Identifying individuals with non‐Alzheimer's disease co‐pathologies: A precision medicine approach to clinical trials in sporadic Alzheimer's disease

INTRODUCTION Biomarkers remain mostly unavailable for non‐Alzheimer's disease neuropathological changes (non‐ADNC) such as transactive response DNA‐binding protein 43 (TDP‐43) proteinopathy, Lewy body disease (LBD), and cerebral amyloid angiopathy (CAA). METHODS A multilabel non‐ADNC classifier using magnetic resonance imaging (MRI) signatures was developed for TDP‐43, LBD, and CAA in an autopsy‐confirmed cohort (N = 214). RESULTS A model using demographic, genetic, clinical, MRI, and ADNC variables (amyloid positive [Aβ+] and tau+) in autopsy‐confirmed participants showed accuracies of 84% for TDP‐43, 81% for LBD, and 81% to 93% for CAA, outperforming reference models without MRI and ADNC biomarkers. In an ADNI cohort (296 cognitively unimpaired, 401 mild cognitive impairment, 188 dementia), Aβ and tau explained 33% to 43% of variance in cognitive decline; imputed non‐ADNC explained an additional 16% to 26%. Accounting for non‐ADNC decreased the required sample size to detect a 30% effect on cognitive decline by up to 28%. DISCUSSION Our results lead to a better understanding of the factors that influence cognitive decline and may lead to improvements in AD clinical trial design.