Additionally, the more favorable therapeutic outcomes observed among APOE ε4 carriers could be partially attributed to accelerated decline within this subgroup. However, the pooled analysis revealed that APOE ε4 non-carriers displayed a non-significantly faster rate of clinical progression[268]. Furthermore, differential reduction of APOE-mediated tau pathology between carriers and non-carriers may account for the disparate effects observed in Aβ-targeted therapies, given the association of APOE ε4 with tau pathology[268]. Moreover, APOE ε4 non-carriers may have additional coexisting pathologies[270], or their cognitive impairment may be influenced to a lesser extent by the underlying amyloidosis[268]. To sum up, the mechanisms underlying the phenomenon are undetermined and these hypotheses warrant further focused investigations.

In addition to Aβ, other factors also contribute to the pathophysiology of AD and are potential targets for disease-modifying therapies, including tau, neuroinflammation, and metabolism[7]. Furthermore, tau pathology is demonstrated to be more correlated with cognitive decline and clinical progression than Aβ[271]. As AD is a multifactorial disorder with various types of interrelated neuropathology[6], single-targeted agents might be insufficient to delay progression. Combined treatment and multitargeted agents have gained more attention in recent years and might be a rational direction. Multitargeted pharmacotherapies under clinical investigation for AD include Ginkgo biloba[272] and AD-35[273]. The DIAN-TU has initiated a concurrent trial[274] combining anti-Aβ and anti-tau therapies. In this study, 168 individuals with familial AD mutations will receive lecanemab, with half of them also receiving the anti-tau antibody E2814, while the other half will receive a placebo.

Passive anti-Aβ immunotherapy is currently regarded as the most promising direction for anti-Aβ treatment. However, there remain many pressing issues that must be addressed to fully harness its potential. Firstly, it is still debatable which form, isoform, or epitope is appropriate to target for clearance. Growing evidence indicates that soluble Aβ oligomers, rather than fibrillary aggregates, are more neurotoxic and better associated with AD clinical symptoms[13,275-277]. Research has demonstrated that selective antibodies targeting soluble Aβ oligomers can block synaptotoxicity and restore memory deficits in animal models[13]. However, some researchers have raised concerns regarding the therapeutic role of Aβ oligomer-specific antibodies, suggesting that they might increase the toxicity of Aβ oligomers[278]. Apart from Aβ40 and Aβ42, additional Aβ isoforms, including pyroglutamate Aβ3-42 and Aβ4-42, have been recognized as significant factors in the development of AD[199]. Treatment targeting these isoforms include donanemab, remternetug, ABBV-916, and ACI-24, and some of them have shown promising outcomes in clinical trials. Novel findings from the pseudo β-hairpin conformation of the N-terminal region of pyroglutamate Aβ monomers also have implications for active and passive immunization strategies in AD[279]. Additionally, ARIA is a common adverse effect of anti-Aβ monoclonal antibody treatment. The exact biological mechanisms underlying ARIA are still not fully understood, but they may result from increased permeability of cerebrovascular structures due to enhanced clearance of Aβ plaques, a saturation of perivascular drainage, direct interaction of monoclonal antibodies with vascular Aβ deposits, and weakening of blood vessel walls[263]. Although most cases of ARIA are transient, it is essential to closely monitor participants for ARIA, particularly after treatment initiation, and consider additional MRI scans if they develop new symptoms suggestive of ARIA[227,280]. Brain atrophy following anti-Aβ immunotherapies has also been overlooked[281]. Considering their association with cognitive decline and AD pathology, it is important to ensure that these changes do not indicate worsening neurodegeneration after treatment. Finally, as these recent trials use biomarkers for enrollment, monitoring, and outcome assessment, healthcare systems must be prepared for this disease-modifying treatment. Blood-based biomarkers appear to be a low-invasive and cost-effective approach for large-scale screening and primary care centers[282]. However, further validation by larger and more diverse populations and the establishment of relevant cut-offs are necessary before they can be implemented into regular usage.

With evolving experience, the development strategies and recommendations for the appropriate use of these Aβ-targeted therapies are continuously updated[184,196]. Recent approvals of the two monoclonal antibodies as the first disease-modifying therapy for AD are encouraging. However, it is too early to draw a conclusion and there is still a long way to go. In conclusion, we expect many results from trials in the next few years. With further research, effective treatment and prevention for AD are possible and anticipated.


Authors’ contributions

Study conception and design: Jia L, Cai H

Literature search and review: Cai H, Fu X, Quan S, Ren Z, Chu C

Draft manuscript and preparation: Cai H, Fu X, Quan S, Ren Z

Review and revision of paper: Jia L, Cai H, Chu C

Approval of final version: Jia L, Cai H, Fu X, Quan S, Ren Z, Chu C

Availability of data and materials

Not applicable.

Financial support and sponsorship

This project was supported by the National Natural Science Foundation of China (82071194); Beijing Brain Initiative from Beijing Municipal Science & Technology Commission (Z201100005520016); Capital’s Funds for Health Improvement and Research (2022-2-2017); and STI 2030 Major Projects of China (2022ZD0211600, 2022ZD0211605).

Conflicts of interest

All authors declared that there are no conflicts of interest.

Ethical approval and consent to participate

Not applicable.

Consent for publication

Not applicable.


© The Author(s) 2023.


1. Jia L, Du Y, Chu L, et al; COAST Group. Prevalence, risk factors, and management of dementia and mild cognitive impairment in adults aged 60 years or older in China: a cross-sectional study. Lancet Public Health 2020;5:e661-71.

2. Jia J, Wei C, Chen S, et al. The cost of Alzheimer's disease in China and re-estimation of costs worldwide. Alzheimers Dement 2018;14:483-91.

3. Zucchella C, Sinforiani E, Tamburin S, et al. The multidisciplinary approach to alzheimer's disease and dementia. a narrative review of non-pharmacological treatment. Front Neurol 2018;9:1058.

4. Tatulian SA. Challenges and hopes for Alzheimer's disease. Drug Discov Today 2022;27:1027-43.

5. Sameem B, Saeedi M, Mahdavi M, Shafiee A. A review on tacrine-based scaffolds as multi-target drugs (MTDLs) for Alzheimer's disease. Eur J Med Chem 2017;128:332-45.

6. Scheltens P, De Strooper B, Kivipelto M, et al. Alzheimer's disease. Lancet 2021;397:1577-90.

7. Cummings J, Zhou Y, Lee G, Zhong K, Fonseca J, Cheng F. Alzheimer's disease drug development pipeline: 2023. Alzheimers Dement 2023;9:e12385.

8. Liu PP, Xie Y, Meng XY, Kang JS. History and progress of hypotheses and clinical trials for Alzheimer's disease. Signal Transduct Target Ther 2019;4:29.

9. Zhang F, Zhong RJ, Cheng C, Li S, Le WD. New therapeutics beyond amyloid-β and Tau for the treatment of Alzheimer's disease. Acta Pharmacol Sin 2021;42:1382-9.

10. Guo Y, Li S, Zeng L, Tan J. Tau-targeting therapy in Alzheimer’s disease: critical advances and future opportunities. Ageing Neur Dis 2022;2:11.

11. Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 2002;297:353-6.

12. O'Brien RJ, Wong PC. Amyloid precursor protein processing and Alzheimer's disease. Annu Rev Neurosci 2011;34:185-204.

13. Walsh DM, Selkoe DJ. A beta oligomers - a decade of discovery. J Neurochem 2007;101:1172-84.

14. Long JM, Holtzman DM. Alzheimer disease: an update on pathobiology and treatment strategies. Cell 2019;179:312-39.

15. Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO Mol Med 2016;8:595-608.

16. Ono K, Yamada M. Low-n oligomers as therapeutic targets of Alzheimer's disease. J Neurochem 2011;117:19-28.

17. Cherny RA, Atwood CS, Xilinas ME, et al. Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer's disease transgenic mice. Neuron 2001;30:665-76.

18. Bush AI, Pettingell WH, Multhaup G, et al. Rapid induction of Alzheimer a beta amyloid formation by zinc. Science 1994;265:1464-7.

19. Atwood CS, Moir RD, Huang X, et al. Dramatic aggregation of Alzheimer abeta by Cu(II) is induced by conditions representing physiological acidosis. J Biol Chem 1998;273:12817-26.

20. Opazo C, Huang X, Cherny RA, et al. Metalloenzyme-like activity of Alzheimer's disease beta-amyloid. Cu-dependent catalytic conversion of dopamine, cholesterol, and biological reducing agents to neurotoxic H2O2. J Biol Chem 2002;277:40302-8.

