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describes some individuals who harbour Alzheimer\u2019s pathologies but are asymptomatic. For this study, we hypothesized that genetic variation may help protect some individuals from Alzheimer\u2019s-related neurodegeneration. We therefore conducted a genome-wide association study using 5\u2009891\u2009064 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.<\/jats:p>\n               <jats:p>We combined and jointly analysed genotype, biomarker and neuroimaging data from non-Hispanic white individuals who were enrolled in four longitudinal ageing studies (n\u2009=\u20091065). Using regression models, we examined the interaction between common genetic variants (Minor Allele Frequency &amp;gt;0.01), including APOE-\u025b4 and APOE-\u025b2, and baseline cerebrospinal levels of amyloid (CSF A\u03b242) on baseline hippocampal volume and the longitudinal rate of hippocampal atrophy. For targeted replication of top findings, we analysed an independent dataset (n\u2009=\u2009808) where amyloid burden was assessed by Pittsburgh Compound B ([11C]-PiB) positron emission tomography.<\/jats:p>\n               <jats:p>In this study, we found that APOE-\u025b4 modified the association between baseline CSF A\u03b242 and hippocampal volume such that APOE-\u025b4 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 A\u03b242. Minor allele carriers of rs62263260, an expression quantitative trait locus for the SEMA5B gene (P\u2009=\u20091.46\u2009\u00d7\u200910\u22128; 3:122675327) had more rapid neurodegeneration when amyloid burden was high and slower neurodegeneration when amyloid was low. The rs62263260\u2009\u00d7\u2009amyloid interaction on longitudinal change in hippocampal volume was replicated in an independent dataset (P\u2009=\u20090.0112) where amyloid burden was assessed by positron emission tomography.<\/jats:p>\n               <jats:p>In addition to supporting the established interaction between APOE and amyloid on neurodegeneration, our study identifies a novel locus that modifies the association between beta-amyloid and hippocampal atrophy. Annotation results may implicate SEMA5B, a gene involved in synaptic pruning and axonal guidance, as a high-quality candidate for functional confirmation and future mechanistic analysis.<\/jats:p>","DOI":"10.1093\/braincomms\/fcac066","type":"journal-article","created":{"date-parts":[[2022,3,15]],"date-time":"2022-03-15T20:18:25Z","timestamp":1647375505000},"source":"Crossref","is-referenced-by-count":17,"title":["Exploring common genetic contributors to neuroprotection from amyloid pathology"],"prefix":"10.1093","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3377-7014","authenticated-orcid":false,"given":"Mabel","family":"Seto","sequence":"first","affiliation":[{"name":"Vanderbilt Memory and Alzheimer\u2019s Center, Vanderbilt University Medical Center, 1207 17th Ave S, Nashville, TN 37212, USA"},{"name":"Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN 37212, USA"},{"name":"Department of Pharmacology, Vanderbilt University, 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UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaj","family":"Blennow","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, M\u00f6lndal 413 90, Sweden"},{"name":"Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, M\u00f6lndal 413 45, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4286-0589","authenticated-orcid":false,"given":"Prashanthi","family":"Vemuri","sequence":"additional","affiliation":[{"name":"Department of Radiology, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angela L.","family":"Jefferson","sequence":"additional","affiliation":[{"name":"Vanderbilt Memory and Alzheimer\u2019s Center, Vanderbilt University Medical Center, 1207 17th Ave S, Nashville, TN 37212, USA"},{"name":"Department of 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