Exploring common genetic contributors to neuroprotection from amyloid pathology.


Preclinical Alzheimer's disease describes some individuals who harbour Alzheimer's pathologies but are asymptomatic. For this study, we hypothesized that genetic variation may help protect some individuals from Alzheimer's-related neurodegeneration. We therefore conducted a genome-wide association study using 5 891 064 common variants to assess whether genetic variation modifies the association between baseline beta-amyloid, as measured by both cerebrospinal fluid and positron emission tomography, and neurodegeneration defined using MRI measures of hippocampal volume. We combined and jointly analysed genotype, biomarker and neuroimaging data from non-Hispanic white individuals who were enrolled in four longitudinal ageing studies ( = 1065). Using regression models, we examined the interaction between common genetic variants (Minor Allele Frequency >0.01), including -ɛ4 and -ɛ2, and baseline cerebrospinal levels of amyloid (CSF Aβ42) on baseline hippocampal volume and the longitudinal rate of hippocampal atrophy. For targeted replication of top findings, we analysed an independent dataset ( = 808) where amyloid burden was assessed by Pittsburgh Compound B ([C]-PiB) positron emission tomography. In this study, we found that -ɛ4 modified the association between baseline CSF Aβ42 and hippocampal volume such that -ɛ4 carriers showed more rapid atrophy, particularly in the presence of enhanced amyloidosis. We also identified a novel locus on chromosome 3 that interacted with baseline CSF Aβ42. Minor allele carriers of rs62263260, an expression quantitative trait locus for the gene ( = 1.46 × 10; 3:122675327) had more rapid neurodegeneration when amyloid burden was high and slower neurodegeneration when amyloid was low. The rs62263260 × amyloid interaction on longitudinal change in hippocampal volume was replicated in an independent dataset ( = 0.0112) where amyloid burden was assessed by positron emission tomography. In addition to supporting the established interaction between and amyloid on neurodegeneration, our study identifies a novel locus that modifies the association between beta-amyloid and hippocampal atrophy. Annotation results may implicate , a gene involved in synaptic pruning and axonal guidance, as a high-quality candidate for functional confirmation and future mechanistic analysis.