21. Ritchie CW, Bush AI, Mackinnon A, et al. Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Abeta amyloid deposition and toxicity in Alzheimer disease: a pilot phase 2 clinical trial. Arch Neurol 2003;60:1685-91.

22. Adlard PA, Cherny RA, Finkelstein DI, et al. Rapid restoration of cognition in Alzheimer's transgenic mice with 8-hydroxy quinoline analogs is associated with decreased interstitial Abeta. Neuron 2008;59:43-55.

23. Lannfelt L, Blennow K, Zetterberg H, et al. PBT2-201-EURO study group. Safety, efficacy, and biomarker findings of PBT2 in targeting Abeta as a modifying therapy for Alzheimer's disease: a phase IIa, double-blind, randomised, placebo-controlled trial. Lancet Neurol 2008;7:779-86.

24. Villemagne VL, Rowe CC, Barnham KJ, et al. A randomized, exploratory molecular imaging study targeting amyloid β with a novel 8-OH quinoline in Alzheimer's disease: The PBT2-204 IMAGINE study. Alzheimers Dement 2017;3:622-35.

25. McLaurin J, Kierstead ME, Brown ME, et al. Cyclohexanehexol inhibitors of Abeta aggregation prevent and reverse Alzheimer phenotype in a mouse model. Nat Med 2006;12:801-8.

26. Fenili D, Brown M, Rappaport R, McLaurin J. Properties of scyllo-inositol as a therapeutic treatment of AD-like pathology. J Mol Med 2007;85:603-11.

27. Salloway S, Sperling R, Keren R, et al. ELND005-AD201 Investigators. A phase 2 randomized trial of ELND005, scyllo-inositol, in mild to moderate Alzheimer disease. Neurology 2011;77:1253-62.

28. Rafii MS, Skotko BG, McDonough ME, et al. ELND005-DS Study Group. A randomized, double-blind, placebo-controlled, phase II study of oral ELND005 (scyllo-Inositol) in young adults with down syndrome without dementia. J Alzheimers Dis 2017;58:401-11.

29. Gervais F, Paquette J, Morissette C, et al. Targeting soluble Abeta peptide with Tramiprosate for the treatment of brain amyloidosis. Neurobiol Aging 2007;28:537-47.

30. Aisen PS, Gauthier S, Ferris SH, et al. Tramiprosate in mild-to-moderate Alzheimer's disease - a randomized, double-blind, placebo-controlled, multi-centre study (the Alphase Study). Arch Med Sci 2011;7:102-11.

31. Abushakra S, Porsteinsson A, Vellas B, et al. Clinical benefits of tramiprosate in alzheimer's disease are associated with higher number of APOE4 alleles: the "APOE4 gene-dose effect". J Prev Alzheimers Dis 2016;3:219-28.

32. Abushakra S, Porsteinsson A, Scheltens P, et al. Clinical effects of tramiprosate in APOE4/4 homozygous patients with mild alzheimer's disease suggest disease modification potential. J Prev Alzheimers Dis 2017;4:149-56.

33. Hey JA, Yu JY, Versavel M, et al. Clinical pharmacokinetics and safety of ALZ-801, a novel prodrug of tramiprosate in development for the treatment of alzheimer's disease. Clin Pharmacokinet 2018;57:315-33.

34. Alzheon Inc. A phase 3, multicenter, randomized, double-blind, placebo-controlled study of the efficacy, safety and biomarker effects of ALZ-801 in subjects with early alzheimer’s disease and APOE4/4 genotype. 2023. Available from: [Last accessed on 27 Jul 2023].

35. Fukumoto H, Cheung BS, Hyman BT, Irizarry MC. Beta-secretase protein and activity are increased in the neocortex in Alzheimer disease. Arch Neurol 2002;59:1381-9.

36. Willem M, Garratt AN, Novak B, et al. Control of peripheral nerve myelination by the beta-secretase BACE1. Science 2006;314:664-6.

37. Laird FM, Cai H, Savonenko AV, et al. BACE1, a major determinant of selective vulnerability of the brain to amyloid-beta amyloidogenesis, is essential for cognitive, emotional, and synaptic functions. J Neurosci 2005;25:11693-709.

38. Rajapaksha TW, Eimer WA, Bozza TC, Vassar R. The Alzheimer's β-secretase enzyme BACE1 is required for accurate axon guidance of olfactory sensory neurons and normal glomerulus formation in the olfactory bulb. Mol Neurodegener 2011;6:88.

39. Kennedy ME, Stamford AW, Chen X, et al. The BACE1 inhibitor verubecestat (MK-8931) reduces CNS β-amyloid in animal models and in Alzheimer's disease patients. Sci Transl Med 2016;8:363ra150.

40. Merck Sharp & Dohme LLC. A two-part, open-label study to investigate the single-dose pharmacokinetics of MK-8931 when administered to subjects with mild and moderate hepatic insufficiency. 2018. Available from: [Last accessed on 27 Jul 2023].

41. Merck Sharp & Dohme LLC. A study to assess the safety, tolerability, and pharmacodynamics of MK-8931/SCH 900931 in patients with alzheimer’s disease [Phase 1b; Protocol No. 010-00 (Also Known as P07820)]. 2015. Available from: [Last accessed on 27 Jul 2023].

42. Merck Sharp & Dohme LLC. An open-label, two-part, single-dose study to investigate the pharmacokinetics of MK-8931 in subjects with renal insufficiency (Protocol No. MK-8931-009 [P08535]). 2015. Available from: [Last accessed on 27 Jul 2023].

43. Egan MF, Kost J, Voss T, et al. Randomized trial of verubecestat for prodromal alzheimer's disease. N Engl J Med 2019;380:1408-20.

44. Egan MF, Kost J, Tariot PN, et al. Randomized trial of verubecestat for mild-to-moderate alzheimer's disease. N Engl J Med 2018;378:1691-703.

45. McKinzie DL, Winneroski LL, Green SJ, et al. Discovery and early clinical development of LY3202626, a low-dose, CNS-penetrant BACE inhibitor. J Med Chem 2021;64:8076-100.

46. Willis BA, Lowe SL, Monk SA, et al. Robust pharmacodynamic effect of LY3202626, a central nervous system penetrant, low dose BACE1 inhibitor, in humans and nonclinical species. J Alzheimers Dis Rep 2022;6:1-15.

47. Eli Lilly and Company. Single- and multiple-ascending dose, safety, tolerability, pharmacokinetic, and pharmacodynamic study of LY3202626. 2021. Available from: [Last accessed on 27 Jul 2023].

48. Eli Lilly and Company. Relative bioavailability and food effect study in healthy subjects administered two different formulations of LY3202626. 2021. Available from: [Last accessed on 27 Jul 2023].

49. Eli Lilly and Company. Disposition of [14C]-LY3202626 following oral administration in healthy male subjects. 2021. Available from: [Last accessed on 27 Jul 2023].

50. Lo AC, Evans CD, Mancini M, et al. Phase II (NAVIGATE-AD study) results of LY3202626 effects on patients with mild alzheimer's disease dementia. J Alzheimers Dis Rep 2021;5:321-36.

51. Grumati P, Morozzi G, Hölper S, et al. Full length RTN3 regulates turnover of tubular endoplasmic reticulum via selective autophagy. Elife 2017;6:e2555.

52. Picking through the rubble, field tries to salvage BACE inhibitors | ALZFORUM. Available from: [Last accessed on 27 Jul 2023].

53. Lopez Lopez C, Tariot PN, Caputo A, et al. The alzheimer's prevention initiative generation program: study design of two randomized controlled trials for individuals at risk for clinical onset of Alzheimer's disease. Alzheimers Dement 2019;5:216-27.

54. Albala B, Lai RY, Aluri J, et al. [P2–003]: Elenbecestat pharmacokinetic drug-drug interactions indicated no dosage adjustments required for most concomitant treatments. Alzheimer's & Dementia 2017:13.

55. Yan R. Stepping closer to treating Alzheimer's disease patients with BACE1 inhibitor drugs. Transl Neurodegener 2016;5:13.

56. Moriyama T, Fukushima T, Kokate T, Albala B. [P3–037]: Preclinical studies with elenbecestat, a novel bace1 inhibitor, show no evidence of hypopigmentation. Alzheimer's & Dementia 2017:13.

57. Hayata N, Yasuda S, Kanekiyo M, et al. P1-040: Elenbecestat, a novel bace inhibitor, demonstrates similar pharmacokinetics and tolerability in japanese subjects with multiple dosings. Alzheimer's & Dementia 2018:14.

