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INTRODUCTION New therapies to prevent or delay the onset of symptoms, slow progression, or improve cognitive and behavioral symptoms of Alzheimer's disease (AD) are needed. METHODS We interrogated clinicaltrials.gov including all clinical trials assessing pharmaceutical therapies for AD active in on January 1, 2024. We used the Common Alzheimer's Disease Research Ontology (CADRO) to classify the targets of therapies in the pipeline. RESULTS There are 164 trials assessing 127 drugs across the 2024 AD pipeline. There were 48 trials in Phase 3 testing 32 drugs, 90 trials in Phase 2 assessing 81 drugs, and 26 trials in Phase 1 testing 25 agents. Of the 164 trials, 34% (N = 56) assess disease‐modifying biological agents, 41% (N = 68) test disease‐modifying small molecule drugs, 10% (N = 17) evaluate cognitive enhancing agents, and 14% (N = 23) test drugs for the treatment of neuropsychiatric symptoms. DISCUSSION Compared to the 2023 pipeline, there are fewer trials (164 vs. 187), fewer drugs (127 vs. 141), fewer new chemical entities (88 vs. 101), and a similar number of repurposed agents (39 vs. 40). Highlights In the 2024 Alzheimer's disease drug development pipeline, there are 164 clinical trials assessing 127 drugs. The 2024 Alzheimer's disease drug development pipeline has contracted compared to the 2023 Alzheimer pipeline with fewer trials, fewer drugs, and fewer new chemical entities. Drugs in the Alzheimer's disease drug development pipeline target a wide array of targets; the most common processes targeted include neurotransmitter receptors, inflammation, amyloid, and synaptic plasticity. The total development time for a potential Alzheimer's disease therapy to progress from nonclinical studies to FDA review is approximately 13 years.

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.

Introduction The number of individuals worldwide with Alzheimer's disease (AD) is growing at a rapid rate. New treatments are urgently needed. We review the current pipeline of drugs in clinical trials for the treatment of AD. Methods We interrogated ClinicalTrials.gov, the federal registry of clinical trials to identify drugs in trials. Results There are 126 agents in 152 trials assessing new therapies for AD: 28 treatments in Phase 3 trials, 74 in Phase 2, and 24 in Phase 1. The majority of drugs in trials (82.5%) target the underlying biology of AD with the intent of disease modification; 10.3% are putative cognitive enhancing agents; and 7.1% are drugs being developed to reduce neuropsychiatric symptoms. Discussion This pipeline analysis shows that target biological processes are more diversified, biomarkers are more regularly used, and repurposed agents are being explored to determine their utility for the treatment of AD.

Introduction Alzheimer's disease (AD) represents a global health crisis. Treatments are needed to prevent, delay the onset, slow the progression, improve cognition, and reduce behavioral disturbances of AD. We review the current clinical trials and drugs in development for the treatment of AD. Methods We searched the governmental website clinicaltrials.gov where are all clinical trials conducted in the United States must be registered. We used artificial intelligence (AI) and machine learning (ML) approaches to ensure comprehensive detection and characterization of trials and drugs in development. We use the Common Alzheimer's Disease Research Ontology (CADRO) to classify drug targets and mechanisms of action of drugs in the pipeline. Results As of January 25, 2022 (index date for this study) there were 143 agents in 172 clinical trials for AD. The pipeline included 31 agents in 47 trials in Phase 3, 82 agents in 94 trials in Phase 2, and 30 agents in 31 trials in Phase 1. Disease‐modifying therapies represent 83.2% of the total number of agents in trials; symptomatic cognitive enhancing treatments represent 9.8% of agents in trials; and drugs for the treatment of neuropsychiatric symptoms comprise 6.9%. There is a diverse array of drug targets represented by agents in trials including nearly all CADRO categories. Thirty‐seven percent of the candidate agents in the pipeline are repurposed drugs approved for other indications. A total of 50,575 participants are needed to fulfill recruitment requirements for all currently active clinical trials. Discussion The AD drug development pipeline has agents representing a substantial array of treatment mechanisms and targets. Advances in drug design, outcome measures, use of biomarkers, and trial conduct promise to accelerate the delivery of new and better treatments for patients with AD. Highlights There are 143 drugs in the current Alzheimer's disease (AD) drug development pipeline. Disease‐modifying therapies represent 83.2% of the candidate treatments. Current trials require 50,575 participants who will donate 3,878,843 participant‐weeks to clinical trials. The biopharmaceutical industry sponsors 50% of all clinical trials including 68% of Phase 3 trials. Sixty‐three percent of Phase 3 trials and 46% of Phase 2 trials include non–North American clinical trial site locations indicating the global ecosystem required for AD drug development.

