👤 Murat Bilgel

The APOE-ε4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease. However, APOE-ε4 is not deterministic, highlighting the need to identify additional genetic and environmental factors. APOE-ε4 has been linked to accelerated cognitive decline, so we sought to investigate genetic factors that modify APOE-ε4-associated cognitive decline. We conduct cross-ancestry APOE-ε4-stratified and interaction GWAS using harmonized cognitive data from 32,778 participants, including 29,354 non-Hispanic White and 3,424 non-Hispanic Black individuals. Our primary outcome is late-life cognition, measured using harmonized composite scores for memory, executive function, and language, modeled as continuous traits reflecting both normative cognitive aging and disease-related decline. We identify two genome-wide significant loci in APOE-ε4 carriers, reaching genome-wide significance for executive function. These loci also demonstrate nominal associations across the other domains, suggesting broad effects on cognition. In non-carriers, we identify a genome-wide significant association at ITGB8 restricted to executive function, and another locus associated with language. We further link these loci to SEMA6D, GRIN3A, and ITGB8 through expression and methylation databases. Post-GWAS analyses implicate additional genes including SLCO1A2, and DNAH11. Genetic correlation analyses reveal differences by APOE-ε4 status for immune-related traits, suggesting immune-related predispositions may exacerbate cognitive risk in APOE-ε4 carriers. Show less

New methods estimate amyloid positivity onset age (EAOA) from amyloid positron emission tomography (PET). We explore the genetics of EAOA to identify molecular factors underlying the earliest Alzheimer's disease (AD) changes. Harmonized amyloid PET data from 4216 participants were used in genome-wide survival, tissue-specific gene expression, and genetic covariance analyses of EAOA. Variants in apolipoprotein E (APOE), ABCA7, and RASGEF1C associated with earlier EAOA. APOE ε4/ε4 and ε3/ε4 converted 6.3 and 5 years earlier than ε3/ε3, respectively. ε2 was protective against earlier EAOA. rs4147929, an expression quantitative trait locus for ABCA7, associated with a 4 year earlier EAOA. This variant was associated with lower brain expression of ABCA7, which was associated with increased amyloid pathology at autopsy. Multiple immune-related diseases shared genetic covariance with EAOA. APOE, ABCA7, and RASGEF1C associated with earlier EAOA, with supporting evidence from tissue-specific expression analyses, offering insights into intervenable targets at early stages of AD. Novel methods estimate how long ago a patient converted to amyloid positivity. Estimating this amyloid clock allows us to determine the onset of the earliest Alzheimer's disease changes. We evaluated what genes influence when someone converts to amyloid positivity. Apolipoprotein E (APOE), ABCA7, and RASGEF1C associated with earlier age of amyloid positivity. Genetic results were supported by tissue-specific expression analyses. Show less

Prior studies have demonstrated the existence of cognitively-defined subgroups among dementia free older adults, however, it is unclear whether such subgroups are characterized by distinct neuroimaging measures of brain function and structure. To address this gap, the current study used latent profile analysis (LPA) to identify cognitively-defined subgroups in a sample of 167 (mean age = 69 years) dementia-free older adults with cognitive testing, amyloid PET, and multimodal brain MRI scans. The cognitive test scores covered the domains of episodic memory, executive function, language, and visuospatial processing. Linear regression models tested the associations between subgroup membership and neuroimaging measures, adjusting for age, sex, and years of education. Based on the LPA, three cognitive subgroups were identified: (1) high-average cognition (n = 61, 36%), (2) average cognition (n = 88, 53%), and low-average cognition (n = 18, 11%). Compared to the high-average group, the low-average group had lower volumes in cortical regions sensitive to Alzheimer's disease, lower global white matter microstructural integrity measured by diffusion tensor imaging, and higher global white matter hyperintensity burden. There were no group differences in global PET amyloid burden. Additionally, the high-average group tended to have higher resting-state functional connectivity within large-scale cognitive networks than the other two groups. These results suggest that cognitively-defined subgroups among older adults without dementia are associated with several measures of brain structure and function. Evaluating brain structure/function differences among dementia-free older adults may help identify individuals at greatest risk for future cognitive decline. Show less