58. Lynch SY, Kaplow J, Zhao J, Dhadda S, Luthman J, Albala B. P4-389: Elenbecestat, e2609, a bace inhibitor: results from a phase-2 study in subjects with mild cognitive impairment and mild-to-moderate dementia due to alzheimer's disease. Alzheimer's & Dementia 2018:14.

59. Irizarry MC, Gee M, Roberts C, et al. Cognitive outcomes in the very mild subgroup in the phase 3 studies of elenbecestat in early AD (mission AD Program). ALZ 2021. Available from: [Last accessed on 27 Jul 2023].

60. Imbimbo BP, Watling M. Investigational BACE inhibitors for the treatment of Alzheimer's disease. Expert Opin Investig Drugs 2019;28:967-75.

61. Eisai Co., Ltd. A placebo-controlled, double-blind, parallel-group, 24 month study with an open-label extension phase to evaluate the efficacy and safety of elenbecestat (E2609) in subjects with early alzheimer’s disease. 2021. Available from: [Last accessed on 27 Jul 2023].

62. Eisai Inc. A placebo-controlled, double-blind, parallel-group, randomized, proof-of-concept, dose-finding study to evaluate safety, tolerability, and efficacy of E2609 in subjects with mild cognitive impairment due to alzheimer’s disease (prodromal alzheimer’s disease) and mild to moderate dementia due to alzheimer’s disease. 2021. Available from: [Last accessed on 27 Jul 2023].

63. Koriyama Y, Hori A, Ito H, et al. Discovery of atabecestat (JNJ-54861911): a thiazine-based β-amyloid precursor protein cleaving enzyme 1 inhibitor advanced to the phase 2b/3 EARLY clinical trial. J Med Chem 2021;64:1873-88.

64. Timmers M, Streffer JR, Russu A, et al. Pharmacodynamics of atabecestat (JNJ-54861911), an oral BACE1 inhibitor in patients with early Alzheimer's disease: randomized, double-blind, placebo-controlled study. Alzheimers Res Ther 2018;10:85.

65. Novak G, Streffer JR, Timmers M, et al. Long-term safety and tolerability of atabecestat (JNJ-54861911), an oral BACE1 inhibitor, in early Alzheimer's disease spectrum patients: a randomized, double-blind, placebo-controlled study and a two-period extension study. Alzheimers Res Ther 2020;12:58.

66. Henley D, Raghavan N, Sperling R, Aisen P, Raman R, Romano G. Preliminary results of a trial of atabecestat in preclinical alzheimer's disease. N Engl J Med 2019;380:1483-5.

67. Sperling R, Henley D, Aisen PS, et al. Findings of efficacy, safety, and biomarker outcomes of atabecestat in preclinical alzheimer disease: a truncated randomized phase 2b/3 clinical trial. JAMA Neurol 2021;78:293-301.

68. van De Jonghe S, Weinstock D, Aligo J, Washington K, Naisbitt D. Biopsy pathology and immunohistochemistry of a case of immune-mediated drug-induced liver injury with atabecestat. Hepatology 2021;73:452-5.

69. Eketjäll S, Janson J, Kaspersson K, et al. AZD3293: a novel, orally active BACE1 inhibitor with high potency and permeability and markedly slow off-rate kinetics. J Alzheimers Dis 2016;50:1109-23.

70. Cebers G, Alexander RC, Haeberlein SB, et al. AZD3293: pharmacokinetic and pharmacodynamic effects in healthy subjects and patients with alzheimer's disease. J Alzheimers Dis 2017;55:1039-53.

71. Wessels AM, Lines C, Stern RA, et al. Cognitive outcomes in trials of two BACE inhibitors in Alzheimer's disease. Alzheimers Dement 2020;16:1483-92.

72. BI 1181181 | ALZFORUM. Available from: [Last accessed on 27 Jul 2023].

73. Boehringer ingelheim. safety, tolerability, pharmacokinetics and pharmacodynamics of single oral doses of BI 1181181 in young healthy male volunteers (randomised, double-blind, placebo-controlled within dose groups phase I trial). 2014. Available from: [Last accessed on 27 Jul 2023].

74. Boehringer ingelheim. safety, tolerability, pharmacokinetics and pharmacodynamics of single rising oral doses of BI 1181181 in healthy male volunteers in a partially randomised, single-blind, placebo-controlled trial, and investigation of relative bioavailability and the effect of food on the pharmacokinetics of BI 1181181(open-label, randomised, three-way cross-over design). 2014. Available from: [Last accessed on 27 Jul 2023].

75. Boehringer ingelheim. safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple rising doses of BI 1181181 Given orally q.d. for 10 days in young healthy male and elderly healthy male/female volunteers (randomized, double-blind, placebo controlled within dose groups phase I study). 2018. Available from: [Last accessed on 27 Jul 2023].

76. Portelius E, Dean RA, Andreasson U, et al. β-site amyloid precursor protein-cleaving enzyme 1(BACE1) inhibitor treatment induces Aβ5-X peptides through alternative amyloid precursor protein cleavage. Alzheimers Res Ther 2014;6:75.

77. May PC, Dean RA, Lowe SL, et al. Robust central reduction of amyloid-β in humans with an orally available, non-peptidic β-secretase inhibitor. J Neurosci 2011;31:16507-16.

78. Kumar D, Ganeshpurkar A, Kumar D, Modi G, Gupta SK, Singh SK. Secretase inhibitors for the treatment of Alzheimer's disease: long road ahead. Eur J Med Chem 2018;148:436-52.

79. May PC, Willis BA, Lowe SL, et al. The potent BACE1 inhibitor LY2886721 elicits robust central Aβ pharmacodynamic responses in mice, dogs, and humans. J Neurosci 2015;35:1199-210.

80. Eli Lilly and Company. A safety, pharmacokinetic, and pharmacodynamic study of LY2886721 in healthy subjects and patients diagnosed with alzheimer’s disease. 2019. Available from: [Last accessed on 27 Jul 2023].

81. Eli Lilly and Company. Multiple-ascending dose, safety, tolerability, pharmacokinetic, and pharmacodynamic study of LY2886721 in healthy subjects. 2019. Available from: [Last accessed on 27 Jul 2023].

82. Eli Lilly and Company. single- and multiple-dose, safety, tolerability, pharmacokinetic, and pharmacodynamic study of LY2886721 in healthy subjects. 2019. Available from: [Last accessed on 27 Jul 2023].

83. Eli Lilly and Company. Disposition of [14C]-LY2886721 following oral administration in healthy human subjects. 2019. Available from: [Last accessed on 27 Jul 2023].

84. Eli Lilly and Company. Single-ascending dose, safety, tolerability, pharmacokinetic, and pharmacodynamic study of LY2886721 in healthy subjects. 2019. Available from: [Last accessed on 27 Jul 2023].

85. Eli Lilly and Company. A comparison study of capsule and orally disintegrating tablet and to determine the effect of food and water on the pharmacokinetics of LY2886721 in healthy subjects. 2019. Available from: [Last accessed on 27 Jul 2023].

86. Eli Lilly and Company. Assessment of safety, tolerability, and pharmacodynamic effects of LY2886721 in patients with mild cognitive impairment due to alzheimer’s disease or mild alzheimer’s disease. 2018. Available from: [Last accessed on 27 Jul 2023].

87. Pfizer. A Phase 1, Open-label, fixed-sequence design study to assess the effect of multiple dose administration of Pf-06751979 on the single dose pharmacokinetics of oral midazolam in healthy adult subjects. 2017. Available from: [Last accessed on 27 Jul 2023].

88. Pfizer. A 3-part phase 1, randomized, double-blind, sponsor-open, placebo controlled trial to evaluate the safety, tolerability, food effect, pharmacokinetics and pharmacodynamics of Pf-06751979 after oral administration: part a - single ascending doses in healthy adults; part b - multiple ascending doses in healthy adults; and part c - multiple doses to older subjects. 2017. Available from: [Last accessed on 27 Jul 2023].

89. Pfizer. A Phase 1, randomized, double-blind, sponsor-open, placebo controlled first-in-human trial to evaluate the safety,tolerability, pharmacokinetics and pharmacodynamics of Pf-06751979 after oral administration of single and multiple ascending doses to healthy adult and elderly subjects. 2018. Available from: [Last accessed on 27 Jul 2023].

90. Qiu R, Ahn JE, Alexander R, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamic effects of PF-06751979, a potent and selective oral BACE1 inhibitor: results from phase i studies in healthy adults and healthy older subjects. J Alzheimers Dis 2019;71:581-95.

