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Aging, the strongest risk factor for AD, is also associated with some overlapping processes, such as neuronal cell transcriptional downregulation and glial cell activation. The middle temporal gyrus (MTG) is a brain region that supports semantic processing and default-mode connectivity and shows early vulnerability in both aging and AD. Here we profile bulk RNA-seq from 606 postmortem MTG samples with the goal of understanding the transcriptional changes associated with AD and aging. In 217 clinical and neuropathologically confirmed AD versus 290 no-dementia controls donors, we identify 613 differentially expressed genes (390 up, 223 down; |log2 fold change| \u2265 0.5; BH P &lt; 0.05), with NPNT and ADAMTS2 among the top upregulated signals. Cell set enrichment indicates reduced excitatory neuronal signatures together with increased microglial, astrocytic, endothelial, and pericyte programs. Gene-set analyses reveal strong activation of angiogenesis, extracellular-matrix organization, wound response, adaptive immunity, and coordinated suppression of neuronal and mitochondrial processes, including synaptic signaling and respiratory-chain complexes. Multiscale coexpression mapping resolves three disease clusters: a neuron-mitochondrial module suppressed in AD (M5; hub PJA2; key driver GABRB3), a microglial immune module upregulated in AD (M6; hub C1QC; key driver FCER1G), and an increased astrocyte-vascular extracellular-matrix module in AD (M8; hub ESAM; key driver TAGLN). Across 324 non-AD controls aged 24\u2013108 years, aging is associated with declines in gene expression associated with translation, proteostasis, and mitochondrial function and increases in those linked to oligodendrocyte and myelination programs (for example M4; hub CNTN2; key driver MOBP); in a 65+ subset, neuronal and protein-folding modules show the strongest decrements with reduced glial gene expression upregulatio. Our results indicate that late-life aging involves increased glial responses and neuronal\/proteostasis suppression, whereas AD is also associated with immune\u2013 vascular\u2013ECM activation and suppression of neuronal programs.<\/jats:p>","DOI":"10.1101\/2025.10.19.683343","type":"posted-content","created":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T14:50:12Z","timestamp":1760971812000},"source":"Crossref","is-referenced-by-count":3,"title":["Transcriptomic profiling of the middle temporal gyrus reveals differential glial\/neuronal dysregulation across Alzheimer\u2019s disease and aging"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4024-3368","authenticated-orcid":false,"given":"IS","family":"Piras","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A","family":"Bonfitto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A","family":"Aldabergenova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J","family":"Sloan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A","family":"Trejo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"JC","family":"Troncoso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C","family":"Geula","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"EJ","family":"Rogalski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"CH","family":"Kawas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Corrada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"TG","family":"Beach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9527-2011","authenticated-orcid":false,"given":"GE","family":"Serrano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"PF","family":"Worley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"CA","family":"Barnes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7390-9918","authenticated-orcid":false,"given":"MJ","family":"Huentelman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025102308550796000_2025.10.19.683343v1.1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00308809"},{"key":"2025102308550796000_2025.10.19.683343v1.2","doi-asserted-by":"publisher","DOI":"10.1002\/alz.13809"},{"key":"2025102308550796000_2025.10.19.683343v1.3","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.120.311911"},{"key":"2025102308550796000_2025.10.19.683343v1.4","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-160726"},{"key":"2025102308550796000_2025.10.19.683343v1.5","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-024-01911-3"},{"key":"2025102308550796000_2025.10.19.683343v1.6","doi-asserted-by":"publisher","DOI":"10.3390\/molecules25215110"},{"key":"2025102308550796000_2025.10.19.683343v1.7","article-title":"Global Burden of Alzheimer\u2019s disease and other dementias in adults aged 65 years and older, 1991\u20132021: population-based study","volume":"13","year":"2025","journal-title":"Front Public Health. 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