👤 Kelly N Nudelman

Alzheimer's disease (AD) pathology disrupts functional brain connectivity long before symptoms emerge. African Americans face elevated AD risk, yet underlying mechanisms remain unclear. Genetic risk differs by ancestry: APOE-ε4 strongly predicts late-onset AD in European ancestry, whereas ABCA7 rs115550680 confers substantial risk in African ancestry. Yet, how these variants influence neural function in African Americans is unclear. The medial temporal lobe (MTL) is an early target of AD pathology and resting-state functional Magnetic Resonance Imaging (rs-fMRI) measures of dynamic network connectivity (hereafter "flexibility"), the brain's capacity to dynamically reconfigure connectivity, provide a sensitive metric of network adaptability, potentially preceding structural decline. However, comparative influence of APOE-ε4 and ABCA7 rs115550680 on MTL flexibility and subregional volumes in this population is unknown. 146 older African Americans (Mean Show less

The genetic basis of sporadic early-onset Alzheimer's disease (EOAD) remains largely unknown, prompting evaluation of late-onset Alzheimer's disease (LOAD) polygenic risk in EOAD. A LOAD polygenic score (PGS) was calculated in the Longitudinal Early-onset Alzheimer's Disease Study (LEADS) and Alzheimer's Disease Neuroimaging Initiative (ADNI) study and tested for associations with AD risk, cognitive performance, and imaging and fluid biomarkers. Though PGS was elevated in LOAD and EOAD, it was not a significant predictor of EOAD adjusting for APOE ε4 carrier status and was not associated with age of EOAD onset (p = 0.106) or with cognitive performance (p = 0.417). In LEADS, greater LOAD PGS was associated with differences in neuroimaging and fluid biomarkers, including elevated synaptosomal-associated protein 25 (SNAP-25) (p = 2.3 × 10 While LOAD polygenic risk contributed minimally to EOAD onset and cognitive dysfunction, PGS association with fluid biomarkers in LEADS suggests a role for LOAD polygenic risk in EOAD pathophysiology. LOAD PGSs were elevated in both LOAD and EOAD compared to controls; however, LOAD PGS did not significantly predict EOAD risk, age at onset, or cognitive performance independent of APOE ε4 in the LEADS. Higher LOAD PGS was associated with lower amyloid PET Centiloids (less brain amyloid deposition) as well as lower CSF biomarker Aβ42 in LEADS (proxy marker suggesting higher brain amyloid deposition) in LEADS; these contradictory findings support the need for larger studies to further investigate whether LOAD PGS is associated with increased amyloid deposition in EOAD. Higher LOAD PGS was also associated with higher levels of CSF synaptosomal-associated protein 25 (SNAP-25), a key component of the SNARE complex, suggesting that LOAD genetic factors may contribute to dysregulation of synaptic transmission and/or pathological protein aggregation in EOAD. Show less