91. Rochin L, Hurbain I, Serneels L, et al. BACE2 processes PMEL to form the melanosome amyloid matrix in pigment cells. Proc Natl Acad Sci USA 2013;110:10658-63.

92. O'Neill BT, Beck EM, Butler CR, et al. Design and synthesis of clinical candidate PF-06751979: a potent, brain penetrant, β-Site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor lacking hypopigmentation. J Med Chem 2018;61:4476-504.

93. Gehlot P, Kumar S, Kumar Vyas V, Singh Choudhary B, Sharma M, Malik R. Guanidine-based β amyloid precursor protein cleavage enzyme 1 (BACE-1) inhibitors for the Alzheimer's disease (AD): a review. Bioorg Med Chem 2022;74:117047.

94. Maia MA, Sousa E. BACE-1 and γ-Secretase as therapeutic targets for alzheimer's disease. Pharmaceuticals 2019;12:41.

95. CoMentis. A phase 1 single escalating dose study to assess the safety and pharmacokinetics of CTS21166 administered intravenously to healthy adult males. 2008. Available from: [Last accessed on 27 Jul 2023].

96. High Point Pharmaceuticals, LLC. A double-blind, randomized, placebo-controlled, Phase I, multiple-dose study to evaluate the safety, tolerability, and pharmacokinetics of orally-administered HPP854 in subjects with mild cognitive impairment or a diagnosis of mild alzheimer’s disease. 2012. Available from: [Last accessed on 27 Jul 2023].

97. Wolfe MS, Kopan R. Intramembrane proteolysis: theme and variations. Science 2004;305:1119-23.

98. Takami M, Nagashima Y, Sano Y, et al. Gamma-Secretase: successive tripeptide and tetrapeptide release from the transmembrane domain of beta-carboxyl terminal fragment. J Neurosci 2009;29:13042-52.

99. Bateman RJ, Siemers ER, Mawuenyega KG, et al. A gamma-secretase inhibitor decreases amyloid-beta production in the central nervous system. Ann Neurol 2009;66:48-54.

100. van De Strooper B, Vassar R, Golde T. The secretases: enzymes with therapeutic potential in Alzheimer disease. Nat Rev Neurol 2010;6:99-107.

101. Doody RS, Raman R, Farlow M, et al. Alzheimer's Disease Cooperative Study Steering Committee; Semagacestat Study Group. A phase 3 trial of semagacestat for treatment of Alzheimer's disease. N Engl J Med 2013;369:341-50.

102. Nicolas M, Wolfer A, Raj K, et al. Notch1 functions as a tumor suppressor in mouse skin. Nat Genet 2003;33:416-21.

103. Xia X, Qian S, Soriano S, et al. Loss of presenilin 1 is associated with enhanced beta-catenin signaling and skin tumorigenesis. Proc Natl Acad Sci U S A 2001;98:10863-8.

104. Gillman KW, Starrett JE Jr, Parker MF, et al. Discovery and evaluation of BMS-708163, a potent, selective and orally bioavailable γ-secretase inhibitor. ACS Med Chem Lett 2010;1:120-4.

105. Crump CJ, Castro SV, Wang F, et al. BMS-708,163 targets presenilin and lacks notch-sparing activity. Biochemistry 2012;51:7209-11.

106. Coric V, van Dyck CH, Salloway S, et al. Safety and tolerability of the γ-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease. Arch Neurol 2012;69:1430-40.

107. Coric V, Salloway S, van Dyck CH, et al. Targeting prodromal alzheimer disease with avagacestat: a randomized clinical trial. JAMA Neurol 2015;72:1324-33.

108. Panza F, Lozupone M, Logroscino G, Imbimbo BP. A critical appraisal of amyloid-β-targeting therapies for Alzheimer disease. Nat Rev Neurol 2019;15:73-88.

109. Miranda A, Montiel E, Ulrich H, Paz C. Selective secretase targeting for alzheimer's disease therapy. J Alzheimers Dis 2021;81:1-17.

110. Lessard CB, Cottrell BA, Maruyama H, Suresh S, Golde TE, Koo EH. γ-secretase modulators and APH1 isoforms modulate γ-secretase cleavage but not position of ε-cleavage of the amyloid precursor protein (APP). PLoS One 2015;10:e0144758.

111. Kukar TL, Ladd TB, Bann MA, et al. Substrate-targeting gamma-secretase modulators. Nature 2008;453:925-9.

112. Anthony JC, Breitner JC, Zandi PP, et al. Reduced prevalence of AD in users of NSAIDs and H2 receptor antagonists: the cache county study. Neurology 2000;54:2066-71.

113. Stewart WF, Kawas C, Corrada M, Metter EJ. Risk of Alzheimer's disease and duration of NSAID use. Neurology 1997;48:626-32.

114. McGeer PL, Schulzer M, McGeer EG. Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer's disease: a review of 17 epidemiologic studies. Neurology 1996;47:425-32.

115. Weggen S, Eriksen JL, Das P, et al. A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature 2001;414:212-6.

116. Weggen S, Eriksen JL, Sagi SA, et al. Evidence that nonsteroidal anti-inflammatory drugs decrease amyloid beta 42 production by direct modulation of gamma-secretase activity. J Biol Chem 2003;278:31831-7.

117. Eriksen JL, Sagi SA, Smith TE, et al. NSAIDs and enantiomers of flurbiprofen target gamma-secretase and lower Abeta 42 in vivo. J Clin Invest 2003;112:440-9.

118. Beher D, Clarke EE, Wrigley JD, et al. Selected non-steroidal anti-inflammatory drugs and their derivatives target gamma-secretase at a novel site. evidence for an allosteric mechanism. J Biol Chem 2004;279:43419-26.

119. Kukar T, Prescott S, Eriksen JL, et al. Chronic administration of R-flurbiprofen attenuates learning impairments in transgenic amyloid precursor protein mice. BMC Neurosci 2007;8:54.

120. Wilcock GK, Black SE, Hendrix SB, Zavitz KH, Swabb EA, Laughlin MA. Tarenflurbil Phase II Study investigators. Efficacy and safety of tarenflurbil in mild to moderate Alzheimer's disease: a randomised phase II trial. Lancet Neurol 2008;7:483-93.

121. Green RC, Schneider LS, Amato DA, et al. Tarenflurbil Phase 3 Study Group. Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: a randomized controlled trial. JAMA 2009;302:2557-64.

122. Lanzillotta A, Sarnico I, Benarese M, et al. The γ-secretase modulator CHF5074 reduces the accumulation of native hyperphosphorylated Tau in a transgenic mouse model of Alzheimer's disease. J Mol Neurosci 2011;45:22-31.

123. Sivilia S, Lorenzini L, Giuliani A, et al. Multi-target action of the novel anti-Alzheimer compound CHF5074: in vivo study of long term treatment in Tg2576 mice. BMC Neurosci 2013;14:44.

124. Imbimbo BP, Hutter-Paier B, Villetti G, et al. CHF5074, a novel gamma-secretase modulator, attenuates brain beta-amyloid pathology and learning deficit in a mouse model of Alzheimer's disease. Br J Pharmacol 2009;156:982-93.

125. Imbimbo BP, Giardino L, Sivilia S, et al. CHF5074, a novel gamma-secretase modulator, restores hippocampal neurogenesis potential and reverses contextual memory deficit in a transgenic mouse model of Alzheimer's disease. J Alzheimers Dis 2010;20:159-73.

126. Ross J, Sharma S, Winston J, et al. CHF5074 reduces biomarkers of neuroinflammation in patients with mild cognitive impairment: a 12-week, double-blind, placebo-controlled study. Curr Alzheimer Res 2013;10:742-53.

127. Ross J, Sharma SK, Chatterjee A, et al. O3-06-05: Sustained cognitive benefit in patients with mild cognitive impairment (MCI) upon prolonged treatment with CHF5074. Alzheimer's & Dementia 2013:9.

128. Xia W. γ-secretase and its modulators: twenty years and beyond. Neurosci Lett 2019;701:162-9.

129. Porrini V, Lanzillotta A, Branca C, et al. CHF5074 (CSP-1103) induces microglia alternative activation in plaque-free Tg2576 mice and primary glial cultures exposed to beta-amyloid. Neuroscience 2015;302:112-20.

130. Hashimoto T, Ishibashi A, Hagiwara H, Murata Y, Takenaka O, Miyagawa T. P1-236: E2012: a novel gamma‐secretase modulator-pharmacology part. Alzheimer's & Dementia 2010:6.

