Jeffrey Cummings,Yadi Zhou,Garam Lee,Kate Zhong,Jorge Fonseca,Feixiong Cheng
Alzheimer's disease drug development pipeline: 2023
Alzheimer's disease,amyloid,biomarkers,clinical trials,Common Alzheimer's Disease Research Ontology (CADRO),drug development,inflammation,pharmaceutical companies,repurposed drugs,synaptic function,tau
Abstract Introduction Drugs that prevent the onset, slow progression, or improve cognitive and behavioral symptoms of Alzheimer's disease (AD) are needed. Methods We searched ClinicalTrials.gov for all current Phase 1, 2 and 3 clinical trials for AD and mild cognitive impairment (MCI) attributed to AD. We created an automated computational database platform to search, archive, organize, and analyze the derived data. The Common Alzheimer's Disease Research Ontology (CADRO) was used to identify treatment targets and drug mechanisms. Results On the index date of January 1, 2023, there were 187 trials assessing 141 unique treatments for AD. Phase 3 included 36 agents in 55 trials; 87 agents were in 99 Phase 2 trials; and Phase 1 had 31 agents in 33 trials. Disease‐modifying therapies were the most common drugs comprising 79% of drugs in trials. Twenty‐eight percent of candidate therapies are repurposed agents. Populating all current Phase 1, 2, and 3 trials will require 57,465 participants. Discussion The AD drug development pipeline is advancing agents directed at a variety of target processes. HIGHLIGHTS There are currently 187 trials assessing 141 drugs for the treatment of Alzheimer's disease (AD). Drugs in the AD pipeline address a variety of pathological processes. More than 57,000 participants will be required to populate all currently registered trials.
Alzheimer's disease drug development pipeline: 2023

Drugs that prevent the onset, slow progression, or improve cognitive and behavioral symptoms of Alzheimer's disease (AD) are needed.

We searched ClinicalTrials.gov for all current Phase 1, 2 and 3 clinical trials for AD and mild cognitive impairment (MCI) attributed to AD. We created an automated computational database platform to search, archive, organize, and analyze the derived data. The Common Alzheimer's Disease Research Ontology (CADRO) was used to identify treatment targets and drug mechanisms.

On the index date of January 1, 2023, there were 187 trials assessing 141 unique treatments for AD. Phase 3 included 36 agents in 55 trials; 87 agents were in 99 Phase 2 trials; and Phase 1 had 31 agents in 33 trials. Disease‐modifying therapies were the most common drugs comprising 79% of drugs in trials. Twenty‐eight percent of candidate therapies are repurposed agents. Populating all current Phase 1, 2, and 3 trials will require 57,465 participants.

The AD drug development pipeline is advancing agents directed at a variety of target processes.

There are currently 187 trials assessing 141 drugs for the treatment of Alzheimer's disease (AD). Drugs in the AD pipeline address a variety of pathological processes. More than 57,000 participants will be required to populate all currently registered trials. 

Alzheimer's disease (AD) is increasing at an alarming pace as the population of the United States and the world age. There are an estimated 6.2 million individuals with AD dementia in the United States and an estimated 50 million individuals with AD dementia globally. These populations will grow to 12.7 million and 150 million in the United States and globally, respectively, by 2050. , In addition to AD dementia, there are an approximately equal number of individuals with prodromal AD and an even larger number of persons with preclinical AD characterized by normal cognition, biomarkers consistent with AD pathology, and an increased risk for progression to cognitive impairment. , These epidemiologic predictions make it increasingly urgent that new medications to prevent the onset, delay progression, or improve symptoms of AD be found. The goal of this review is to describe the current AD drug development pipeline; note trends in clinical trial design, clinical outcome measures, and biomarker use in trials; and review which drug mechanisms of action (MoAs) and biological targets are being pursued. Monoclonal antibodies and other biological agents in the current AD pipeline are discussed, small molecules intended to produce disease modification currently in clinical trials are reviewed, and symptomatic agents seeking to produce cognitive enhancement or reduce neuropsychiatric symptoms in AD are reported. This review is based on data derived from the ClinicalTrials.gov registry. The report follows the approach of our previous annual reviews of the AD drug development pipeline. ,

The US National Library of Medicine of the National Institutes of Health (NIH) maintains a clinical research registry, ClinicalTrials.gov, which serves as the source of information for this review. The US Food and Drug Administration (FDA) Amendments Act requires that all clinical trials be registered on ClinicalTrials.gov. The “Common Rule” governing ClinicalTrials.gov requires registration for studies that meet the definition of an “applicable clinical trial” (HR3580, 2007). Registration must occur within 21 days of enrolling the first patient in the trial. Studies of compliance with the Common Rule indicate that compliance with the rule is high and most trials are registered appropriately. , The United States has more clinical trials than any other country, ClinicalTrials.gov includes most therapies currently in clinical trials for AD globally, and ClinicalTrials.gov is more comprehensive than any other trial registry. The information in this review can be regarded as comprehensive but not exhaustive.

