Beyond the streetlight: a TREAT‐AD perspective on where to find new Alzheimer's targets
Year: 2026
Type: article
Abstract: Despite extensive investments in Alzheimer's disease (AD) therapeutic development, progress toward effective interventions remains modest. The landscape of potential novel therapeutic strategies is rapidly growing, but prioritization, validation, and tools to advance targets to trial are lagging. The Target Enablement to Accelerate Therapy Development for Alzheimer's Disease (TREAT-AD) consortium has integrated systems-level data from large-scale studies profiling thousands of human brains, yielding target-specific risk scores that partition disease risk into discrete biological domains and enable data-driven target interrogation. Here, we compared clinical trial targets with top-ranked TREAT-AD targets and found a limited overlap as well as differences in the biology emphasized by each set. The current AD therapeutic development landscape remains largely under the "streetlight" of familiar biology, while unbiased measures of disease risk point toward other disease-associated processes that remain comparatively underexplored. These findings underscore opportunities to more deliberately diversify therapeutic portfolios and complement existing development efforts with evidence derived from unbiased human data. HIGHLIGHTS: Clinical AD trials remain focused on well-characterized biology. TREAT-AD integrates genetic and multi-omic data to prioritize novel targets. Limited overlap exists between clinical and high-risk data-driven targets. Risk-associated targets uniquely implicate mitochondrial, lipid, and other pathways. Advancing "dark" targets is critical to diversify AD therapeutic strategies.
Source: Alzheimer s & Dementia
DOI: 10.1002/alz.71142
Institutions: Jackson Laboratory, University of Kansas, Emory University
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,200
Awards: Epidemiologic Study of Neural Reserve and Neurobiology of Aging, Integrative Network Modeling of Cognitive Resilience to Alzheimer's Disease, Integrative analysis of genomic and epigenomic architecture in cognitive decline, Genetic Epidemiology of Cognitive Decline in an Aging Population Sample, Epidemiologic Study of TDP-43 Pathology in Aging and Dementia, Gene discovery in PSP by transcriptome, neuropathology and sequence analysis, Integrative Network Biology Approaches to Identify, Characterize and Validate Molecular Subtypes in Alzheimer's Disease, Molecular Characterization and Validation of Gender Differences in Alzheimers Disease Pathogenesis, Plasma AB as a Surrogate Genetic Marker for LOAD, Exploring the Role of the Brain Transcriptome in Cognitive Decline, Mayo Clinic Center for Translational Science Activities, Pathway discovery, validation and compound identification for Alzheimer's disease, Alzheimers Disease Patient Registry, Einstein Aging Study, Risk Factors for Incident Alzheimer's Disease in a Biracial Community, Exploring the Genetics of Alzheimer's Disease in Humans and Drosophila, Exploring the Role of the Brain Epigenome: Cognitive Decline and Life Experiences, Altered monocyte function in relation to the CD33 Alzheimers disease locus, Risk Factors, Pathology, and Clinical Expressions of AD, Towards a comprehensive signaling pathway map of parahippocampal vulnerability in Alzheimers Disease, Rush Alzheimer's Disease Core Center, Cognitive Decline and Dementia: Life Experiences and the Brain Histone Epigenome, Florida Alzheimer's Disease Research, Genome wide association study of gene expression levels in Alzheimer's disease, Arizona Alzheimer's Disease Core Center, Production sequencing of reference human epigenomes, Tau and Neurodegeneration II: A therapeutic target, A Systems Approach to Targeting Innate Immunity in AD, National Brain and Tissue Resource for Parkinson's Disease and Related Disorders, TREAT AD, Mayo Alzheimer's Disease Research Center
OpenAlex ID: W7128820525