Introduction Alzheimer's disease (AD) is a growing public health concern affecting millions of patients worldwide and costing billions of dollars annually. We review the pipeline of drugs and biologics in clinical trials for the treatment of AD. We use the Common Alzheimer's and Related Dementias Research Ontology (CADRO) to classify treatment targets and mechanisms of action. We review our annual pipeline reports for the past 5 years to provide longitudinal insight into clinical trials and drug development for AD. Methods We reviewed ClinicalTrials.gov as of February 27, 2020, and identified all trials of pharmacologic agents currently being developed for treatment of AD as represented on this widely used U.S. Food and Drug Administration registry. Results There are 121 agents in clinical trials for the treatment of AD. Twenty‐nine agents are in 36 Phase 3 trials, 65 agents are in 73 Phase 2 trials, and 27 agents are in 27 Phase 1 trials. Twelve agents in trials target cognitive enhancement and 12 are intended to treat neuropsychiatric and behavioral symptoms. There are 97 agents in disease modification trials. Compared to the 2019 pipeline, there is an increase in the number of disease‐modifying agents targeting pathways other than amyloid or tau. Discussion The 2020 pipeline has innovations in clinical trials and treatment targets that provide hope for greater success in AD drug development programs. Review of clinical trials over the past 5 years show that there is progressive emphasis on non‐amyloid targets, including candidate treatments for inflammation, synapse and neuronal protection, vascular factors, neurogenesis, and epigenetic interventions. There has been a marked growth in repurposed agents in the pipeline.

Clinical trials for Alzheimer's disease (AD) must be registered on clinicaltrials.gov. The registry presents a variety of types of information related to the planned clinical trial. We assess clinicaltrials.gov to document and compare aspects of drug development across the AD pipeline. Currently, there are 138 drugs being assessed in 182 clinical trials in the AD pipeline. Biological disease‐targeted therapies (DTTs) comprise 30% of the pipeline; small molecule DTTs account for 43% of the pipeline; drugs addressing cognitive enhancement account for 14% of the pipeline; and drugs aiming to ameliorate neuropsychiatric symptoms in participants with AD contribute 11% of the pipeline. Biomarkers are among the primary outcomes of 27% of active trials. Repurposed agents represent 33% of the pipeline agents. The pipeline has more trials and more drugs compared to the 2024 pipeline. Highlights The 2025 Alzheimer's disease drug development pipeline hosts 182 trials and 138 novel drugs. The 2025 Alzheimer's disease drug development pipeline is diverse, with agents that address 15 basic disease processes. The 2025 Alzheimer's disease drug development pipeline has more trials and more drugs than the 2024 pipeline. Biomarkers play an important role in current trials to determine trial eligibility and as outcomes of trials. Repurposed agents comprise approximately one‐third of the agents and trials in the 2025 Alzheimer's disease drug development pipeline.

Biomarkers are vital to Alzheimer's disease (AD) drug development and clinical trials, and will have an increasing role in clinical care. In this narrative review, we demonstrate the use of the National Institutes on Aging/Alzheimer's Association (NIA/AA) Common Alzheimer's Disease Research Ontology (CADRO) system for the categorization of biomarkers based on the primary mechanism on which they report. We show that biomarkers are available (in various levels of validation) for all CADRO processes. Application of the CADRO system demonstrates gaps in the field where novel biomarkers are needed for specific aspects of the disease, and assays to detect and measure biological changes, in individuals with symptomatic or preclinical AD. We demonstrate the CADRO system as a means of categorizing established and candidate AD biomarkers, showing the feasibility and practicality of the system. CADRO can assist with biomarker selection for AD clinical trials and drug development, and may eventually be applied to implementing biomarkers in patient care.  Highlights The Common Alzheimer's Disease Research Ontology (CADRO) system can be used to categorize biomarkers for drug development. We demonstrate the use of CADRO with Alzheimer's disease (AD) biomarkers. We identified AD biomarkers in each of the CADRO categories. CADRO can be incorporated into current AD drug development and clinical trial systems.