Systemic Review: Alzheimer's disease (AD) represents a complex disorder for which there are few treatments. Candidate therapies for AD are assessed in clinical trials and are registered on ClinicalTrials.gov. We reviewed clinical trials and the drugs being assessed to understand the flow of drugs from laboratories to the clinic. Interpretation: There are currently 187 Phase 1, 2, and 3 clinical trials assessing 141 unique drugs. Thirty‐six drugs are being assessed in Phase 3, 87 in Phase 2, and 31 in Phase 1. Transmitter receptors, amyloid, synaptic function, and inflammation are the most common targets of drugs in the pipeline. Future Directions: Clinical trials represent the only means of generating efficacy and safety data that can lead to drug approval and widespread availability. The AD drug development pipeline includes agents addressing a variety of targets and intended for different phases of AD. Incentives for AD drug development are needed. 

The index date for this review is January 1, 2023, and the text and tables apply to the information as registered on ClinicalTrials.gov on this date. We searched all terms related to AD and mild cognitive impairment (MCI) for inclusion in the review. We do not include studies whose participants have dementia of any cause or in which AD is included with other dementias not separated by inclusion and exclusion criteria. We do not include trials in which the MCI is specified to be part of a non‐AD disease such as MCI of Parkinson's disease. We include all trials of agents in Phases 1, 2, and 3. We did not include Phase 4 trials or trials without a phase designation. If a trial is designated as 1/2 or 2/3 we include it with trials of the higher number. We archive information on the trial agent, trial title, trial number assigned on ClinicalTrials.gov, start date, projected primary end date, duration of treatment exposure, number of arms of the study (usually a placebo arm and one or more treatment arms with different doses), whether a biomarker was collected at entry or as an outcome, whether the agent was repurposed, and where the trials were performed. We use the “funder type” trial sponsorship categories specified on ClinicalTrials.gov (the biopharmaceutical industry; public– private partnership; NIH and related including individuals, universities, and organizations; and “other” [non‐NIH] federal entities). We identified “public–private partnerships” as any trial in which a biopharmaceutical company was one of two or more sponsors for the trial. We included trials labeled as recruiting, active but not recruiting (i.e., trials that have completed recruitment and are continuing with the exposure portion of the trial), enrolling by invitation (i.e., open‐label extensions of trials limited to those participating in the double‐blind portion of the trials), and not yet recruiting (i.e., registered on ClinicalTrials.gov but no patients have been enrolled). We note if the trial population comprises participants with preclinical AD (cognitively normal with biomarker evidence of AD or an autosomal dominant AD‐causing mutation participating in AD prevention trials), MCI, AD dementia (mild, moderate, severe), or healthy volunteers. We note the trials listed as completed, terminated, suspended, unknown, or withdrawn since the last index date. The report does not include trials of non‐pharmacologic therapeutic approaches such as exercise trials, cognitive‐behavior therapies, caregiver interventions, supplements, medical foods, or devices. We do not include trials of biomarkers if no intervention is being tested; we note whether biomarkers were collected at trial entry or were included as outcome measures in the intervention trials we report. Cell therapies are included among the interventions described (they are not included in Figure 1).



We use the Actual Study Start Date as listed on ClinicalTrials.gov for the beginning of the trial and the Estimated Primary Completion Date for the anticipated end of the trial. The total trial duration is the projected period between the actual study start date and the estimated primary completion date. The treatment exposure duration is specified on ClinicalTrials.gov; the recruitment period is calculated as the total trial duration minus the treatment study period.

The Common Alzheimer's Disease Research Ontology (CADRO) of the National Institute on Aging and the Alzheimer's Association; the International Alzheimer's and Related Dementias Research Portfolio (IADRP; iadrp.nia.nih.gov) provides the basis for the description of the biological processes in AD that comprise possible targets for therapeutic intervention. The CADRO Translational Research and Clinical Interventions Category lists potential targets for AD clinical therapies. The targets include amyloid beta; tau; apolipoprotein E (APOE), lipids, and lipoprotein receptors; neurotransmitter receptors; neurogenesis; inflammation; oxidative stress; cell death; proteostasis/proteinopathies; metabolism and bioenergetics; vasculature; growth factors and hormones; synaptic plasticity/neuroprotection; gut–brain axis; circadian rhythm; epigenetic regulators; multi‐target; unknown target; and other. These processes/targets are used to classify the target category of the agents. Some agents may have more than one MoA; for these, we reviewed the literature to identify the putative predominant mechanisms.