131. Boggs LN, Lindstrom T, Watson B, Sheehan S, Audia JE, May PC. P3-304: Proof-of-concept pharmacodynamic assessment of a prototypic BACE1 inhibitor at steady-state using IV infusion dosing in the PDAPP transgenic mouse model of Alzheimer's disease. Alzheimer's & Dementia 2010:6.

132. Nagy C, Schuck E, Ishibashi A, Nakatani Y, Rege B, Logovinsky V. P3-415: E2012, a novel gamma-secretase modulator, decreases plasma amyloid-beta (Aβ) levels in humans. Alzheimer's & Dementia 2010:6.

133. Nakano-Ito K, Fujikawa Y, Hihara T, et al. E2012-induced cataract and its predictive biomarkers. Toxicol Sci 2014;137:249-58.

134. Yu Y, Logovinsky V, Schuck E, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of the novel γ-secretase modulator, E2212, in healthy human subjects. J Clin Pharmacol 2014;54:528-36.

135. Schenk D, Barbour R, Dunn W, et al. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 1999;400:173-7.

136. Song C, Shi J, Zhang P, et al. Immunotherapy for Alzheimer's disease: targeting β-amyloid and beyond. Transl Neurodegener 2022;11:18.

137. Cribbs DH, Ghochikyan A, Vasilevko V, et al. Adjuvant-dependent modulation of Th1 and Th2 responses to immunization with beta-amyloid. Int Immunol 2003;15:505-14.

138. Holmes C, Boche D, Wilkinson D, et al. Long-term effects of Abeta42 immunisation in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet 2008;372:216-23.

139. Orgogozo JM, Gilman S, Dartigues JF, et al. Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology 2003;61:46-54.

140. Gilman S, Koller M, Black RS, et al. AN1792(QS-21)-201 Study Team. Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology 2005;64:1553-62.

141. Winblad B, Andreasen N, Minthon L, et al. Safety, tolerability, and antibody response of active Aβ immunotherapy with CAD106 in patients with Alzheimer's disease: randomised, double-blind, placebo-controlled, first-in-human study. Lancet Neurol 2012;11:597-604.

142. Ma Y, Li Y, Zong LX, Xing XN, Zhang WG, Cao YP. Improving memory and decreasing cognitive impairment in Tg-APPswe/PSEN1dE9 mice with Aβ3-10 repeat fragment plasmid by reducing Aβ deposition and inflammatory response. Brain Res 2011;1400:112-24.

143. Sha S, Xing XN, Cao YP. Active immunotherapy facilitates Aβ plaque removal following through microglial activation without obvious T cells infiltrating the CNS. J Neuroimmunol 2014;274:62-70.

144. Xing XN, Sha S, Chen XH, et al. Active immunization with DNA vaccine reduced cerebral inflammation and improved cognitive ability in APP/PS1 transgenic mice by in vivo electroporation. Neurochem Res 2015;40:1032-41.

145. Kwan P, Konno H, Chan KY, Baum L. Rationale for the development of an Alzheimer's disease vaccine. Hum Vaccin Immunother 2020;16:645-53.

146. Malonis RJ, Lai JR, Vergnolle O. Peptide-based vaccines: current progress and future challenges. Chem Rev 2020;120:3210-29.

147. Wiessner C, Wiederhold KH, Tissot AC, et al. The second-generation active Aβ immunotherapy CAD106 reduces amyloid accumulation in APP transgenic mice while minimizing potential side effects. J Neurosci 2011;31:9323-31.

148. Vandenberghe R, Riviere ME, Caputo A, et al. Active Aβ immunotherapy CAD106 in Alzheimer's disease: a phase 2b study. Alzheimers Dement 2017;3:10-22.

149. Novartis Pharmaceuticals. A randomized, double-blind, placebo-controlled, two-cohort, parallel group study to evaluate the efficacy of CAD106 and CNP520 in participants at risk for the onset of clinical symptoms of alzheimer’s disease. 2021. Available from: [Last accessed on 27 Jul 2023].

150. Muhs A, Hickman DT, Pihlgren M, et al. Liposomal vaccines with conformation-specific amyloid peptide antigens define immune response and efficacy in APP transgenic mice. Proc Natl Acad Sci U S A 2007;104:9810-5.

151. Belichenko PV, Madani R, Rey-Bellet L, et al. An anti-β-amyloid vaccine for treating cognitive deficits in a mouse model of down syndrome. PLoS One 2016;11:e0152471.

152. Vukicevic M, Fiorini E, Siegert S, et al. An amyloid beta vaccine that safely drives immunity to a key pathological species in Alzheimer's disease: pyroglutamate amyloid beta. Brain Commun 2022;4:fcac022.

153. EudraCT Number 2008-006257-40 -clinical trial results - EU clinical trials Register. Available from: [Last accessed on 27 Jul 2023].

154. EudraCT Number 2018-000445-39 - clinical trial results - EU clinical trials Register. Available from: [Last accessed on 27 Jul 2023].

155. Rafii MS, Sol O, Mobley WC, et al. Safety, tolerability, and immunogenicity of the ACI-24 vaccine in adults with down syndrome: a phase 1b randomized clinical trial. JAMA Neurol 2022;79:565-74.

156. Wang CY, Wang PN, Chiu MJ, et al. UB-311, a novel UBITh(®) amyloid β peptide vaccine for mild Alzheimer's disease. Alzheimers Dement 2017;3:262-72.

157. United Neuroscience Ltd. An extension study of a phase iia study in patients with mild alzheimer’s disease to evaluate the safety, tolerability, immunogenicity, and efficacy of UBITh® AD immunotherapeutic vaccine (UB-311). 2021. Available from: [Last accessed on 27 Jul 2023].

158. United Neuroscience Ltd. A randomized, double-blind, placebo-controlled, 3-arm parallel-group, multicenter, phase IIa study to evaluate the safety, tolerability, immunogenicity, and efficacy of UBITh® AD immunotherapeutic vaccine (UB-311) in patients with mild alzheimer’s disease. 2020. Available from: [Last accessed on 27 Jul 2023].

159. UB-311 ALZFORUM. Available from: [Last accessed on 27 Jul 2023].

160. Lacosta AM, Pascual-Lucas M, Pesini P, et al. Safety, tolerability and immunogenicity of an active anti-Aβ40 vaccine (ABvac40) in patients with Alzheimer's disease: a randomised, double-blind, placebo-controlled, phase I trial. Alzheimers Res Ther 2018;10:12.

161. Herzig MC, Van Nostrand WE, Jucker M. Mechanism of cerebral beta-amyloid angiopathy: murine and cellular models. Brain Pathol 2006;16:40-54.

162. Chimon S, Shaibat MA, Jones CR, Calero DC, Aizezi B, Ishii Y. Evidence of fibril-like β-sheet structures in a neurotoxic amyloid intermediate of Alzheimer's β-amyloid. Nat Struct Mol Biol 2007;14:1157-64.

163. Montañés M, Casabona D, Sarasa L, Pesini P, Sarasa M. Prevention of amyloid-β fibril formation using antibodies against the C-terminal region of amyloid-β1-40 and amyloid-β1-42. J Alzheimers Dis 2013;34:133-7.

164. Lacosta AM, Insua D, Badi H, Pesini P, Sarasa M. Neurofibrillary tangles of Aβx-40 in alzheimer's disease brains. J Alzheimers Dis 2017;58:661-7.

165. Näslund J, Schierhorn A, Hellman U, et al. Relative abundance of Alzheimer A beta amyloid peptide variants in Alzheimer disease and normal aging. Proc Natl Acad Sci U S A 1994;91:8378-82.

166. Araclon biotech advances in its innovative vaccine and diagnostic test for Alzheimer’s. Available from: [Last accessed on 27 Jul 2023].

167. Movsesyan N, Ghochikyan A, Mkrtichyan M, et al. Reducing AD-like pathology in 3xTg-AD mouse model by DNA epitope vaccine - a novel immunotherapeutic strategy. PLoS One 2008;3:e2124.

168. Derhovanessian E, Solana R, Larbi A, Pawelec G. Immunity, ageing and cancer. Immun Ageing 2008;5:11.

169. Petrushina I, Hovakimyan A, Harahap-Carrillo IS, et al. Characterization and preclinical evaluation of the cGMP grade DNA based vaccine, AV-1959D to enter the first-in-human clinical trials. Neurobiol Dis 2020;139:104823.

170. Davtyan H, Ghochikyan A, Petrushina I, et al. The MultiTEP platform-based Alzheimer's disease epitope vaccine activates a broad repertoire of T helper cells in nonhuman primates. Alzheimers Dement 2014;10:271-83.