The role of microglial cells in the development and progression of Alzheimer’s disease (AD) has not been elucidated. Here, we demonstrated the existence of a weak microglial response in human AD hippocampus which is in contrast to the massive microglial activation observed in APP-based models. Most importantly, microglial cells displayed a prominent degenerative profile (dentate gyrus > CA3 > CA1 > parahippocampal gyrus), including fragmented and dystrophic processes with spheroids, a reduced numerical density, and a significant decrease in the area of surveillance (“microglial domain”). Consequently, there was a substantial decline in the area covered by microglia which may compromise immune protection and, therefore, neuronal survival. In vitro experiments demonstrated that soluble fractions (extracellular/cytosolic) from AD hippocampi were toxic for microglial cells. This toxicity was abolished by AT8 and/or AT100 immunodepletion, validating that soluble phospho-tau was the toxic agent. These results were reproduced using soluble fractions from phospho-tau-positive Thy-tau22 hippocampi. Cultured microglial cells were not viable following phagocytosis of SH-SY5Y cells expressing soluble intracellular phospho-tau. Because the phagocytic capacity of microglial cells is highly induced by apoptotic signals in the affected neurons, we postulate that accumulation of intraneuronal soluble phospho-tau might trigger microglial degeneration in the AD hippocampus. This microglial vulnerability in AD pathology provides new insights into the immunological mechanisms underlying the disease progression and highlights the need to improve or develop new animal models, as the current models do not mimic the microglial pathology observed in the hippocampus of AD patients.

Multifactorial diseases are characterized by inter-individual variation in etiology, age of onset, and penetrance. These diseases tend to be relatively common and arise from the combined action of genetic and environmental factors; however, parsing the convoluted mechanisms underlying these gene-by-environment interactions presents a significant challenge to their study and management. For neurodegenerative disorders, resolving this challenge is imperative, given the enormous health and societal burdens they impose. The mechanisms by which genetic and environmental effects may act in concert to destabilize homeostasis and elevate risk has become a major research focus in the study of common disease. Emphasis is further being placed on determining the extent to which a unifying biological principle may account for the progressively diminishing capacity of a system to buffer disease phenotypes, as risk for disease increases. Data emerging from studies of common, neurodegenerative diseases are providing insights to pragmatically connect mechanisms of genetic and environmental risk that previously seemed disparate. In this review, we discuss evidence positing inflammation as a unifying biological principle of homeostatic destabilization affecting the risk, onset, and progression of neurodegenerative diseases. Specifically, we discuss how genetic variation associated with Alzheimer disease and Parkinson disease may contribute to pro-inflammatory responses, how such underlying predisposition may be exacerbated by environmental insults, and how this common theme is being leveraged in the ongoing search for effective therapeutic interventions.

Aβ (beta-amyloid peptide) is an important contributor to Alzheimer's disease (AD). We modeled Aβ toxicity in yeast by directing the peptide to the secretory pathway. A genome-wide screen for toxicity modifiers identified the yeast homolog of phosphatidylinositol binding clathrin assembly protein (PICALM) and other endocytic factors connected to AD whose relationship to Aβ was previously unknown. The factors identified in yeast modified Aβ toxicity in glutamatergic neurons of Caenorhabditis elegans and in primary rat cortical neurons. In yeast Aβ impaired the endocytic trafficking of a plasma membrane receptor, which was ameliorated by endocytic pathway factors identified in the yeast screen. Thus, links between Aβ, endocytosis, and human AD risk factors can be ascertained with yeast as a model system.