Treatments whose purpose is cognitive enhancement or control of neuropsychiatric symptoms without claiming to impact the underlying biological causes of AD are classified as “symptomatic.” Treatments intended to change the biology of AD and slow the course of the disease are listed as “disease modifying.” If the sponsor did not specify the therapeutic purpose, we used the features of the trial (e.g., clinical outcomes, trial duration, use of biomarkers for participant inclusion, use of biomarkers as outcomes, number of participants) to infer if a trial was structured to demonstrate disease modification or symptomatic benefit. We divided disease‐modifying therapies (DMTs) into biologics (e.g., monoclonal antibodies, vaccines, antisense oligonucleotides [ASOs], gene therapy, etc.) and small molecules (e.g., drugs typically taken orally and less than 500 Daltons in molecular weight).

To determine whether an agent is approved for a non‐AD indication and considered a repurposed agent in the pipeline, we used the currently available version of DrugBank (https://go.drugbank.com/).

We downloaded all the original data using the ClinicalTrials.gov application programming interface (API) (https://clinicaltrials.gov/api/gui). We implemented an automated Python script‐based computational database platform to search for the appropriate trials on ClinicalTrials.gov and to interrogate and analyze data from the derived database. As an initial filtering step, we identified all the interventional trials designed with the primary purpose of prevention, treatment, or basic science, and including at least one intervention type including drug, dietary supplement, or biological. We then eliminated all non‐drug trials. Stem cell trials were assembled separately. If questions arose during the analytic process about the nature of the intervention or other trial aspects, they were resolved by expert curation. We generated summary statistics (e.g., mean and count) using the annotated trial data for all analyses.

There were 187 Phase 1, 2, or 3 clinical trials assessing 141 unique treatments for AD as of the index date of January 1, 2023. There were 36 agents in 55 Phase 3 trials, 87 agents in 99 Phase 2 trials, and 31 agents in 33 Phase 1 trials (some agents are in more than one trial; Figure 1). Among the Phase 1, 2, and 3 trials, the most common agents being studied are DMTs (111 agents; 78% of the total number of drugs in these trials). Symptomatic agents comprise 21% (N = 30) of the pipeline including 15 (11% of all agents in Phase 1, 2, or 3 trials) cognitive enhancers and 15 (11% of all agents in these trials) psychotropic agents. Of the DMTs, there were 49 (44% of DMTs) biologics and 62 (56% of DMTs) small molecules. From the target perspective, 22 (16%) of agents have amyloid, 13 (9%) tau, 24 (17%) inflammation, 18 (13%) synaptic plasticity/neuroprotection, 10 (7%) metabolism and bioenergetics, 7 (5%) oxidative stress, and 4 (3%) proteostasis/proteinopathy as their primary mechanistic targets. Twenty‐eight agents (29%) have neurotransmitters as their biological target; this class includes cognitive‐enhancing agents and drugs being developed to reduce neuropsychiatric symptoms. Sixteen drugs (11%) target processes represented by only one to three agents per CADRO category. Considering DMTs only, 24 (67%) of Phase 3 agents are DMTs; 74 (85%) Phase 2 drugs are DMTs; and 25 (81%) of Phase 1 agents are DMTs. There are 40 repurposed agents in the pipeline comprising 28% of candidate therapies (all phases combined). There are eight ongoing trials involving stem cell therapies. Since January 25, 2022, 31 trials have been completed, 2 were suspended, 15 are of unknown status, and 1 each was terminated or withdrawn. Fifty‐eight new trials (16 in Phase 1, 27 in Phase 2, 15 in Phase 3) have entered the pipeline in the past year (since index date of January 25, 2022).

