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We integrated genetic correlation, polygenic risk scores (PRSs), and Mendelian randomization (MR) to assess whether mtDNAcn influences the risk of AD and PD, and evaluate how study\u2010specific factors in mtDNAcn genome\u2010wide association studies (GWASs) distort these causal estimates.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      Using GWASs of four mtDNAcn measures, AD, AD\/dementia, and PD, we evaluated genetic correlations, generated ancestry\u2010normalized PRS in the Alzheimer's Disease Genetics Consortium (\n                      <jats:italic>N<\/jats:italic>\n                      \u00a0=\u00a027,383), and applied MR methods including latent heritable confounder\u2010MR (LHC\u2010MR).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>Across the four mtDNAcn GWASs, only one was consistently associated with AD\/dementia and PD, with genetic correlations and PRSs showing negative correlations and MR indicating that higher mtDNAcn reduced AD\/dementia and PD risk.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>Higher blood\u2010based mtDNAcn was causally associated with reduced risk of AD\/dementia and PD, with limited evidence to suggest a bidirectional effect.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.71469","type":"journal-article","created":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T04:06:01Z","timestamp":1779336361000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Evaluating the causal effect of mitochondrial dysfunction on Alzheimer's disease and Parkinson's disease using polygenic risk scores and Mendelian randomization"],"prefix":"10.1002","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-6642-6541","authenticated-orcid":false,"given":"Aadrita","family":"Chatterjee","sequence":"first","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences University of California San Francisco  San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Alvarez","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genomic Sciences Icahn School of Medicine at Mount Sinai  New York New York 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 California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Jonson","sequence":"additional","affiliation":[{"name":"Center for Alzheimer's and Related Dementias National Institutes of Health  Bethesda Maryland USA"},{"name":"DataTecnica LLC  Washington District of Columbia USA"},{"name":"Memory and Aging Center, Department of Neurology Weill Institute for Neurosciences, University of California  San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather M.","family":"Wilkins","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Kansas Medical Center  Kansas City Kansas USA"},{"name":"Department of Biochemistry and Molecular Biology University of Kansas Medical Center  Kansas City Kansas USA"},{"name":"University of Kansas Alzheimer's Disease Research Center University of Kansas Medical Center  Kansas City Kansas 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