{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T08:03:33Z","timestamp":1784361813077,"version":"3.55.0"},"posted":{"date-parts":[[2026,7,15]]},"group-title":"Epidemiology","reference-count":46,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T00:00:00Z","timestamp":1784073600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Importance<\/jats:title>\n                  <jats:p>Alzheimer\u2019s disease (AD) arises from complex interactions among genetic, clinical, and social determinants of health (SDoH) risk factors, yet their independent contributions to underlying AD pathophysiology remain elusive.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>To quantify the effects of risk factors across amyloid (A\u03b2)\/tau, neurodegeneration, and cognition.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Design<\/jats:title>\n                  <jats:p>Cross-sectional analysis using structural equation modeling (SEM).<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Setting<\/jats:title>\n                  <jats:p>Health and Aging Brain Study\u2013Health Disparities (HABS-HD), a community-based cohort study.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Participants<\/jats:title>\n                  <jats:p>A total of 2,276 participants with demographics, genetic, clinical, and biomarker data from the baseline visit.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Exposures<\/jats:title>\n                  <jats:p>\n                    <jats:italic>APOE<\/jats:italic>\n                    \u03b54 carrier status, AD polygenic risk score (AD-PRS), clinical risk score (CogDRisk), and a social determinants of health (SDoH) latent score derived using factor analysis.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Main Outcomes and Measures<\/jats:title>\n                  <jats:p>\n                    Latent variables representing A\u03b2\/tau pathology (plasma pTau\n                    <jats:sub>181<\/jats:sub>\n                    , plasma pTau\n                    <jats:sub>217<\/jats:sub>\n                    \/A\u03b2\n                    <jats:sub>42<\/jats:sub>\n                    , amyloid PET positivity, and global standardized uptake value ratio), neurodegeneration (plasma neurofilament light, cortical thickness, hippocampal volume), and cognition (memory, executive, and language tests) were modeled and regressed on AD latent variables using SEM adjusted for age, sex, genetic principal components, and spoken language.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    The total analytic sample included 2,276 participants (mean age: 65.3 \u00b1 8.7; non-Hispanic White: 43.0%, non-Hispanic Black: 16.2%, and Latinx\/Hispanic adults: 40.8%).\n                    <jats:italic>APOE<\/jats:italic>\n                    \u03b54 was strongly associated with worse A\u03b2\/tau latent variable (\u03b2=0.31; p&lt;0.001), with smaller but significant associations with neurodegeneration (\u03b2=0.085; p&lt;0.001) and cognition (\u03b2=0.083; p&lt;0.001). Higher AD-PRS was modestly associated with worse A\u03b2\/tau (\u03b2=0.075; p&lt;0.01) but was not associated with neurodegeneration or cognition. A higher clinical risk score was significantly associated with worse neurodegeneration (\u03b2=0.16; p&lt;0.001) but not with A\u03b2\/tau or cognition. Adverse SDoH was associated with worse neurodegeneration (\u03b2=0.071; p&lt;0.05) and strongly associated with worse cognition (\u03b2=0.22; p&lt;0.001), with no associations with A\u03b2\/tau.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion and Relevance<\/jats:title>\n                  <jats:p>Genetic risks were primarily associated with A\u03b2 and tau pathology, clinical risks with neurodegeneration, and SDoH risks with cognition, suggesting that risk factors exert differential effects on AD pathophysiology. Future studies investigating additional risk factors and their longitudinal associations with AD pathophysiological changes are warranted.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Key Points<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Questions<\/jats:title>\n                    <jats:p>Do Alzheimer\u2019s disease (AD) risk factors differentially influence underlying AD pathophysiological processes, and do these associations vary across demographic subgroups?<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Findings<\/jats:title>\n                    <jats:p>Genetic and genomic risk burdens demonstrated the strongest associations with amyloid and tau pathology; clinical risk burden with neurodegeneration; and adverse social determinants of health with cognition.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Meaning<\/jats:title>\n                    <jats:p>Because of the differential effects of risk factors on the underlying AD pathophysiology, a one-size-fits-all approach to AD risk prediction and prevention is insufficient. AD risk assessment should leverage multidomain frameworks incorporating genomic, clinical, and social determinants of health information to better inform disease development and progression.<\/jats:p>\n                  <\/jats:sec>\n                <\/jats:sec>","DOI":"10.64898\/2026.07.07.26357509","type":"posted-content","created":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T17:30:27Z","timestamp":1784136627000},"source":"Crossref","is-referenced-by-count":0,"title":["Orthogonal Contributions of Genetic, Clinical, and Social Determinants of Health Risk Burdens on Alzheimer\u2019s Disease Pathophysiology"],"prefix":"10.64898","author":[{"given":"Meri","family":"Okorie","sequence":"first","affiliation":[{"name":"Fein Memory and Aging Center, University of California, San Francisco, San Francisco, CA, USA"},{"name":"Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaqing","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paulina","family":"Tolosa-Tort","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rakshya U.","family":"Sharma","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra L.","family":"Clark","sequence":"additional","affiliation":[{"name":"Department of Psychology, University of Texas at Austin, Austin, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristine","family":"Yaffe","sequence":"additional","affiliation":[{"name":"Fein Memory and Aging Center, University of California, San Francisco, San Francisco, CA, USA"},{"name":"Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, San Francisco, CA, USA"},{"name":"Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA"},{"name":"San Francisco Veterans Affairs Health Care System, San Francisco, CA, USA"},{"name":"The Center for Population Brain Health, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7274-2634","authenticated-orcid":false,"given":"Jennifer S.","family":"Yokoyama","sequence":"additional","affiliation":[{"name":"Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA"},{"name":"Fein Memory and Aging Center, University of California, San Francisco, San Francisco, CA, USA"},{"name":"Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1921-9470","authenticated-orcid":false,"given":"Shea","family":"Andrews","sequence":"additional","affiliation":[{"name":"Fein Memory and Aging Center, University of California, San Francisco, San Francisco, CA, USA"},{"name":"Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Health and Aging Brain Study - Health Disparities","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026071800401187000_2026.07.07.26357509v1.1","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1038\/s41392-024-01911-3","article-title":"Recent advances in Alzheimer\u2019s disease: mechanisms, clinical trials and new drug development strategies","volume":"9","year":"2024","journal-title":"Signal Transduct. 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