Phase 3 has 36 agents in 55 trials (Figure 1, Figure 2, and Table 1). DMTs represent 67% (N = 24) of agents in Phase 3 trials including 9 (25% of the Phase 3 agents) biologics and 15 (42%) small molecules. Five (14% of Phase 3 agents) are putative cognitive‐enhancing agents and seven (19%) drugs target neuropsychiatric symptoms of AD. CADRO mechanisms represented among Phase 3 agents include amyloid (7 agents; 19%), synaptic plasticity/neuroprotection (6; 17%), oxidative stress (3; 8%), metabolism and bioenergetics (3; 8%), tau (2; 6%), inflammation (2; 6%), proteostasis/proteinopathies (1; 3%), and circadian rhythm (1; 3%). Eleven agents in Phase 3 (31%) address transmitter receptor mechanisms. Figures 1 and 2 show the CADRO‐based MOAs of agents in Phase 3. Twelve (33%) of Phase 3 agents are repurposed treatments approved for use in another indication (6 = DMT; 3 = for cognitive enhancement; 3 = for treatment for behavioral symptoms). Six trials that were active in 2022 were completed, one was suspended, and one is of unknown status. Fifteen Phase 3 trials were initiated between January 25, 2022, and January 1, 2023. Five of the trials in Phase 3 are prevention trials enrolling cognitively normal participants, 25 trials enroll early AD defined as MCI/prodromal AD and mild AD dementia (45% of all Phase 3 trials), 11 trials include participants with mild‐to‐moderate AD or moderate AD dementia, 8 enroll moderate‐to‐severe or severe participants, and 6 trials enroll participants with AD dementia of any severity. Taken together currently active trials in Phase 3 require a total enrollment of 41,864 participants. Prevention trials require 5565 participants with preclinical AD; trials of MCI due to AD or prodromal AD require 2284 participants; trials focusing on early AD (prodromal AD or mild AD dementia) require 20,482 participants; trials for mild‐to‐moderate or moderate AD dementia plan to enroll 6359 participants; and trials of moderate‐to‐severe and severe AD plan enrollment of 4546 participants. Phase 3 DMT trials of biologics require 24,528 participants; DMT small molecule trials will enroll 9450; cognitive enhancer trials plan enrollment of 2360 participants; and trials of drugs being developed for neuropsychiatric syndromes plan enrollment of 5526 participants. DMT trials assessing biological agents enroll a mean of 1168 participants, DMT trials testing small molecules enroll a mean of 556 individuals, cognitive enhancer trials enroll of a mean of 393 persons per trial, and trials of neuropsychiatric syndrome therapies enroll a mean of 502 participants. Mean treatment exposure period for prevention trials of DMT biologics was 143 weeks and for DMT small molecules was 78 weeks. DMT trials for symptomatic patients averaged 103 weeks for biologics and 56 weeks for small molecule trials. Cognitive enhancer trials had an average of 25 treatment weeks. Trials for the treatment of neuropsychiatric syndromes had a mean of 19 treatment weeks. Recruitment is a major challenge for clinical trials. The average recruitment (calculated as the total trial duration minus the treatment period) time for prevention trials of DMT biological agents was 107 and for DMT small molecules was 233 weeks. Non‐prevention DMT trials required 147 weeks for biologics and 99 weeks for small molecules. Cognitive enhancer trials had mean recruitment times of 142 weeks. Recruitment time for trials of treatments for neuropsychiatric syndromes had a mean of 194 weeks.

