{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T19:21:37Z","timestamp":1789154497488,"version":"build-2803163510"},"reference-count":72,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,3,23]],"date-time":"2021-03-23T00:00:00Z","timestamp":1616457600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2021,3,23]],"date-time":"2021-03-23T00:00:00Z","timestamp":1616457600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Please see dedicated manuscript section for complete details on funding sources."}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["acta neuropathol commun"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Although abnormal accumulation of amyloid in the brain is an early biomarker of Alzheimer\u2019s disease (AD), wide variation in cognitive trajectories during life can be seen in the setting of brain amyloidosis, ranging from maintenance of normal function to progression to dementia. It is widely presumed that cognitive resilience (i.e., coping) to amyloidosis may be influenced by environmental, lifestyle, and inherited factors, but relatively little in specifics is known about this architecture. Here, we leveraged multimodal longitudinal data from a large, population-based sample of older adults to discover genetic factors associated with differential cognitive resilience to brain amyloidosis determined by positron emission tomography (PET). Among amyloid-PET positive older adults, the AD risk allele\n                    <jats:italic>APOE<\/jats:italic>\n                    \u025b4 was associated with worse longitudinal memory trajectories as expected, and was thus covaried in the main analyses. Through a genome-wide association study (GWAS), we uncovered a novel association with cognitive resilience on chromosome 8 at the\n                    <jats:italic>MTMR7\/CNOT7\/ZDHHC2\/VPS37A<\/jats:italic>\n                    locus (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20094.66\u2009\u00d7\u200910\n                    <jats:sup>\u20138<\/jats:sup>\n                    , \u03b2\u2009=\u20090.23), and demonstrated replication in an independent cohort. Post-hoc analyses confirmed this association as specific to the setting of elevated amyloid burden and not explained by differences in tau deposition or cerebrovascular disease. Complementary gene-based analyses and publically available functional data suggested that the causative variant at this locus may tag\n                    <jats:italic>CNOT7<\/jats:italic>\n                    (CCR4-NOT Transcription Complex Subunit 7), a gene linked to synaptic plasticity and hippocampal-dependent learning and memory. Pathways related to cell adhesion and immune system activation displayed enrichment of association in the GWAS. Our findings, resulting from a unique study design, support the hypothesis that genetic heterogeneity is one of the factors that explains differential cognitive resilience to brain amyloidosis. Further characterization of the underlying biological mechanisms influencing cognitive resilience may facilitate improved prognostic counseling, therapeutic application, and trial enrollment in AD.\n                  <\/jats:p>","DOI":"10.1186\/s40478-021-01154-1","type":"journal-article","created":{"date-parts":[[2021,3,23]],"date-time":"2021-03-23T03:02:52Z","timestamp":1616468572000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Coping with brain amyloid: genetic heterogeneity and cognitive resilience to Alzheimer\u2019s pathophysiology"],"prefix":"10.1186","volume":"9","author":[{"name":"for the Alzheimer\u2019s Disease Neuroimaging Initiative (ADNI)","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6591-8734","authenticated-orcid":false,"given":"Vijay K.","family":"Ramanan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy G.","family":"Lesnick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott A.","family":"Przybelski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael G.","family":"Heckman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David S.","family":"Knopman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Graff-Radford","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Val J.","family":"Lowe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary M.","family":"Machulda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle M.","family":"Mielke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"Clifford R.","family":"Jack","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald C.","family":"Petersen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Owen A.","family":"Ross","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prashanthi","family":"Vemuri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,3,23]]},"reference":[{"key":"1154_CR1","doi-asserted-by":"publisher","first-page":"1680","DOI":"10.1038\/s41591-019-0611-3","volume":"25","author":"JF Arboleda-Velasquez","year":"2019","unstructured":"Arboleda-Velasquez JF, Lopera F, O\u2019Hare M, Delgado-Tirado S, Marino C, Chmielewska N, Saez-Torres KL, Amarnani D, Schultz AP, Sperling RA et al (2019) Resistance to autosomal dominant Alzheimer\u2019s disease in an APOE3 Christchurch homozygote: a case report. 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Dr. Graff-Radford reported receiving research support from the National Institute on Aging outside the submitted work. Dr. Lowe reported receiving consulting fees from Bayer Schering Pharma, Piramal Life Sciences, and Merck Research and grants from GE Healthcare, Siemens Molecular Imaging, AVID Radiopharmaceuticals, and the NIH outside the submitted work. Dr. Mielke reported receiving research support from the NIH, Department of Defense, and unrestricted research grants from Biogen outside the submitted work. Dr. Jack reported consulting for Eli Lilly, serving on an independent data monitoring board for Roche, and serving as a speaker for Eisai but receives no personal compensation from any commercial entity; he also reported receiving research support from the NIH and the Alexander Family Alzheimer's Disease Research Professorship of the Mayo Clinic. Dr. Petersen reported receiving consulting fees from Hoffman-La Roche Inc, Merck Inc, Genentech Inc, Biogen Inc, GE Healthcare, and Eisai Inc. outside the submitted work. Dr. Vemuri reported receiving grants from the NIH during the conduct of the study. No other disclosures were reported.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"48"}}