Document Type
Article
Publication Date
2-1-2026
Original Citation
Cary G,
Wiley J,
Carter GW,
Levey A.
Beyond the streetlight: a TREAT-AD perspective on where to find new Alzheimer's targets. Alzheimers Dement. 2026;22(2):e71142.
Keywords
JMG, Alzheimer Disease, Humans, Clinical Trials as Topic, Brain
JAX Source
Alzheimers Dement. 2026;22(2):e71142.
ISSN
1552-5279
PMID
41685448
DOI
https://doi.org/10.1002/alz.71142
Grant
Data collection was supported through funding by NIA grants P50 AG016574, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216, R01 AG003949, National Institute of Neurological Disorders and Stroke (NINDS) grant R01 NS080820, CurePSP Foundation, and support from Mayo Foundation. The Brain and Body Donation Program is supported by the NINDS (U24 NS072026 National Brain and Tissue Resource for Parkinson’s Disease and Related Disorders), the NIA (P30 AG19610 Arizona Alzheimer’s Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer’s Research Cen- ter), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901, and 1001 to the Arizona Parkinson’s Disease Consor- tium), and the Michael J. Fox Foundation for Parkinson’s Research. Religious Orders Study/Memory and Aging Project (ROSMAP). This work was supported by the US National Institutes of Health (U01 AG046152, R01 AG043617, R01 AG042210, R01 AG036042, R01 AG036836, R01 AG032990, R01 AG18023, RC2 AG036547, P50 AG016574, U01 ES017155, KL2 RR024151, K25 AG041906-01, R01 AG30146, P30 AG10161, R01 AG17917, R01 AG15819, K08 AG034290, P30 AG10161, and R01 AG11101). Mount Sinai Brain Bank (MSBB): This work was supported by grants R01AG046170, RF1AG054014, RF1AG057440, and R01AG057907 from the NIH/NIA. R01AG046170 is a component of the AMP-AD Tar- get Discovery and Preclinical Validation Project. Brain tissue collection and characterization was supported by NIH HHSN271201300031C. The research reported in this manuscript was carried out by the Emory-Sage-SGC-JAX TREAT-AD Center and supported by NIA grant U54AG065187.
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.
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.