Phase 2 has 87 agents in 99 trials (Figure 1, Figure 3, and Table 2). DMTs represent 85% (N = 74) of agents in Phase 2 trials including 31 (36% of the Phase 2 agents) biologics and 43 (49%) small molecules. Eight (9% of Phase 2 agents) are putative cognitive enhancing agents and five (6%) drugs target neuropsychiatric symptoms of AD. CADRO mechanisms represented among Phase 2 treatments include inflammation (17 agents; 20%), synaptic plasticity/neuroprotection (14; 16%), transmitter receptors (12; 14%), amyloid (11 agents; 13%), tau (8; 9%), metabolism and bioenergetics (5; 6%), oxidative stress (3; 3%), proteostasis/proteinopathies (3; 3%), growth factors and hormones (3; 3%), APOE and lipids (3; 3%), vasculature (2; 2%), circadian rhythm (2; 2%), neurogenesis (2; 2%), epigenetic regulators (1; 1%), and cell death (1; 1%). Figures 1 and 3 show the CADRO‐based targets of agents in Phase 2. Twenty‐four (28%) of the Phase 2 agents are repurposed treatments approved for use in another indication (92% = DMT; N = 22), 4% (N = 1) for cognitive enhancement and 4% (N = 1) for treatment for behavioral symptoms. Fourteen trials that were active in 2022 were completed; seven are of unknown status; and one each was suspended, terminated, or withdrawn. Twenty‐seven new Phase 2 trials were initiated between January 25, 2022, and January 1, 2023. Four Phase 2 trials enroll preclinical participants, 30 (30% of Phase 2 trials) trials enroll MCI prodromal participants, 29 (29% of Phase 2 trials) trials enroll early AD participants, 27 (27% of Phase 2 trials) trials enroll mild‐to‐moderate or moderate AD dementia, 5 (5%) enroll participants with moderate‐to‐severe and severe AD dementia, and 3 (3%) trials include participants with AD dementia of any severity. Taken together, currently active trials in Phase 2 trials require a total enrollment of 13,829 participants. DMT trials for biological agents will enroll 5769 participants, trials of small molecule DMTs will enroll 6308 individuals, trials of cognitive enhancing agents will enroll 1282 participants, and trials of drugs being developed for neuropsychiatric syndromes will enroll 470 participants. DMT biological trials have a mean enrollment of 170 participants, DMT small molecule trials have a mean enrollment of 121 participants, trials for cognitive enhancers include a mean of 160 participants, and trials focusing on neuropsychiatric syndromes enroll a mean of 94 participants. Treatment duration of biologic DMTs in treatment trials for symptomatic AD is 56 weeks and for small molecules in treatments trials is 42 weeks. Treatment exposure in cognitive enhancer trials has a mean of 24 weeks; treatment duration for therapies addressing neuropsychiatric syndromes has a mean exposure period of 8 weeks. Mean recruitment time for trials of DMT biological agents for symptomatic AD is 104 weeks (on average); recruitment of trials for DMT small molecules took a mean of 125 weeks. Cognitive enhancer trials required a mean recruitment period of 114 weeks. Recruitment for trials of agents addressing behavioral changes in AD had a mean recruitment period of 109 weeks.

There are 31 agents in 33 Phase 1 trials (Figure 1, Table 3). There are 25 DMTs (81% of Phase 1 agents) in Phase 1 trials including 16 (52% of the Phase 1 agents) biologics and 9 (29%) small molecules. There are three (10% of Phase 1 agents) putative cognitive enhancing agents and three (10%) drugs targeting behavioral symptoms. CADRO mechanisms represented among Phase 1 therapies include amyloid (7 agents; 23%); inflammation (6 agents; 19%); transmitter receptors (6; 19%); tau (4; 13%); metabolism and bioenergetics (2; 6%); and 1 (3%) each for APOE and lipoproteins, neurogenesis, oxidative stress, synaptic plasticity/neuroprotection, and “other.” Seven (23%) of the Phase 1 agents are repurposed treatments approved for use in another indication (four DMTs, two cognitive enhancers, one neuropsychiatric agent). Eleven trials that were active in 2022 were completed and seven are of unknown status. Sixteen new Phase 1 trials have been initiated in the past year. Phase 1 trials include both single ascending dose and multiple ascending dose studies and will enroll 1772 participants into currently registered trials. Most Phase 1 participants are healthy volunteers (N = 1165); immunotherapy trials in Phase 1 trial may include participants with AD of a variety of severities. Trials of biological agents in Phase 1 will require 994 participants, trials of small molecule DMTs will enroll 514 participants, trials of cognitive enhancing agents will enroll 204 participants, and trials of drugs addressing neuropsychiatric syndromes plan to enroll 60 participants. The mean number of participants in DMT biological trials is 62, DMT small molecules will enroll a means of 47 participants, trials of cognitive enhancers enroll a mean of 68 participants, and trials of drugs of neuropsychiatric syndromes will enroll a mean of 20 participants. Treatment exposure for DMT biologics is 45 weeks and for DMT small molecules is 13 weeks. Treatment duration for cognitive enhancers in Phase 1 is typically 6 weeks; the mean duration for neuropsychiatric agents in Phase 1 is 5 weeks. Recruitment for Phase 1 DMT trials of biologics averages 65 weeks and for DMT small molecules averages 77 weeks. Cognitive enhancer trials require 113 weeks to recruit and trials for drugs addressing neuropsychiatric symptoms have average recruitment periods of 87 weeks.

There are 8 stem cells trials developing cell therapies for AD (Table 4).

