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We assessed cross-sectionally the relative contributions of three potential mechanisms causing hypometabolism in the retrosplenial and inferior parietal cortices: local molecular (amyloid and tau) pathology and atrophy, distant factors including contributions from the degenerating medial temporal lobe or molecular pathology in functionally connected regions, and the presence of the apolipoprotein E (APOE) \u03b54 allele.<\/jats:p>\n                  <jats:p>Two hundred and thirty-two amyloid-positive cognitively impaired patients from two cohorts [University of California, San Francisco (UCSF), and Alzheimer\u2019s Disease Neuroimaging Initiative (ADNI)] underwent MRI and PET with FDG, amyloid-PET using 11C-Pittsburgh Compound-B, 18F-florbetapir or 18F-florbetaben, and 18F-flortaucipir tau-PET in 1 year. Standard uptake value ratios (SUVRs) were calculated using tracer-specific reference regions. Regression analyses were run within cohorts to identify variables associated with retrosplenial or inferior parietal FDG standard uptake value ratios.<\/jats:p>\n                  <jats:p>On average, ADNI patients were older and were less impaired than the UCSF patients. Regional patterns of hypometabolism were similar between cohorts, although there were cohort differences in regional grey matter atrophy. Local cortical thickness and tau-PET (but not amyloid-PET) were independently associated with both retrosplenial and inferior parietal FDG SUVRs (\u0394R2 = 0.09 to 0.21) across cohorts in models that also included age and disease severity (local model). Including medial temporal lobe volume improved the retrosplenial FDG model in the ADNI cohort (\u0394R2 = 0.04, P = 0.008) but not for the UCSF (\u0394R2 &amp;lt; 0.01, P = 0.52), and did not improve the inferior parietal models (\u0394R2 &amp;lt; 0.01, P &amp;gt; 0.37). Interaction analyses revealed that medial temporal volume was more strongly associated with retrosplenial FDG SUVRs at earlier disease stages (P = 0.06 in UCSF, P = 0.046 in ADNI). Exploratory analyses across the cortex confirmed overall associations between hypometabolism and local tau pathology and thickness and revealed associations between medial temporal degeneration and hypometabolism in retrosplenial, orbitofrontal and anterior cingulate cortices. Finally, our data did not support hypotheses of a detrimental effect of pathology in connected regions or of an effect of the APOE \u03b54 allele in impaired participants.<\/jats:p>\n                  <jats:p>Overall, in two independent groups of patients at symptomatic stages of Alzheimer\u2019s disease, cortical hypometabolism mainly reflected structural neurodegeneration and tau, but not amyloid, pathology.<\/jats:p>","DOI":"10.1093\/brain\/awab294","type":"journal-article","created":{"date-parts":[[2021,8,6]],"date-time":"2021-08-06T15:12:19Z","timestamp":1628262739000},"page":"713-728","source":"Crossref","is-referenced-by-count":100,"title":["Cortical hypometabolism reflects local atrophy and tau pathology in symptomatic Alzheimer\u2019s disease"],"prefix":"10.1093","volume":"145","author":[{"given":"Amelia","family":"Strom","sequence":"first","affiliation":[{"name":"Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California, San 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USA"},{"name":"Department of Diagnostic Imaging, Sheba Medical Center, Tel Hashomer , Ramat Gan, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4197-3039","authenticated-orcid":false,"given":"David N","family":"Soleimani-Meigooni","sequence":"additional","affiliation":[{"name":"Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco , San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Pham","sequence":"additional","affiliation":[{"name":"Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco , San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0209-3127","authenticated-orcid":false,"given":"Suzanne L","family":"Baker","sequence":"additional","affiliation":[{"name":"Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley National Laboratory , Berkeley, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan M","family":"Landau","sequence":"additional","affiliation":[{"name":"Helen Wills Neuroscience Institute, University of California, Berkeley , Berkeley, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4458-113X","authenticated-orcid":false,"given":"William J","family":"Jagust","sequence":"additional","affiliation":[{"name":"Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley National Laboratory , Berkeley, CA, USA"},{"name":"Helen Wills Neuroscience Institute, University of California, Berkeley , Berkeley, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce L","family":"Miller","sequence":"additional","affiliation":[{"name":"Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco , San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Howard J","family":"Rosen","sequence":"additional","affiliation":[{"name":"Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco , San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Luisa","family":"Gorno-Tempini","sequence":"additional","affiliation":[{"name":"Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco , San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gil D","family":"Rabinovici","sequence":"additional","affiliation":[{"name":"Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco , San Francisco, CA, USA"},{"name":"Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley National Laboratory , Berkeley, CA, USA"},{"name":"Helen Wills Neuroscience Institute, University of California, Berkeley , Berkeley, CA, USA"},{"name":"Department of Radiology and Biomedical Imaging, University of California , San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2581-8100","authenticated-orcid":false,"given":"Renaud","family":"La Joie","sequence":"additional","affiliation":[{"name":"Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco , San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"for the Alzheimer\u2019s Disease Neuroimaging 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