{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T12:15:35Z","timestamp":1776946535528,"version":"3.51.4"},"reference-count":47,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2023,2,8]],"date-time":"2023-02-08T00:00:00Z","timestamp":1675814400000},"content-version":"vor","delay-in-days":38,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["alz-journals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["A&amp;D Transl Res &amp; Clin Interv"],"published-print":{"date-parts":[[2023,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Alzheimer's disease (AD) is a neurodegenerative disorder involving interactions between different cell types in the brain. Previous single\u2010cell and bulk expression Alzheimer's studies have reported conflicting findings about the key cell types and cellular pathways whose expression is primarily altered in this disease. We re\u2010analyzed these data in a uniform, coherent manner aiming to resolve and extend past findings. Our analysis sheds light on the observation that females have higher AD incidence than males.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We re\u2010analyzed three single\u2010cell transcriptomics datasets. We used the software Model\u2010based Analysis of Single\u2010cell Transcriptomics (MAST) to seek differentially expressed genes comparing AD cases to matched controls for both sexes together and each sex separately. We used the GOrilla software to search for enriched pathways among the differentially expressed genes. Motivated by the male\/female difference in incidence, we studied genes on the X\u2010chromosome, focusing on genes in the pseudoautosomal region (PAR) and on genes that are heterogeneous across individuals or tissues for X\u2010inactivation. We validated findings by analyzing bulk AD datasets from the cortex in the Gene Expression Omnibus.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Our results resolve a contradiction in the literature, showing that by comparing AD patients to unaffected controls, excitatory neurons have more differentially expressed genes than do other cell types. Synaptic transmission and related pathways are altered in a sex\u2010specific analysis of excitatory neurons. PAR genes and X\u2010chromosome heterogeneous genes, including, for example,\n                      <jats:italic>BEX1 and ELK1<\/jats:italic>\n                      , may contribute to the difference in sex incidence of Alzheimer's disease.\n                      <jats:italic>GRIN1<\/jats:italic>\n                      , stood out as an overexpressed autosomal gene in cases versus controls in all three single\u2010cell datasets and as a functional candidate gene contributing to pathways upregulated in cases.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Taken together, these results point to a potential linkage between two longstanding questions concerning AD pathogenesis, involving which cell type is the most important and why females have a higher incidence than males.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Highlights<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>By reanalyzing three, published, single\u2010cell RNAseq datasets, we resolved a contradiction in the literature and showed that when comparing AD patients to unaffected controls, excitatory neurons have more differentially expressed genes than do other cell types.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Further analysis of the published single\u2010cell datasets showed that synaptic transmission and related pathways are altered in a sex\u2010specific analysis of excitatory neurons.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            Combining analysis of single\u2010cell datasets and publicly available bulk transcriptomics datasets revealed that X\u2010chromosome genes, such as\n                            <jats:italic>BEX1<\/jats:italic>\n                            ,\n                            <jats:italic>ELK1<\/jats:italic>\n                            ,\n                            <jats:italic>and USP11<\/jats:italic>\n                            , whose X\u2010inactivation status is heterogeneous may contribute to the higher incidence in females of Alzheimer's disease.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/trc2.12373","type":"journal-article","created":{"date-parts":[[2023,2,9]],"date-time":"2023-02-09T02:56:16Z","timestamp":1675911376000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Altered gene expression in excitatory neurons is associated with Alzheimer's disease and its higher incidence in women"],"prefix":"10.1002","volume":"9","author":[{"given":"A. Xavier","family":"Garcia","sequence":"first","affiliation":[{"name":"Cancer Data Science Laboratory Center for Cancer Research National Cancer Institute National Institutes of Health  Bethesda Maryland USA"},{"name":"Weill Cornell\/Rockefeller\/Sloan Kettering Tri\u2010Institutional MD\u2010PhD Program  New York NY USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jielin","family":"Xu","sequence":"additional","affiliation":[{"name":"Genomic Medicine Institute Lerner Research Institute Cleveland Clinic  Cleveland Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Feixiong","family":"Cheng","sequence":"additional","affiliation":[{"name":"Genomic Medicine Institute Lerner Research Institute Cleveland Clinic  Cleveland Ohio USA"},{"name":"Department of Molecular Medicine Cleveland Clinic Lerner College of Medicine Case Western Reserve University  Cleveland Ohio USA"},{"name":"Case Comprehensive Cancer Center Case Western Reserve University School 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