Biomarkers are commonly collected at study entry and at study termination. For trials with biomarker descriptions on ClinicalTrials.gov, 72 Phase 2 trials and 34 Phase 3 trials require magnetic resonance imaging (MRI) at baseline. Thirty‐one Phase 2 trials and 9 Phase 3 trials collect baseline cerebrospinal fluid (CSF) amyloid; and 29 Phase 2 and 12 Phase 3 collect baseline amyloid positron emission tomography (PET). Plasma amyloid is collected in four Phase 2 and one Phase 3 trial. Tau measures collected at baseline include CSF tau in seven Phase 2 trials and three Phase 3 trials; CSF phospho‐tau (p‐tau) in six Phase 2 trials and two Phase 3 trials; tau PET in six Phase 2 trials and three Phase 3 trials. Twenty Phase 2 trials and 17 Phase 3 trials do not assess biomarkers at baseline. MRI is the most common biomarker collected as an outcome measure. MRI data are captured as outcome assessments in 27 Phase 2 trials and 10 Phase 3 trials. Amyloid PET and tau PET are commonly collected as outcomes; amyloid PET in seven Phase 2 and thirteen Phase 3 trials and tau PET in six Phase 2 and nine Phase 3 trials. Amyloid and tau measures are collected in CSF and in plasma are collected as outcomes. Thirteen Phase 2 trials and three Phase 3 trials collect CSF amyloid; fifteen Phase 2 trials and six Phase 3 trials collect CSF tau; eleven Phase 2 trials and five Phase 3 trials collect CSF p‐tau. These same three biomarkers are also collected in plasma. Twelve Phase 2 trials and two Phase 3 trials collect plasma amyloid, five Phase 2 trials and one Phase 3 trial collect plasma tau, and eight Phase 2 trials and three Phase 3 trials collect plasma p‐tau. A few trials collect neurofilament light (CSF: six Phase 2 trials, three Phase 3 trials; plasma: four Phase 2 trials, four Phase 3 trials) and glial fibrillary acidic protein (GFAP) in CSF and in plasma (CSF: one Phase 2 trial; plasma: one Phase 3 trial). Electroencephalography (EEG) is collected in seven Phase 2 trials and no Phase 3 trials.

To fully populate the 187 trials in the pipeline, 57,465 participants are needed. Of these, 41,864 are required for Phase 3 trials; 13,829 for Phase 2 trials; and 1772 for Phase 1 trials. An additional 4632 participants are required for Phase 4 trials or trials with unlabeled phases.

Of the 187 currently active Phase 1, 2, and 3 trials, 108 (58%) are industry sponsored; 17 (9%) are public–private partnerships; 60 (32%) include the NIH, individuals, universities, advocacy groups, and other organizations; and 2 are funded through other US federal agencies. Industry contributes to 67% of all current clinical trials. Thirty‐nine of 55 (71%) Phase 3 trials are industry sponsored, 50 of 99 (51%) Phase 2 trials are sponsored by industry and 19 of 33 (58%) Phase 1 trials are funded through industry. NIH, academic, advocacy, and philanthropic enterprises sponsor 9 of 55 (16%) Phase 3 trials, 41 of 99 (41%) Phase 2 trials, and 10 of 33 (30%) Phase 1 trials.

Repurposed agents represent 28% (56/187) of clinical trials in the current AD pipeline and 28% (40/141) of drugs in the current pipeline. These agents tend to have their greatest role in Phase 2 proof‐of‐concept (POC) trials in which they represent 24 of 99 (24%) drugs. Of all repurposed agents, 60% are in Phase 2 (24/40). There are 12 repurposed agents (33%) in Phase 3 and 7 such agents (23%) in Phase 1. There are seven (18%) repurposed biological agents addressing disease modification in the pipeline. Of repurposed small molecules, 58% (23/40) target disease modification, 13% (5/40) address neuropsychiatric symptoms, and 13% (5/40) target cognitive enhancement. Funding of repurposed drugs differs markedly from that of the pipeline generally. Seven of 40 (18%) repurposed drugs in the pipeline are funded by industry; 1 is funded through a public–private partnership; and 32 (80%) are funded through NIH, academic, advocacy, and philanthropic enterprises.

Eighty‐three of 187 (44%) trials are conducted in North America only; 42 of 187 (22%) are conducted only outside of North America; and 46 of 187 (25%) are conducted in both North American and non–North American sites (the data are missing for 16 trials). In Phase 3, 14 of 55 (25%) trials are conducted in North America only, 9 of 55 (16%) are conducted outside of North America only, and 28 of 55 (51%) are conducted in both North American and non–North American sites. Forty‐nine of 99 (49%) Phase 2 trials used North American sites only, 26 of 99 (26%) used only non–North American sites, and 15 of 99 (15%) used both North American and non–North American sites. Phase 1 trials are conducted primarily in North America (20 of 33; 61%), with a substantial number of Phase 1 trials conducted only in non–North American sites (7 of 33; 21%), and few Phase 1 trials involve both North American and non–North American sites (3 of 33; 9%).

