{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T05:57:09Z","timestamp":1790575029915,"version":"4.1.0"},"reference-count":73,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging Neurosci."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      The\n                      <jats:italic>APOE\u03b54<\/jats:italic>\n                      allele is the strongest known genetic risk factor for late-onset Alzheimer disease (AD). However, the risk effect of\n                      <jats:italic>APOE\u03b54<\/jats:italic>\n                      varies substantially by ancestry, with individuals of African ancestry (AF) demonstrating markedly lower risk compared to those of European ancestry (EU). This difference in risk is associated with distinct levels of\n                      <jats:italic>APOE<\/jats:italic>\n                      gene expression. Here, we investigate whether mitochondrial processes in brain cells are also influenced by ancestry in AD\n                      <jats:italic>APOE\u03b54<\/jats:italic>\n                      carriers, potentially contributing to the observed risk differences.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Single nuclei RNA sequencing was performed on frontal cortex from 17\u202fAD patients homozygous for\n                      <jats:italic>APOEe4<\/jats:italic>\n                      with either African Local Ancestry (AF-LA;\n                      <jats:italic>N<\/jats:italic>\n                      \u202f=\u202f7) or European Local Ancestry (EU-LA;\n                      <jats:italic>N<\/jats:italic>\n                      \u202f=\u202f10). Differential gene expression was compared between AF and EU samples, with particular focus on mitochondrial pathways. Differential expression and functional enrichment analyses were performed using MAST and PathFindR, respectively. MitoXplorer was used to identify differential mitochondrial processes, while REACTOME facilitated the building of regulatory networks.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Multiple cell types and biological processes contribute to the differences in\n                      <jats:italic>APOEe4<\/jats:italic>\n                      risk seen between individuals of AF and EU ancestry. AF astrocytes show a less reactive phenotype and L6 and L5\/6 excitatory neurons appear to be less vulnerable in AF compared to EU samples. Mitochondrial alterations were more pronounced in EU-LA\n                      <jats:italic>APOEe4<\/jats:italic>\n                      AD carriers relative to their AF counterparts. Cells highly expressing\n                      <jats:italic>APOE<\/jats:italic>\n                      (astrocytes, microglia, and vascular leptomeningeal cells) showed increased expression of mitochondrial genes, particularly in EU-LA samples. We observed increased expression of pro-apoptotic, oxidative phosphorylation, and mitophagy-related genes in EU samples. Regulatory network analysis identified the transcription factor PPARG as a potential mediator linking\n                      <jats:italic>APOE\u03b54<\/jats:italic>\n                      expression to mitochondrial gene programs in a cell-type- and ancestry-dependent manner.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Our snRNA-seq analysis demonstrates that ancestry-linked regulation of\n                      <jats:italic>APOE\u03b54<\/jats:italic>\n                      expression influences mitochondrial transcriptome and astrocyte activation in AD. The stronger\n                      <jats:italic>APOE\u2013PPARG<\/jats:italic>\n                      \u2013mitochondrial gene coupling in EU ancestry particularly in astrocytes may underlie increased AD risk, while AF ancestry confers partial decoupling of these pathways. These results underscore the importance of considering ancestry in AD research and suggest that precision therapeutic strategies targeting mitochondrial and glial pathways should account for\n                      <jats:italic>APOE<\/jats:italic>\n                      local ancestry.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnagi.2026.1888862","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T05:44:15Z","timestamp":1790574255000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Unraveling changes in mitochondrial processes influenced by ancestry in APOE\u03b54 carriers with Alzheimer disease"],"prefix":"10.3389","volume":"18","author":[{"given":"M. D. M. Muniz","family":"Moreno","sequence":"first","affiliation":[{"name":"Hussman Institute for Human Genomics, University of Miami Miller School of Medicine","place":["Miami, FL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K.","family":"Celis","sequence":"additional","affiliation":[{"name":"Hussman Institute for Human Genomics, University of Miami Miller School of Medicine","place":["Miami, FL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F.","family":"Rajabli","sequence":"additional","affiliation":[{"name":"Hussman