171. Davtyan H, Hovakimyan A, Zagorski K, et al. BTX AgilePulse(TM) system is an effective electroporation device for intramuscular and intradermal delivery of DNA vaccine. Curr Gene Ther 2014;14:190-9.

172. Ghochikyan A, Davtyan H, Petrushina I, et al. Refinement of a DNA based Alzheimer's disease epitope vaccine in rabbits. Hum Vaccin Immunother 2013;9:1002-10.

173. Evans CF, Davtyan H, Petrushina I, et al. Epitope-based DNA vaccine for Alzheimer's disease: translational study in macaques. Alzheimers Dement 2014;10:284-95.

174. Institute for Molecular Medicine. A phase I, randomized, double-blind study to evaluate safety and tolerability of amyloid-β vaccine, AV-1959D, in Patients with early alzheimer’s disease. 2023. Available from: [Last accessed on 27 Jul 2023].

175. Pasquier F, Sadowsky C, Holstein A, et al. ACC-001 (QS-21) Study Team. Two phase 2 multiple ascending-dose studies of vanutide cridificar (ACC-001) and QS-21 adjuvant in mild-to-moderate alzheimer's disease. J Alzheimers Dis 2016;51:1131-43.

176. Shanghai Hengrui Pharmaceutical Co., Ltd. A phase Ib, randomized, double-blind, placebo-controlled, multiple-ascending dose study to evaluate the safety, tolerability and pharmacodynamics of intravenous administration of SHR-1707 In patients with mild cognitive impairment due to alzheimer’s disease or mild alzheimer’s disease. 2023. Available from: [Last accessed on 27 Jul 2023].

177. Acumen Pharmaceuticals. A phase 1 Placebo-controlled, single- and multiple-dose study of the safety, tolerability, and pharmacokinetics of intravenous ACU193 in mild cognitive impairment or mild dementia due to alzheimer’s disease. 2023. Available from: [Last accessed on 27 Jul 2023].

178. AbbVie. A randomized, double-blind, placebo-controlled study to evaluate the safety, efficacy, pharmacokinetics and pharmacodynamics of ABBV-916 in subjects with early alzheimer’s disease. 2023. Available from: [Last accessed on 27 Jul 2023].

179. Dhillon S. Aducanumab: first approval. Drugs 2021;81:1437-43.

180. Budd Haeberlein S, Aisen PS, Barkhof F, et al. Two randomized phase 3 studies of aducanumab in early alzheimer's disease. J Prev Alzheimers Dis 2022;9:197-210.

181. Kuller LH, Lopez OL. Engage and emerge: truth and consequences? Alzheimers Dement 2021;17:692-5.

182. Alexander GC, Emerson S, Kesselheim AS. Evaluation of Aducanumab for alzheimer disease: scientific evidence and regulatory review involving efficacy, safety, and futility. JAMA 2021;325:1717-8.

183. Salloway S, Chalkias S, Barkhof F, et al. Amyloid-related imaging abnormalities in 2 phase 3 studies evaluating aducanumab in patients with early alzheimer disease. JAMA Neurol 2022;79:13-21.

184. Cummings J, Rabinovici GD, Atri A, et al. Aducanumab: appropriate use recommendations update. J Prev Alzheimers Dis 2022;9:221-30.

185. Biogen. Phase 3b Open-label, multicenter, safety study of BIIB037 (Aducanumab) in subjects with alzheimer’s disease who had previously participated in the aducanumab studies 221AD103, 221AD301, 221AD302 and 221AD205. 2023. Available from: [Last accessed on 27 Jul 2023].

186. Castrillo-Viguera C, Chalkias S, Burkett P, et al. EMBARK: A phase 3b, open-label, single-arm, safety study to evaluate the long-term safety and efficacy of aducanumab in eligible participants with alzheimer’s disease (2448). Available from: [Last accessed on 27 Jul 2023].

187. Biogen. A phase 3b/4 multicenter, randomized, double-blind, placebo-controlled, parallel-group study to verify the clinical benefit of aducanumab (BIIB037) in participants with alzheimer’s disease. 2023. Available from: [Last accessed on 27 Jul 2023].

188. Tucker S, Möller C, Tegerstedt K, et al. The murine version of BAN2401 (mAb158) selectively reduces amyloid-β protofibrils in brain and cerebrospinal fluid of tg-ArcSwe mice. J Alzheimers Dis 2015;43:575-88.

189. Söllvander S, Nikitidou E, Gallasch L, et al. The Aβ protofibril selective antibody mAb158 prevents accumulation of Aβ in astrocytes and rescues neurons from Aβ-induced cell death. J Neuroinflammation 2018;15:98.

190. McDade E, Cummings JL, Dhadda S, et al. Lecanemab in patients with early Alzheimer's disease: detailed results on biomarker, cognitive, and clinical effects from the randomized and open-label extension of the phase 2 proof-of-concept study. Alzheimers Res Ther 2022;14:191.

191. Swanson CJ, Zhang Y, Dhadda S, et al. A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer's disease with lecanemab, an anti-Aβ protofibril antibody. Alzheimers Res Ther 2021;13:80.

192. van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in early alzheimer's disease. N Engl J Med 2023;388:9-21.

193. Honig LS, Barakos J, Dhadda S, et al. ARIA in patients treated with lecanemab (BAN2401) in a phase 2 study in early Alzheimer's disease. Alzheimers Dement 2023;9:e12377.

194. Scientists tie third clinical trial death to experimental Alzheimer’s drug | Science | AAAS. Available from: [Last accessed on 27 Jul 2023].

195. Reish NJ, Jamshidi P, Stamm B, et al. Multiple cerebral hemorrhages in a patient receiving lecanemab and treated with t-PA for stroke. N Engl J Med 2023;388:478-9.

196. Cummings J, Apostolova L, Rabinovici GD, et al. Lecanemab: appropriate use recommendations. J Prev Alzheimers Dis 2023;10:362-77.

197. Thambisetty M, Howard R. Lecanemab trial in AD brings hope but requires greater clarity. Nat Rev Neurol 2023;19:132-3.

198. Rafii MS, Sperling RA, Donohue MC, et al. The AHEAD 3-45 study: design of a prevention trial for alzheimer's disease. Alzheimers Dement 2023;19:1227-33.

199. Demattos RB, Lu J, Tang Y, et al. A plaque-specific antibody clears existing β-amyloid plaques in Alzheimer's disease mice. Neuron 2012;76:908-20.

200. Mintun MA, Lo AC, Duggan Evans C, et al. Donanemab in early alzheimer's disease. N Engl J Med 2021;384:1691-704.

201. Shcherbinin S, Evans CD, Lu M, et al. Association of amyloid reduction after donanemab treatment with Tau pathology and clinical outcomes: the TRAILBLAZER-ALZ randomized clinical trial. JAMA Neurol 2022;79:1015-24.

202. Bayer TA. Pyroglutamate Aβ cascade as drug target in Alzheimer's disease. Mol Psychiatry 2022;27:1880-5.

203. Sims JR, Zimmer JA, Evans CD, et al. TRAILBLAZER-ALZ 2 Investigators. Donanemab in early symptomatic alzheimer disease: the TRAILBLAZER-ALZ 2 randomized clinical trial. JAMA 2023; doi: 10.1001/jama.2023.13239.

204. Eli Lilly and Company. A phase 3, open-label, parallel-group, 2-arm study to investigate amyloid plaque clearance with donanemab compared with aducanumab-avwa in participants with early symptomatic Alzheimer’s disease. 2023. Available from: [Last accessed on 27 Jul 2023].

205. Eli Lilly and Company. A study of donanemab versus placebo in participants at risk for cognitive and functional decline of Alzheimer’s disease. 2023. Available from: [Last accessed on 27 Jul 2023].

206. Eli Lilly and Company. Global study to investigate safety and efficacy of donanemab in early symptomatic Alzheimer’s disease. 2023. Available from: [Last accessed on 27 Jul 2023].

207. Eli Lilly and Company. Investigating the effect of different donanemab dosing regimens on ARIA-E and amyloid lowering in adults with early symptomatic alzheimer’s disease. 2023. Available from: [Last accessed on 27 Jul 2023].

208. Remternetug | ALZFORUM. Available from: [Last accessed on 27 Jul 2023].

209. Next goals for immunotherapy: make it safer, less of a hassle. Available from: [Last accessed on 27 Jul 2023].

210. Eli Lilly and Company. A single-dose and multiple-dose, dose-escalation study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of LY3372993 in healthy subjects and patients with Alzheimer’s disease. 2019. Available from: [Last accessed on 27 Jul 2023].