Thirty‐seven new therapies—22 new chemical entities and 15 biologics—were approved by the FDA in 2022 across all therapeutic categories. Five agents are active in the central nervous system (CNS) including one agent for relapsing multiple sclerosis, one treatment for amyotrophic lateral sclerosis, one anticonvulsant, and one therapy for the treatment of insomnia. One biological agent was directed at cerebral adrenoleukodystrophy to slow the progression of neurologic dysfunction. This is the smallest number of new drugs approved since 2016. There were no new treatments approved for AD in 2022. In 2021 and 2023, respectively, aducanumab and lecanemab received accelerated approval for the treatment of AD. Development for AD continues to be challenging with only these two drugs approved since 2003. Review of the CADRO categories of disease processes that represent drug targets demonstrates that inflammation, amyloid, neurotransmitter receptors, synaptic plasticity, tau biology, oxidation, and proteostasis/proteinopathy represent the major targets for drug development (Figure 4). Targets related to inflammation comprise one of the largest categories in the pipeline, with 16% (N = 25) of agents; in Phase 2, agents addressing inflammatory targets represent 20% of all drugs in development. There has been a consistent number of anti‐inflammatory agents in the pipeline over the past few years. In 2020, there were 20 anti‐inflammatory agents (16.5%); 2021 had 19 agents (15%); and 2022 had 23 agents (16%). Nearly every anti‐inflammatory agent has a different target within the inflammatory cascade (Tables 1, 2, 3). Outcomes of the trials may inform which targets can be modulated with therapeutic benefit and what combinations of targets may be desirable. Other common targets of drugs in the pipeline include amyloid 16%, transmitters 20%, synaptic plasticity and circuits 13%, tau targets 9%, and metabolism and bioenergetics drugs 6% (Figures 2, 3, 4). The canonical targets of amyloid and tau comprise 25% of the AD drug development pipeline; the remaining 75% include 14 CADRO categories representing a diverse array of targets among drugs being developed. Less target diversity is evident in Phase 3 (9 CADRO categories) than Phase 2 (15 categories) reflecting the POC purpose of Phase 2 and the exploration of novel targets at this stage of development. Treatments related to APOEare uncommon in the pipeline despite the influential role played by APOE ε4 in the biology of AD. Cell death as a drug development target is also uncommon, notwithstanding its role in the amyloid, tau, neurodegeneration (AT[N]) approach to AD pathogenesis and biomarkers. Neurotransmitter receptor agents are well represented in the pipeline in part because cognitive enhancing agents and treatments for neuropsychiatric syndromes address transmitter receptor biology. The large number of target processes being addressed by agents in the pipeline will provide important information regarding which processes represent viable targets for AD drug development. Conclusions about the efficacy demonstrated must be considered in the context of the features of the trial, including sample size, target exposure, and population assessed. Repurposed agents represent 33% of Phase 3 agents, 28% of Phase 2 agents, and 23% of Phase 1 agents. These drugs have been approved for another indication and are being explored for their possible utility in the treatment of AD. Most but not all these drugs are generic. Most repurposed agents are studied in Phase 2 POC trials. In the current pipeline, there are 12 repurposed agents in Phase 3, 24 in Phase 2, and 7 in Phase 1. Development programs for repurposed agents are most likely to be funded by academic (in conjunction with the NIH), advocacy, and philanthropic organizations. Eighty percent of repurposed agents are funded through these mechanisms. The disproportionately smaller role played by the biopharmaceutical industry compared to NIH, academics, advocacy, and philanthropic entities in the development of repurposed agents reflects the difficulty of protecting intellectual property for generic drugs that comprise the foundation for marketability and return on investment. , Deployment and marketing of a successfully developed repurposed compound requires substantial funding. Policy changes, financial incentives, innovation surcharges, and tax advantages will be necessary to attract the funding required to advance repurposed agents to market. , These policy revisions are needed to allow repurposed agents to move beyond their current value in POC trials and become viable therapies for patients. The globalization of trials is increasingly evident, especially in large late‐stage trials; 51% of Phase 3 trials include both North American and non–North American sites. This reflects the large number of patients and sites required to recruit the large populations required for Phase 3 trials. Trials increasingly require biological confirmation of the presence of amyloid in participants. Sixty‐four Phase 2 trials and 21 Phase 3 trials require CSF amyloid, CSF amyloid/tau ratios, or amyloid PET at entry. A few trials (four Phase 2; one Phase 3) collect plasma amyloid measures at entry. Tau PET is beginning to have a larger role in clinical trials with six Phase 2 and three Phase 3 trials requiring tau imaging documentation at baseline. The profile of biomarkers collected as trial outcomes differs from that of biomarkers collected at entry. Outcomes of anti‐amyloid therapies would require amyloid measures as an outcome; non‐amyloid therapeutics might use amyloid for diagnostic confirmation but not as an outcome. There are 20 Phase 2 trials and 16 Phase 3 trials with CSF amyloid or amyloid PET as outcomes. Tau PET is used as an outcome in six Phase 2 trials and nine Phase 3 trials. Biomarkers are playing an increasingly large role in clinical trials in which they may have one or more defined contexts of use including risk determination, diagnosis, monitoring, pharmacodynamic measurement, prognosis determination, response prediction, and safety. , Use of markers in drug development increases the probability of success and is increasingly viewed as a foundational aspect of clinical trials of DMTs. Recruitment is a major challenge for AD clinical trials and a key reason for delay in drug development decisions and advancing new therapies to late‐stage development and possible approval. A Phase 3 biological agent (for symptomatic participants) has a mean treatment duration of 103 weeks and will require, on average, 147 weeks to recruit the participants; a Phase 3 DMT small molecule with a mean treatment period of 56 weeks will require an average of 99 weeks to recruit. The recruitment challenges are more extreme for symptomatic agents. A trial of a cognitive enhancing agent with a mean exposure period of 25 weeks will require an average of 142 weeks for recruitment; trials of treatments for neuropsychiatric symptoms with an average treatment period of 19 weeks require a mean of 194 weeks for recruitment. The AD drug development pipeline is leading to new therapies. After a 17‐year hiatus in drug approvals, two agents—aducanumab and lecanemab—have entered the market since 2021; brexpiprazole ameliorated agitation in a Phase 3 AD trial; and suvorexant reduced insomnia in AD in a Phase 3 trial. Aducanumab and lecanemab are the first DMTs for AD and among the first DMTs for any neurodegenerative disease. , , Both agents were approved by the FDA using the accelerated pathway based on the reasonable likelihood that amyloid plaque reduction seen on amyloid PET predicts clinical benefit characterized by the slowing of disease progression. A confirmatory trial to demonstrate the clinical efficacy of aducanumab was required by the FDA and a confirmatory trial for lecanemab has been completed. The success of these agents suggests that the understanding of AD‐related biology has progressed sufficiently to allow identification of targets whose modulation ameliorates clinical decline. In addition to improvements in the definition of targets, the availability of more informative biomarkers, identification of candidate drugs with more promising pharmacokinetic and pharmacodynamic characteristics, better definition of appropriate trial populations, and improved trial conduct contributed to the recent successes and provide the foundation for additional productive drug development programs. The recently approved therapies provide treatment for a relatively limited segment (e.g., early AD) of the large and growing AD population. They represent initial steps in the march toward more comprehensive treatments with multiple therapeutic options for those with or at risk for AD.

