Alzheimer’s disease drug development pipeline: 2023
Open accessAbstract
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.
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Aβ deposition can precede cognitive decline, and a preclinical stage with neuropathologic changes and positive biomarkers of AD pathology, including Aβ and tau, can last many years or decades without symptoms.
“As amyloid beta (Aβ) deposition can precede cognitive decline, a preclinical stage with neuropathologic changes, positive biomarkers of AD pathology, including Aβ and tau, can last many years or decades without any symptoms.”
From Treatment of Alzheimer’s Disease: Beyond Symptomatic Therapies (2023) · cites this paper as [3]
The Introduction describes preclinical AD as normal cognition with biomarkers consistent with AD pathology and an increased risk of later cognitive impairment. The Results section on biomarkers identifies amyloid and tau measures, but the paper does not establish that this symptom-free stage lasts many years or decades. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIn phase III clinical trials, 15 of 36 DMT agents are small molecules, representing 42% of total DMT agents.
“Fifteen agents of the 36 in phase III are small molecules and represent 42% of the total DMT agents [3]”
From Treatment of Alzheimer’s Disease: Beyond Symptomatic Therapies (2023) · cites this paper as [3]
The Results (Phase 3) report 36 agents in Phase 3, including 24 DMTs and 15 small-molecule DMTs. The 42% figure is the share of all 36 Phase 3 agents, not the share of DMT agents; the claim incorrectly describes all 36 as DMTs. (LLM, conf=0.90)
Experimental — accuracy not yet measuredGlucose metabolism amelioration in the CNS is supposed to improve cognitive decline in early and late amnestic MCI patients or prevent cognitive decline in obese people.
“Glucose metabolism amelioration in the Central Nervous System (CNS) is supposed to improve the cognitive decline of early and late amnestic Mild Cognitive Impairment patients or prevent the cognitive decline in obese people [3,105,106].”
From Treatment of Alzheimer’s Disease: Beyond Symptomatic Therapies (2023) · cites this paper as [3]
The Results (Phase 2; page unavailable) list insulin-based therapies intended to reduce glucose resistance and increase insulin signaling in the brain, and the Methods identify metabolism as a potential AD treatment target. The paper does not say that improving CNS glucose metabolism would improve cognitive decline in early or late amnestic MCI, or prevent decline in people with obesity. (LLM, conf=0.83)
Experimental — accuracy not yet measuredAs of January 1, 2023, 156 clinical trials were underway testing additional disease-modifying therapies.
“As of January 1, 2023, 156 clinical trials were underway testing additional disease‐modifying therapies.”
From 2024 Alzheimer's disease facts and figures (2024) · cites this paper as [62]
The Results > Overview reports ongoing Alzheimer’s trials as of January 1, 2023, and identifies disease-modifying therapies as the most common agents studied. It reports 187 trials assessing all treatment types, but does not support the claimed count of 156 trials testing disease-modifying therapies. (LLM, conf=0.85)
Experimental — accuracy not yet measuredAs of January 1, 2023, 31 clinical trials were underway testing additional agents to treat Alzheimer's cognitive, behavioral and neuropsychiatric symptoms.
“As of January 1, 2023, 31 clinical trials were underway testing additional agents to treat Alzheimer's cognitive, behavioral and neuropsychiatric symptoms.”
From 2024 Alzheimer's disease facts and figures (2024) · cites this paper as [62]
The Results Overview reports that, as of January 1, 2023, the pipeline included agents for cognitive enhancement and neuropsychiatric symptoms. But it counts 30 unique symptomatic agents, not 31 clinical trials testing them; its figure of 31 refers to Phase 1 agents, most of which were disease-modifying therapies. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Current FDA-approved treatments offer modest symptomatic benefit or partial slowing of progression but do not halt neurodegeneration or restore lost neuronal circuits.
“Current FDA-approved treatments, including cholinesterase inhibitors, memantine, and anti-amyloid monoclonal antibodies, offer modest symptomatic benefit or partial slowing of progression but do not halt neurodegeneration or restore lost neuronal circuits.”
From Reverse the progression of Alzheimer’s disease through Nano-ERASER-based adult neuroregeneration (2026) · cites this paper as [4]
The Discussion (page unavailable) identifies aducanumab and lecanemab as FDA-approved therapies and describes their anticipated clinical benefit as slowing disease progression. The Methods (page unavailable) distinguish symptomatic treatment from disease modification. Our copy does not establish the claimed modest benefit for cholinesterase inhibitors or memantine, or explicitly address whether approved treatments halt neurodegeneration or restore lost neuronal circuits. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe 2024 AD drug development pipeline includes 164 trials, of which 127 are exploring possible treatments or medicines.
“The most recent list of studies was provided by the 2024 AD drug development pipeline, which includes 164 trials (of which 127 are exploring possible treatments or medicines).”
From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [71]
Of these trials, 41% look into disease-modifying small molecule medications, 34% look into biological agents that change disease, and the remaining trials focus on treatments that improve cognitive function or address neuropsychiatric symptoms linked to AD.
“Of these trials, 41% look into disease-modifying small molecule medications, 34% look into biological agents that change disease, and the remaining trials focus on treatments that improve cognitive function or address neuropsychiatric symptoms linked to ADs [68,70,71,182,183,184].”
From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [71]
Anti-amyloid monoclonal antibodies aducanumab, lecanemab, and donanemab have been approved by the US Food and Drug Administration for Alzheimer's disease.
“with the approval by the US Food and Drug Administration (FDA) of the anti-amyloid monoclonal antibodies aducanumab, lecanemab, and donanemab [11, 12].”
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- Authors
- Cummings, J., Zhou, Y., Lee, G., Zhong, K., Fonseca, J., & Cheng, F.
- Affiliations
- University of Nevada, Las Vegas (US)
- Cleveland Clinic (US)
- Department of Molecular Medicine Cleveland Clinic Lerner College of Medicine Case Western Reserve University Cleveland Ohio USA
- Corresponding author
- Cummings, Jeffrey
- Venue
- Alzheimer's & Dementia: Translational Research & Clinical Interventions
- Publisher
- Wiley
- Published
- 2023-04
- Volume
- 9
- Issue
- 2
- Pages
- e12385-e12385
- ISSN
- 2352-8737 (ISSN-L)
- PMC
- PMC10210334
- OpenAlex
- W4378219872
- Cited by
- 477
- References
- 21
- Citations by year
- 2026: 62 · 2025: 125 · 2024: 205 · 2023: 54 · 2022: 3 · 2021: 11 · 2020: 9 · 2019: 6 · 2018: 2
- FWCI
- 79.20
- Type
- journal article
- Language
- en
- Update notices
- erratum (2023-06-28)
- Open access
- gold
- doi.org
- Licence
- Locations
- Alzheimer s & Dementia Translational Research & Clinical Interventions (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institute of General Medical Sciences (P20GM109025)
- National Institute of Neurological Disorders and Stroke (U01NS093334)
- National Institute on Aging (R01AG053798, P20AG068053, R35AG71476)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Keywords
- Alzheimer's disease, drug development pipeline, clinical trials, disease-modifying therapy, mild cognitive impairment, drug repurposing, treatment goals, drug mechanisms
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