Genetic Resilience and Resistance in Alzheimer's Disease Diagnosis and Pathology.
OBJECTIVE Some individuals avoid Alzheimer's disease (AD) pathology as they age, or retain cognition despite substantial pathology, suggesting mechanisms of resistance or resilience to neurodegeneration. Educational attainment (EA) is associated with reduced risk of cognitive decline, although the underlying mechanisms remain unclear. We investigated whether genome-wide polygenic scores (GPS) based on cognitive and non-cognitive components of EA, reflecting intelligence and behavioral/social traits, respectively, show differential associations with AD diagnosis and neuropathology. METHODS Associations between GPS for cognitive and non-cognitive components of EA and AD outcomes were examined across four cohorts: two cohorts included living participants with biomarker assessments (BioHermes-1, n = 770; Alzheimer's Disease Neuroimaging Initiative [ADNI], n = 1,361), and two included postmortem neuropathological evaluations (Religious Orders Study and Rush Memory and Aging Project [ROSMAP], n = 841; Brain for Dementia Research [BDR], n = 511). Outcomes included clinical diagnosis, amyloid status, plasma neurodegenerative biomarkers, and neuropathological measurements. RESULTS We found a significant negative association between cognitive EA GPS and clinical diagnosis of AD across all four cohorts and with Braak stage in ROSMAP and BDR cohorts. In contrast, the GPS for non-cognitive component of EA showed no significant association with AD diagnosis, neurodegenerative plasma biomarkers or amyloid positron emission tomography (PET) status and the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) scores. INTERPRETATION These results suggest a brain maintenance mechanism that supports the brain's ability to resist to changes in neuronal integrity. This indicates that interventions focused on increasing EA solely by additional years of schooling are unlikely to affect AD incidence, whereas alternative approaches targeting the cognitive component of EA (intelligence) may offer greater potential for prevention. ANN NEUROL 2026.