J.C. has provided consultation to Acadia, Alkahest, AlphaCognition, AriBio, Avanir, Axsome, Behren Therapeutics, Biogen, Biohaven, Cassava, Cerecin, Cortexyme, Diadem, EIP Pharma, Eisai, GemVax, Genentech, Green Valley, Grifols, Janssen, LSP, Merck, NervGen, Novo Nordisk, Oligomerix, Ono, Otsuka, PRODEO, ReMYND, Renew, Resverlogix, Roche, Signant Health, Suven, United Neuroscience, and Unlearn AI pharmaceutical, assessment, and investment companies. J.C. is supported by NIGMS grant P20GM109025. NINDS grant U01NS093334. NIA grant R01AG053798. NIA grant P20AG068053. NIA grant R35AG71476. and the Alzheimer's Disease Drug Discovery Foundation (ADDF). J.C. owns the copyright of the Neuropsychiatric Inventory. G.L. is a full‐time employee of Biogen. K.Z. is the CEO of CNS Innovations. Y.Z. and J.F. declare no competing interests. F.C. is supported by the NIA under Award Numbers U01AG073323, R01AG076448, R01AG082211, R01AG066707, 3R01AG066707‐01S1, 3R01AG066707‐02S1, R56AG074001, and R35AG71476. F.C. declares no other competing interests. Author disclosures are available in thesupporting information.

Not applicable. All data are from an anonymized publicly available clinical trial registry (ClinicalTrials.gov). No individual patient‐level data are available on the registry.

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