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We investigate the effect of polygenic risk for coronary artery disease on brain atrophy in Alzheimer\u2019s disease using whole-brain volume and put our findings in context with the polygenic risk for Alzheimer\u2019s disease and presumed small vessel disease as quantified by white-matter hyperintensities. We use 730 subjects from the Alzheimer\u2019s disease neuroimaging initiative database to investigate polygenic risk score effects (beyond APOE) on whole-brain volumes, total and regional white-matter hyperintensities and amyloid beta across diagnostic groups. In a subset of these subjects (N = 602), we utilized longitudinal changes in whole-brain volume over 24 months using the boundary shift integral approach. Linear regression and linear mixed-effects models were used to investigate the effect of white-matter hyperintensities at baseline as well as Alzheimer\u2019s disease-polygenic risk score and coronary artery disease-polygenic risk score on whole-brain atrophy and whole-brain atrophy acceleration, respectively. All genetic associations were examined under the oligogenic (P = 1e-5) and the more variant-inclusive polygenic (P = 0.5) scenarios. Results suggest no evidence for a link between the polygenic risk score and markers of Alzheimer\u2019s disease pathology at baseline (when stratified by diagnostic group). However, both Alzheimer\u2019s disease-polygenic risk score and coronary artery disease-polygenic risk score were associated with longitudinal decline in whole-brain volume (Alzheimer\u2019s disease-polygenic risk score t = 3.3, PFDR = 0.007 over 24 months in healthy controls) and surprisingly, under certain conditions, whole-brain volume atrophy is statistically more correlated with cardiac polygenic risk score than Alzheimer\u2019s disease-polygenic risk score (coronary artery disease-polygenic risk score t = 2.1, PFDR = 0.04 over 24 months in the mild cognitive impairment group). Further, in our regional analysis of white-matter hyperintensities, Alzheimer\u2019s disease-polygenic risk score beyond APOE is predictive of white-matter volume in the occipital lobe in Alzheimer\u2019s disease subjects in the polygenic regime. Finally, the rate of change of brain volume (or atrophy acceleration) may be sensitive to Alzheimer\u2019s disease-polygenic risk beyond APOE in healthy individuals (t = 2, P = 0.04). For subjects with mild cognitive impairment, beyond APOE, a more inclusive polygenic risk score including more variants, shows coronary artery disease-polygenic risk score to be more predictive of whole-brain volume atrophy, than an oligogenic approach including fewer larger effect size variants.<\/jats:p>","DOI":"10.1093\/braincomms\/fcac314","type":"journal-article","created":{"date-parts":[[2022,11,30]],"date-time":"2022-11-30T09:18:18Z","timestamp":1669799898000},"source":"Crossref","is-referenced-by-count":11,"title":["Polygenic coronary artery disease association with brain atrophy in the cognitively impaired"],"prefix":"10.1093","volume":"4","author":[{"given":"Eric","family":"de Silva","sequence":"first","affiliation":[{"name":"Centre for Medical Image Computing, University College London , London , UK"},{"name":"NIHR University College London Hospitals Biomedical Research Centre , London , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carole H","family":"Sudre","sequence":"additional","affiliation":[{"name":"Centre for Medical Image Computing, University College London , London , UK"},{"name":"MRC Unit for Lifelong Health and Ageing, University College London , London , UK"},{"name":"School of Biomedical Engineering and Imaging Sciences, King\u2019s College London , London , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josephine","family":"Barnes","sequence":"additional","affiliation":[{"name":"Dementia Research Centre, UCL Queen Square Institute of Neurology , London , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marzia A","family":"Scelsi","sequence":"additional","affiliation":[{"name":"Centre for Medical Image Computing, University College London , London , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9265-2393","authenticated-orcid":false,"given":"Andre","family":"Altmann","sequence":"additional","affiliation":[{"name":"Centre for Medical Image Computing, University College London , London , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"for the Alzheimer\u2019s Disease Neuroimaging Initiative","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,11,30]]},"reference":[{"issue":"6","key":"2022121316302888200_fcac314-B1","doi-asserted-by":"crossref","first-page":"834","DOI":"10.3390\/jcm8060834","article-title":"A population perspective on prevention of dementia","volume":"8","author":"Eggink","year":"2019","journal-title":"J Clin Med"},{"issue":"3","key":"2022121316302888200_fcac314-B2","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/j.jalz.2019.01.010","article-title":"2019 Alzheimer\u2019s disease facts and figures","volume":"15","author":"Gaugler","year":"2019","journal-title":"Alzheimers Dement"},{"issue":"4","key":"2022121316302888200_fcac314-B3","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1038\/nrneurol.2018.9","article-title":"Imaging tau and amyloid-\u03b2 proteinopathies in Alzheimer disease and other conditions","volume":"14","author":"Villemagne","year":"2018","journal-title":"Nat Rev Neurol"},{"issue":"5","key":"2022121316302888200_fcac314-B4","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1016\/j.tins.2019.03.003","article-title":"A unifying hypothesis for Alzheimer\u2019s disease: From plaques to neurodegeneration","volume":"42","author":"Edwards","year":"2019","journal-title":"Trends Neurosci"},{"key":"2022121316302888200_fcac314-B5","doi-asserted-by":"crossref","first-page":"117996","DOI":"10.1016\/j.lfs.2020.117996","article-title":"Alzheimer\u2019s disease; a review of the pathophysiological basis and therapeutic interventions","volume":"256","author":"Abeysinghe","year":"2020","journal-title":"Life Sci"},{"issue":"4-5","key":"2022121316302888200_fcac314-B6","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/j.neuropharm.2010.02.010","article-title":"Neurochemical basis for symptomatic treatment of Alzheimer\u2019s disease","volume":"59","author":"Francis","year":"2010","journal-title":"Neuropharmacology"},{"key":"2022121316302888200_fcac314-B7","doi-asserted-by":"crossref","first-page":"116662","DOI":"10.1016\/j.jns.2019.116662","article-title":"Mixed dementia: Neglected clinical entity or nosographic artifice?","volume":"410","author":"Fierini","year":"2020","journal-title":"J Neurol Sci"},{"issue":"4","key":"2022121316302888200_fcac314-B8","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1016\/j.neuron.2013.10.008","article-title":"The pathobiology of vascular dementia","volume":"80","author":"Iadecola","year":"2013","journal-title":"Neuron"},{"issue":"7","key":"2022121316302888200_fcac314-B9","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.1161\/01.STR.26.7.1171","article-title":"White matter hyperintensities on MRI in the neurologically nondiseased elderly. 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