Raffaele Cacciaglia1, José Luis Molinuevo2, Carles Falcón3, Anna Brugulat-Serrat1, Gonzalo Sánchez-Benavides1, Nina Gramunt4, Manel Esteller5, Sebastián Morán6, Carolina Minguillón1, Karine Fauria1, Juan Domingo Gispert7. 1. Barcelonabeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Catalonia, Spain. 2. Barcelonabeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Catalonia, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain; CIBER Fragilidad y Envejecimiento Saludable (CIBERFES), Madrid, Spain. Electronic address: jlmolinuevo@fpmaragall.org. 3. Barcelonabeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Catalonia, Spain; Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Zaragoza, Spain. 4. Barcelonabeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Catalonia, Spain; CIBER Fragilidad y Envejecimiento Saludable (CIBERFES), Madrid, