{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"Research Square"}],"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T11:18:22Z","timestamp":1787915902774,"version":"build-2784847793"},"posted":{"date-parts":[[2026,8,14]]},"group-title":"In Review","reference-count":40,"publisher":"Springer Science and Business Media LLC","license":[{"start":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T00:00:00Z","timestamp":1786665600000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,24]]},"abstract":"<title>Abstract<\/title>\n                <p>\n                  The\n                  <italic>APOE3<\/italic>\n                  Christchurch (\n                  <italic>APOE3<\/italic>\n                  <sup>\n                    <italic>Ch<\/italic>\n                  <\/sup>\n                  ) is a rare genetic variant associated with marked protection against autosomal-dominant Alzheimer\u2019s disease (ADAD) due to the\n                  <italic>PSEN1<\/italic>\n                  <sup>\n                    <italic>E280A<\/italic>\n                  <\/sup>\n                  variant, by delaying the onset of clinical symptoms. In this study, we investigate age-related alterations in cerebral glucose metabolism, measured with 18F-fluorodeoxyglucose positron emission tomography, and cognitive performance in: 1)\n                  <italic>APOE3<\/italic>\n                  <sup>\n                    <italic>Ch<\/italic>\n                  <\/sup>\n                  -\n                  <italic>PSEN1<\/italic>\n                  <sup>\n                    <italic>E280A<\/italic>\n                  <\/sup>\n                  carriers (n\u2009=\u20097) compared to typical\n                  <italic>PSEN1<\/italic>\n                  <sup>\n                    <italic>E280A<\/italic>\n                  <\/sup>\n                  carriers (n\u2009=\u200948) across the ADAD continuum; and 2) cognitively-unimpaired\n                  <italic>APOE3<\/italic>\n                  <sup>\n                    <italic>Ch<\/italic>\n                  <\/sup>\n                  carriers (n\u2009=\u200929) compared to non-carriers (n\u2009=\u200943) across the adult lifespan. Across ADAD,\n                  <italic>APOE3<\/italic>\n                  <sup>\n                    <italic>Ch<\/italic>\n                  <\/sup>\n                  -\n                  <italic>PSEN1<\/italic>\n                  <sup>\n                    <italic>E280A<\/italic>\n                  <\/sup>\n                  carriers had a 58% smaller age-related reduction in glucose metabolism in the precuneus, along with a 50% smaller reduction in episodic memory, compared to typical\n                  <italic>PSEN1<\/italic>\n                  <sup>\n                    <italic>E280A<\/italic>\n                  <\/sup>\n                  carriers. Across the adult lifespan,\n                  <italic>APOE3<\/italic>\n                  <sup>\n                    <italic>Ch<\/italic>\n                  <\/sup>\n                  carriers had remarkably preserved glucose metabolism in the anterior cingulate cortex, compared to non-carriers (slope: 0.001 versus \u2212\u20090.009 \/year). In this region, higher glucose metabolism in\n                  <italic>APOE3<\/italic>\n                  <sup>\n                    <italic>Ch<\/italic>\n                  <\/sup>\n                  carriers correlated with greater global cognition and episodic memory, as well as with fewer subjective memory complaints and depressive symptoms. Our findings suggest that the\n                  <italic>APOE3<\/italic>\n                  <sup>\n                    <italic>Ch<\/italic>\n                  <\/sup>\n                  variant may be protective against brain metabolic changes both in ADAD and across the disease-free adult lifespan, with corresponding benefits in cognitive function. Understanding the pathways through which\n                  <italic>APOE3<\/italic>\n                  <sup>\n                    <italic>Ch<\/italic>\n                  <\/sup>\n                  confers metabolic protective effects could inform novel therapeutic avenues to enhance resilience against AD and promote healthy brain aging.\n                <\/p>","DOI":"10.21203\/rs.3.rs-10145165\/v1","type":"posted-content","created":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T11:08:11Z","timestamp":1786705691000},"source":"Crossref","is-referenced-by-count":0,"title":["Brain metabolic resilience conferred by the APOE3 Christchurch variant in autosomal dominant Alzheimer\u2019s disease and across the adult lifespan"],"prefix":"10.21203","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9714-8244","authenticated-orcid":false,"given":"Yakeel","family":"Quiroz","sequence":"first","affiliation":[{"name":"Massachusetts General Hospital, Harvard Medical School"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catarina","family":"Trist\u00e3o-Pereira","sequence":"additional","affiliation":[{"name":"Boston University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Malotaux","sequence":"additional","affiliation":[{"name":"Boston University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yesica","family":"Zuluaga","sequence":"additional","affiliation":[{"name":"Grupo de Neurociencias de Antioquia, Facultad de Medicina, Universidad de Antioquia, Medell\u00edn, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Mu\u00f1oz","sequence":"additional","affiliation":[{"name":"Grupo de Neurociencias de Antioquia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Silva","sequence":"additional","affiliation":[{"name":"Boston University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing","family":"He","sequence":"additional","affiliation":[{"name":"Boston University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Alzate","sequence":"additional","affiliation":[{"name":"Grupo de Neurociencias de Antioquia, Facultad de Medicina, Universidad de Antioquia, Medell\u00edn, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yamile","family":"Bocanegra","sequence":"additional","affiliation":[{"name":"Universidad de Antioquia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3952-1412","authenticated-orcid":false,"given":"Alejandro","family":"Guerrero","sequence":"additional","affiliation":[{"name":"Universidad de Antioquia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Serna","sequence":"additional","affiliation":[{"name":"Universidad de Antioquia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8666-7273","authenticated-orcid":false,"given":"Carolina","family":"Ospina","sequence":"additional","affiliation":[{"name":"Universidad de Antioquia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Vidal","sequence":"additional","affiliation":[{"name":"Hospital Pablo Tob\u00f3n Uribe"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergio","family":"Alvarez","sequence":"additional","affiliation":[{"name":"Hospital Pablo Tob\u00f3n Uribe"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael","family":"Posada-Duque","sequence":"additional","affiliation":[{"name":"Universidad de Antioquia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3192-9117","authenticated-orcid":false,"given":"Joseph","family":"Arboleda-Velasquez","sequence":"additional","affiliation":[{"name":"Schepens Eye Research Institute of Mass Eye and Ear and Department of Ophthalmology, Harvard Medical School, Boston, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2283-536X","authenticated-orcid":false,"given":"David","family":"Aguillon","sequence":"additional","affiliation":[{"name":"Universidad de Antioquia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","reference":[{"key":"ref1","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/S1474-4422(10)70323-9","article-title":"Pre-dementia clinical stages in presenilin 1 E280A familial early-onset Alzheimer\u2019s disease: a retrospective cohort study","volume":"10","author":"Acosta-Baena N","year":"2011","unstructured":"Acosta-Baena N et al (2011) Pre-dementia clinical stages in presenilin 1 E280A familial early-onset Alzheimer\u2019s disease: a retrospective cohort study. 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