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Metabolic network modularity, recently applied to the study of dementia, is increased in Alzheimer\u2019s disease patients compared with controls, but network modularity in cognitively unimpaired elderly with various risks of developing Alzheimer\u2019s disease needs to be determined. Based on their 5-year cognitive progression, we stratified 117 cognitively normal participants (78.3\u2009\u00b1\u20094.0 years of age, 52 women) into three age-matched groups, each with a different level of risk for Alzheimer\u2019s disease. From their fluorodeoxyglucose PET we constructed metabolic networks, evaluated their modular structures using the Louvain algorithm, and compared them between risk groups. As the risk for Alzheimer\u2019s disease increased, the metabolic connections among brain regions weakened and became more modular, indicating network fragmentation and functional impairment of the brain. We then set out to determine the correlation between regional brain metabolism, particularly in the modules derived from the previous analysis, and the regional expression of Alzheimer-risk genes in the brain, obtained from the Allen Human Brain Atlas. In all risk groups of this elderly population, the regional brain expression of most Alzheimer-risk genes showed a strong correlation with brain metabolism, particularly in the module that corresponded to regions of the brain that are affected earliest and most severely in Alzheimer\u2019s disease. Among the genes, APOE and CD33 showed the strongest negative correlation and SORL1 showed the strongest positive correlation with brain metabolism. The Pearson correlation coefficients remained significant when contrasted against a null-hypothesis distribution of correlation coefficients across the whole transcriptome of 20\u2009736 genes (SORL1: P\u2009=\u20090.0130; CD33, P\u2009=\u20090.0136; APOE: P\u2009=\u20090.0093). The strong regional correlation between Alzheimer-related gene expression in the brain and brain metabolism in older adults highlights the role of brain metabolism in the genesis of dementia.<\/jats:p>","DOI":"10.1093\/braincomms\/fcac216","type":"journal-article","created":{"date-parts":[[2022,8,25]],"date-time":"2022-08-25T00:32:12Z","timestamp":1661387532000},"source":"Crossref","is-referenced-by-count":17,"title":["In Alzheimer-prone brain regions, metabolism and risk-gene expression are strongly correlated"],"prefix":"10.1093","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3896-4003","authenticated-orcid":false,"given":"Fengdan","family":"Ye","sequence":"first","affiliation":[{"name":"Department of Physics and Astronomy, Rice University , Houston, TX 77005 , USA"},{"name":"Center for Theoretical Biological Physics, Rice University , Houston, TX 77005 , USA"},{"name":"Nantz National Alzheimer Center, Houston Methodist Neurological and Research Institute, Houston Methodist Hospital, Weill Cornell Medicine , Houston, TX 77030 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Quentin","family":"Funk","sequence":"additional","affiliation":[{"name":"Nantz National Alzheimer Center, Houston Methodist Neurological and Research Institute, Houston Methodist Hospital, Weill Cornell Medicine , Houston, TX 77030 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1488-7661","authenticated-orcid":false,"given":"Elijah","family":"Rockers","sequence":"additional","affiliation":[{"name":"Nantz National Alzheimer Center, Houston Methodist Neurological and Research Institute, Houston Methodist Hospital, Weill Cornell Medicine , Houston, TX 77030 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joshua M","family":"Shulman","sequence":"additional","affiliation":[{"name":"Department of Neurology, Baylor College of Medicine , Houston, TX 77030 , USA"},{"name":"Department of Neuroscience, Baylor College of Medicine , Houston, TX 77030 , USA"},{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine , Houston, TX 77030 , USA"},{"name":"Center for Alzheimer\u2019s and Neurodegenerative Diseases, Baylor College of Medicine , Houston, TX 77030 , USA"},{"name":"Jan and Dan Duncan Neurological Research Institute, Texas Children\u2019s Hospital , Houston, TX 77030 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9955-6954","authenticated-orcid":false,"given":"Joseph C","family":"Masdeu","sequence":"additional","affiliation":[{"name":"Nantz National Alzheimer Center, Houston Methodist Neurological and Research Institute, Houston Methodist Hospital, Weill Cornell Medicine , Houston, TX 77030 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4467-7406","authenticated-orcid":false,"given":"Belen","family":"Pascual","sequence":"additional","affiliation":[{"name":"Nantz National Alzheimer Center, Houston Methodist Neurological and Research Institute, Houston Methodist Hospital, Weill Cornell Medicine , Houston, TX 77030 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"for the Alzheimer\u2019s Disease Neuroimaging Initiative","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2022,8,25]]},"reference":[{"issue":"3","key":"2022092013345775100_fcac216-B1","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1038\/s41583-019-0132-6","article-title":"Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease","volume":"20","author":"Butterfield","year":"2019","journal-title":"Nat Rev 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