Institute for Human Genomics, University of Miami Miller School of Medicine","place":["Miami, FL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P. L.","family":"Whitehead","sequence":"additional","affiliation":[{"name":"Hussman Institute for Human Genomics, University of Miami Miller School of Medicine","place":["Miami, FL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K. L.","family":"Hamilton-Nelson","sequence":"additional","affiliation":[{"name":"Hussman Institute for Human Genomics, University of Miami Miller School of Medicine","place":["Miami, FL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. M.","family":"Dykxhoorn","sequence":"additional","affiliation":[{"name":"Hussman Institute for Human Genomics, University of Miami Miller School of Medicine","place":["Miami, FL, United States"]},{"name":"Dr. John T Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine","place":["Miami, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K.","family":"Nuytemans","sequence":"additional","affiliation":[{"name":"Hussman Institute for Human Genomics, University of Miami Miller School of Medicine","place":["Miami, FL, United States"]},{"name":"Dr. John T Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine","place":["Miami, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. M.","family":"Mesulam","sequence":"additional","affiliation":[{"name":"Northwestern ADC Neuropathology Core, Northwestern University Feinberg School of Medicine","place":["Chicago, IL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. A.","family":"Bennett","sequence":"additional","affiliation":[{"name":"Department of Neurological Sciences and Rush Alzheimer's Disease Center, Rush University Medical Center","place":["Chicago, IL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T.","family":"Schuck","sequence":"additional","affiliation":[{"name":"The Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, The Perelman School of Medicine at the University of Pennsylvania","place":["Philadelphia, PA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.","family":"Weintraub","sequence":"additional","affiliation":[{"name":"Northwestern ADC Neuropathology Core, Northwestern University Feinberg School of Medicine","place":["Chicago, IL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.","family":"Geula","sequence":"additional","affiliation":[{"name":"Northwestern ADC Neuropathology Core, Northwestern University Feinberg School of Medicine","place":["Chicago, IL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Gearing","sequence":"additional","affiliation":[{"name":"Goizueta Alzheimer\u2019s Disease Research Center, Emory University","place":["Atlanta, GA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.","family":"Alba","sequence":"additional","affiliation":[{"name":"Department of Anatomy Physiology and Genetics, Uniformed Services University","place":["Bethesda, MD, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. L.","family":"Dalgard","sequence":"additional","affiliation":[{"name":"Department of Anatomy Physiology and Genetics, Uniformed Services University","place":["Bethesda, MD, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. A.","family":"Davis","sequence":"additional","affiliation":[{"name":"Brain Endowment Bank, Department of Neurology, University of Miami Miller School of Medicine","place":["Miami, FL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W. K.","family":"Scott","sequence":"additional","affiliation":[{"name":"Hussman Institute for Human Genomics, University of Miami Miller School of Medicine","place":["Miami, FL, United States"]},{"name":"Dr. John T Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine","place":["Miami, United States"]},{"name":"Brain Endowment Bank, Department of Neurology, University of Miami Miller School of Medicine","place":["Miami, FL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. L.","family":"Haines","sequence":"additional","affiliation":[{"name":"Cleveland Institute for Computational Biology, Case Western Reserve University","place":["Cleveland, OH, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. A.","family":"Pericak-Vance","sequence":"additional","affiliation":[{"name":"Hussman Institute for Human Genomics, University of Miami Miller School of Medicine","place":["Miami, FL, United States"]},{"name":"Dr. John T Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine","place":["Miami, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. J.","family":"Griswold","sequence":"additional","affiliation":[{"name":"Hussman Institute for Human Genomics, University of Miami Miller School of Medicine","place":["Miami, FL, United States"]},{"name":"Dr. John T Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine","place":["Miami, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. 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