Mol Psychiatry. 2026 Apr 27. doi: 10.1038/s41380-026-03617-0. Online ahead of print.
ABSTRACT
Preventing Alzheimer's disease (AD) requires early-warning biomarkers. We developed a Regional Vulnerability Index (RVI) that quantifies individual brain similarity to AD patients' expected brain deficit patterns. We calculated regional effect sizes to establish brain deficit patterns in amyloid-positive AD cases compared to amyloid-negative healthy controls. RVI-AD was calculated as a linear index of individual similarity to this established brain pattern in AD. We demonstrated RVI-AD elevation associated with risk factors in 335 participants (mean age: 49 ± 13 years) in the Amish Connectome Project, followed by an independent sample consisting of 26,010 participants (mean age: 64 ± 7 years) from the UK Biobank. Genetic and cardiovascular risks were evaluated using APOE-e4 genotype and Framingham Cardiovascular Risk Scores (FCVRS), respectively. Additionally, we assessed the risk of converting from MCI to dementia in N = 1932 participants (mean age: ~74) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Healthy participants with the APOE-e4 allele had significantly elevated RVI-AD indices (p = 0.03 and 2·10-5, for ACP and UKBB samples respectively). FCVRS significantly contributed to higher RVI-AD in an interaction with APOE-e4-specific manner (p = 2·10-4 and 7·10-6 for ACP and UKBB samples respectively). In ADNI cohort, RVI-AD significantly predicted conversion from MCI to dementia in the next decade, particularly in the first three years (AUC = 70-74%, OR = 2.16, 95% CI = 1.8-2.6, p < 10-16). In healthy individuals, the RVI-AD detected the insidious impact of APOE-ε4 and cardiovascular risks in otherwise normally aging cohorts. Elevated RVI-AD also predicted conversion to dementia within ten years in the older, high-risk cohort. Further development of this brain-pattern similarity-based approach may yield a noninvasive, clinically accessible biomarker to aid early detection of the subtle to more imminent effects of AD risks.
PMID:42045435 | DOI:10.1038/s41380-026-03617-0