211. Eli Lilly and Company. A study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of LY3372993 in participants with Alzheimer’s disease and healthy participants. 2023. Available from: [Last accessed on 27 Jul 2023].

212. Eli Lilly and Company. Assessment of Safety, Tolerability, and Efficacy Measured by Amyloid Reduction of LY3372993 in Early Symptomatic Alzheimer’s Disease. 2023. Available from: [Last accessed on 27 Jul 2023].

213. Bohrmann B, Baumann K, Benz J, et al. Gantenerumab: a novel human anti-Aβ antibody demonstrates sustained cerebral amyloid-β binding and elicits cell-mediated removal of human amyloid-β. J Alzheimers Dis 2012;28:49-69.

214. Bateman RJ, Cummings J, Schobel S, et al. Gantenerumab: an anti-amyloid monoclonal antibody with potential disease-modifying effects in early Alzheimer's disease. Alzheimers Res Ther 2022;14:178.

215. Ostrowitzki S, Deptula D, Thurfjell L, et al. Mechanism of amyloid removal in patients with Alzheimer disease treated with gantenerumab. Arch Neurol 2012;69:198-207.

216. Perneczky R, Jessen F, Grimmer T, et al. Anti-amyloid antibody therapies in Alzheimer's disease. Brain 2023;146:842-9.

217. Gantenerumab mystery: how did it lose potency in phase 3? | ALZFORUM. Available from: [Last accessed on 27 Jul 2023].

218. Hoffmann-La Roche. A phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group, efficacy, and safety study of gantenerumab in patients with early (Prodromal to Mild) Alzheimer’s Disease. 2023. Available from: [Last accessed on 27 Jul 2023].

219. Salloway S, Farlow M, McDade E, et al. Dominantly Inherited Alzheimer Network–Trials Unit. A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer's disease. Nat Med 2021;27:1187-96.

220. Bard F, Cannon C, Barbour R, et al. Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med 2000;6:916-9.

221. Bard F, Barbour R, Cannon C, et al. Epitope and isotype specificities of antibodies to beta -amyloid peptide for protection against Alzheimer's disease-like neuropathology. Proc Natl Acad Sci U S A 2003;100:2023-8.

222. Salloway S, Sperling R, Fox NC, et al. Bapineuzumab 301 and 302 Clinical Trial Investigators. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer's disease. N Engl J Med 2014;370:322-33.

223. Liu E, Schmidt ME, Margolin R, et al. Bapineuzumab 301 and 302 Clinical Trial Investigators. Amyloid-β 11C-PiB-PET imaging results from 2 randomized bapineuzumab phase 3 AD trials. Neurology 2015;85:692-700.

224. Blennow K, Zetterberg H, Rinne JO, et al. AAB-001 201/202 Investigators. Effect of immunotherapy with bapineuzumab on cerebrospinal fluid biomarker levels in patients with mild to moderate Alzheimer disease. Arch Neurol 2012;69:1002-10.

225. Vandenberghe R, Rinne JO, Boada M, et al. Bapineuzumab 3000 and 3001 Clinical Study Investigators. Bapineuzumab for mild to moderate Alzheimer's disease in two global, randomized, phase 3 trials. Alzheimers Res Ther 2016;8:18.

226. Brashear HR, Ketter N, Bogert J, Di J, Salloway SP, Sperling R. Clinical evaluation of amyloid-related imaging abnormalities in bapineuzumab phase III studies. J Alzheimers Dis 2018;66:1409-24.

227. Sperling RA, Jack CR Jr, Black SE, et al. Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer's association research roundtable workgroup. Alzheimers Dement 2011;7:367-85.

228. DeMattos RB, Bales KR, Cummins DJ, Dodart JC, Paul SM, Holtzman DM. Peripheral anti-A beta antibody alters CNS and plasma A beta clearance and decreases brain A beta burden in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A 2001;98:8850-5.

229. Siemers ER, Friedrich S, Dean RA, et al. Safety and changes in plasma and cerebrospinal fluid amyloid beta after a single administration of an amyloid beta monoclonal antibody in subjects with Alzheimer disease. Clin Neuropharmacol 2010;33:67-73.

230. Godyń J, Jończyk J, Panek D, Malawska B. Therapeutic strategies for Alzheimer's disease in clinical trials. Pharmacol Rep 2016;68:127-38.

231. Eli Lilly and Company. Multiple-dose safety in Japanese subjects with mild-to-moderate alzheimer’s disease. 2010. Available from: [Last accessed on 27 Jul 2023].

232. Eli Lilly and Company. LY2062430: Multiple-dose safety in subjects with mild-to-moderate alzheimer’s disease and single-dose safety in healthy volunteers. 2009. Available from: [Last accessed on 27 Jul 2023].

233. Joseph-Mathurin N, Llibre-Guerra JJ, Li Y, et al. Dominantly Inherited Alzheimer Network Trials Unit. Amyloid-related imaging abnormalities in the DIAN-TU-001 trial of gantenerumab and solanezumab: lessons from a trial in dominantly inherited Alzheimer disease. Ann Neurol 2022;92:729-44.

234. Farlow M, Arnold SE, van Dyck CH, et al. Safety and biomarker effects of solanezumab in patients with Alzheimer's disease. Alzheimers Dement 2012;8:261-71.

235. Racke MM, Boone LI, Hepburn DL, et al. Exacerbation of cerebral amyloid angiopathy-associated microhemorrhage in amyloid precursor protein transgenic mice by immunotherapy is dependent on antibody recognition of deposited forms of amyloid beta. J Neurosci 2005;25:629-36.

236. Doody RS, Thomas RG, Farlow M, et al. Alzheimer's Disease Cooperative Study Steering Committee; Solanezumab Study Group. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer's disease. N Engl J Med 2014;370:311-21.

237. Siemers ER, Sundell KL, Carlson C, et al. Phase 3 solanezumab trials: secondary outcomes in mild Alzheimer's disease patients. Alzheimers Dement 2016;12:110-20.

238. Honig LS, Vellas B, Woodward M, et al. Trial of solanezumab for mild dementia due to Alzheimer's disease. N Engl J Med 2018;378:321-30.

239. Lilly provides update on A4 study of solanezumab for preclinical Alzheimer’s disease | Eli Lilly and Company. Available from: [Last accessed on 27 Jul 2023].

240. Eli Lilly and Company. Anti-amyloid treatment in asymptomatic Alzheimer’s disease (A4 Study). 2023. Available from:[Last accessed on 27 Jul 2023].

241. Zhao J, Nussinov R, Ma B. Mechanisms of recognition of amyloid-β (Aβ) monomer, oligomer, and fibril by homologous antibodies. J Biol Chem 2017;292:18325-43.

242. Ultsch M, Li B, Maurer T, et al. Structure of crenezumab complex with Aβ shows loss of β-hairpin. Sci Rep 2016;6:39374.

243. Adolfsson O, Pihlgren M, Toni N, et al. An effector-reduced anti-β-amyloid (Aβ) antibody with unique aβ binding properties promotes neuroprotection and glial engulfment of Aβ. J Neurosci 2012;32:9677-89.

244. Meilandt WJ, Maloney JA, Imperio J, et al. Characterization of the selective in vitro and in vivo binding properties of crenezumab to oligomeric Aβ. Alzheimers Res Ther 2019;11:97.

245. Wilcock DM, Alamed J, Gottschall PE, et al. Deglycosylated anti-amyloid-beta antibodies eliminate cognitive deficits and reduce parenchymal amyloid with minimal vascular consequences in aged amyloid precursor protein transgenic mice. J Neurosci 2006;26:5340-6.

246. Yang T, Dang Y, Ostaszewski B, et al. Target engagement in an alzheimer trial: crenezumab lowers amyloid β oligomers in cerebrospinal fluid. Ann Neurol 2019;86:215-24.

247. Cummings JL, Cohen S, van Dyck CH, et al. ABBY: A phase 2 randomized trial of crenezumab in mild to moderate Alzheimer disease. Neurology 2018;90:e1889-97.

248. Ostrowitzki S, Bittner T, Sink KM, et al. Evaluating the safety and efficacy of crenezumab vs placebo in adults with early Alzheimer disease: two phase 3 randomized placebo-controlled trials. JAMA Neurol 2022;79:1113-21.

249. Tariot PN, Lopera F, Langbaum JB, et al. Alzheimer's Prevention Initiative. The Alzheimer's prevention initiative autosomal-dominant Alzheimer's disease trial: a study of crenezumab versus placebo in preclinical PSEN1 E280A mutation carriers to evaluate efficacy and safety in the treatment of autosomal-dominant Alzheimer's disease, including a placebo-treated noncarrier cohort. Alzheimers Dement 2018;4:150-60.

