👤 Gil D Rabinovici

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

The spatial progression of longitudinal tau pathology has been inferred using cross-sectional data, but longitudinal voxel-wise analyses allow these patterns to be established without inference. We pooled 1426 flortaucipir (FTP) positron emission tomography (PET) scans from 583 participants across the aging and Alzheimer's disease (AD) spectrum from four studies. Using longitudinal tau-PET slope maps, we examined tau accumulation by clinical group and its associations with participant characteristics, baseline beta-amyloid (Aβ), and tau. Tau accumulation was limited to temporoparietal cortices in unimpaired participants but widespread in patients. Baseline Aβ, entorhinal, and inferior temporal tau predicted progressively more severe tau accumulation patterns. Age, sex, and apolipoprotein E (APOE) ε4 had modest moderating effects. Aβ and early tau interactions showed synergistic effects. Greater tau accumulation was linked to worse follow-up cognition than baseline. While Aβ influences early tau progression, baseline tau drives later progression. These results may guide future trials targeting tau accumulation at different disease stages. Faster tau spread from temporal to frontal lobes was linked to clinical impairment. Global beta-amyloid (Aβ), entorhinal, and inferior temporal gyrus (ITG) tau predicted progressively worse tau accumulation. Age, sex, and apolipoprotein E (APOE) had minimal effects on tau accumulation. Aβ and early tau burden interact synergistically to drive tau accumulation. More severe tau accumulation was linked to worse cognition at follow-up than baseline. Show less

Cardiovascular (CV)- and lifestyle-associated risk factors (RFs) are increasingly recognized as important for Alzheimer's disease (AD) pathogenesis. Beyond the ε4 allele of apolipoprotein E (APOE), comparatively little is known about whether CV-associated genes also increase risk for AD. Using large genome-wide association studies and validated tools to quantify genetic overlap, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with AD and one or more CV-associated RFs, namely body mass index (BMI), type 2 diabetes (T2D), coronary artery disease (CAD), waist hip ratio (WHR), total cholesterol (TC), triglycerides (TG), low-density (LDL) and high-density lipoprotein (HDL). In fold enrichment plots, we observed robust genetic enrichment in AD as a function of plasma lipids (TG, TC, LDL, and HDL); we found minimal AD genetic enrichment conditional on BMI, T2D, CAD, and WHR. Beyond APOE, at conjunction FDR < 0.05 we identified 90 SNPs on 19 different chromosomes that were jointly associated with AD and CV-associated outcomes. In meta-analyses across three independent cohorts, we found four novel loci within MBLAC1 (chromosome 7, meta-p = 1.44 × 10 Show less