250. API colombian trial of crenezumab missed primary endpoints | ALZFORUM. Available from: [Last accessed on 27 Jul 2023].

251. NIA statement on crenezumab trial results: Anti-amyloid drug did not demonstrate a statistically significant clinical benefit in people with inherited form of Alzheimer’s disease. Natl. Inst. Aging. 2022. Available from: [Last accessed on 27 Jul 2023].

252. Setten RL, Rossi JJ, Han SP. The current state and future directions of RNAi-based therapeutics. Nat Rev Drug Discov 2019;18:421-46.

253. Wolfrum C, Shi S, Jayaprakash KN, et al. Mechanisms and optimization of in vivo delivery of lipophilic siRNAs. Nat Biotechnol 2007;25:1149-57.

254. Brown KM, Nair JK, Janas MM, et al. Expanding RNAi therapeutics to extrahepatic tissues with lipophilic conjugates. Nat Biotechnol 2022;40:1500-8.

255. Alnylam Pharmaceuticals. A randomized, double-blind, placebo-controlled single ascending dose and open-label multi-dose study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of intrathecally administered ALN-APP in adult patients with early-onset Alzheimer’s disease (EOAD). 2023. Available from: [Last accessed on 27 Jul 2023].

256. Alnylam and regeneron report positive interim phase 1 clinical data on ALN-APP, an investigational RNAi therap. Invest. Relat. Alnylam Pharm. Inc. Available from: [Last accessed on 27 Jul 2023].

257. Weaver DF. β-Amyloid is an Immunopeptide and Alzheimer's is an Autoimmune Disease. Curr Alzheimer Res 2021;18:849-57.

258. Rischel EB, Gejl M, Brock B, Rungby J, Gjedde A. In Alzheimer's disease, amyloid beta accumulation is a protective mechanism that ultimately fails. Alzheimers Dement ;2022:771-83.

259. Lee JH, Yang DS, Goulbourne CN, et al. Faulty autolysosome acidification in Alzheimer's disease mouse models induces autophagic build-up of Aβ in neurons, yielding senile plaques. Nat Neurosci 2022;25:688-701.

260. Banerjee R, Rai A, Iyer SM, Narwal S, Tare M. Animal models in the study of Alzheimer's disease and Parkinson's disease: a historical perspective. Animal Model Exp Med 2022;5:27-37.

261. Ackley SF, Zimmerman SC, Brenowitz WD, et al. Effect of reductions in amyloid levels on cognitive change in randomized trials: instrumental variable meta-analysis. BMJ 2021;372:n156.

262. Karran E, De Strooper B. The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics. Nat Rev Drug Discov 2022;21:306-18.

263. Hardy J, Mummery C. An anti-amyloid therapy works for Alzheimer's disease: why has it taken so long and what is next? Brain 2023;146:1240-2.

264. The Lancet Neurology. Solanezumab: too late in mild Alzheimer's disease? Lancet Neurol 2017;16:97.

265. Haass C, Selkoe D. If amyloid drives Alzheimer disease, why have anti-amyloid therapies not yet slowed cognitive decline? PLoS Biol 2022;20:e3001694.

266. Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 1991;82:239-59.

267. Bateman RJ, Benzinger TL, Berry S, et al. DIAN-TU Pharma Consortium for the Dominantly Inherited Alzheimer Network. The DIAN-TU next generation alzheimer's prevention trial: Adaptive design and disease progression model. Alzheimers Dement 2017;13:8-19.

268. Evans CD, Sparks J, Andersen SW, et al. APOE ε4's impact on response to amyloid therapies in early symptomatic Alzheimer's disease: analyses from multiple clinical trials. Alzheimers Dement 2023; doi: 10.1002/alz.13128.

269. Gleason A, Ayton S, Bush AI. Unblinded by the light: amyloid-related imaging abnormalities in Alzheimer's clinical trials. Eur J Neurol 2021;28:e1.

270. Robinson JL, Lee EB, Xie SX, et al. Neurodegenerative disease concomitant proteinopathies are prevalent, age-related and APOE4-associated. Brain 2018;141:2181-93.

271. Arriagada PV, Growdon JH, Hedley-Whyte ET, Hyman BT. Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease. Neurology 1992;42:631-9.

272. Wu T. Clinical study on improving the cognitive function of patients with mild to moderate alzheimer’s disease by using ginkgo biloba dispersible tablets. 2019. Available from: [Last accessed on 27 Jul 2023].

273. Zhejiang Hisun Pharmaceutical Co. Ltd. A randomized, double blind, placebo controlled, parallel-group 52-week multicenter phase II study to investigate the safety, efficacy and pharmacokinetics of AD-35 tablet in subjects with mild to moderate Alzheimer’s disease. 2018. Available from: [Last accessed on 27 Jul 2023].

274. Washington University School of Medicine. A phase II/III multicenter randomized, double-blind, placebo-controlled platform trial of potential disease modifying therapies utilizing biomarker, cognitive, and clinical endpoints in dominantly inherited Alzheimer’s disease. 2023. Available from: [Last accessed on 27 Jul 2023].

275. Sengupta U, Nilson AN, Kayed R. The role of amyloid-β oligomers in toxicity, propagation, and immunotherapy. EBioMedicine 2016;6:42-9.

276. Chen XQ, Mobley WC. Alzheimer disease pathogenesis: insights from molecular and cellular biology studies of oligomeric Aβ and Tau species. Front Neurosci 2019;13:659.

277. Kirkitadze MD, Bitan G, Teplow DB. Paradigm shifts in Alzheimer's disease and other neurodegenerative disorders: the emerging role of oligomeric assemblies. J Neurosci Res 2002;69:567-77.

278. Morkuniene R, Zvirbliene A, Dalgediene I, et al. Antibodies bound to Aβ oligomers potentiate the neurotoxicity of Aβ by activating microglia. J Neurochem 2013;126:604-15.

279. Bakrania P, Hall G, Bouter Y, et al. Discovery of a novel pseudo β-hairpin structure of N-truncated amyloid-β for use as a vaccine against Alzheimer's disease. Mol Psychiatry 2022;27:840-8.

280. Cogswell PM, Barakos JA, Barkhof F, et al. Amyloid-related imaging abnormalities with emerging alzheimer disease therapeutics: detection and reporting recommendations for clinical practice. AJNR Am J Neuroradiol 2022;43:E19-35.

281. Alves F, Kalinowski P, Ayton S. Accelerated brain volume loss caused by anti-β-amyloid drugs: a systematic review and meta-analysis. Neurology 2023;100:e2114-24.

282. Teunissen CE, Verberk IMW, Thijssen EH, et al. Blood-based biomarkers for Alzheimer's disease: towards clinical implementation. Lancet Neurol 2022;21:66-77.

Cite This Article

Export citation file: BibTeX | RIS

OAE Style

Cai H, Fu X, Quan S, Ren Z, Chu C, Jia L. Amyloid-β-targeted therapies for Alzheimer's disease: currently and in the future. Ageing Neur Dis 2023;3:13.

AMA Style

Cai H, Fu X, Quan S, Ren Z, Chu C, Jia L. Amyloid-β-targeted therapies for Alzheimer's disease: currently and in the future. Ageing and Neurodegenerative Diseases. 2023; 3(3): 13.

Chicago/Turabian Style

Huimin Cai, Xiaofeng Fu, Shuiyue Quan, Ziye Ren, Changbiao Chu, Longfei Jia. 2023. "Amyloid-β-targeted therapies for Alzheimer's disease: currently and in the future" Ageing and Neurodegenerative Diseases. 3, no.3: 13.

ACS Style

Cai, H.; Fu X.; Quan S.; Ren Z.; Chu C.; Jia L. Amyloid-β-targeted therapies for Alzheimer's disease: currently and in the future. Ageing. Neur. Dis. 2023, 3, 13.

About This Article

© The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License (, which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Data & Comments




Comments must be written in English. Spam, offensive content, impersonation, and private information will not be permitted. If any comment is reported and identified as inappropriate content by OAE staff, the comment will be removed without notice. If you have any queries or need any help, please contact us at

Download PDF
Cite This Article 13 clicks
Like This Article 13 likes
Share This Article
Scan the QR code for reading!
See Updates
Ageing and Neurodegenerative Diseases
ISSN 2769-5301 (Online)


All published articles will be preserved here permanently:


All published articles will be preserved here permanently: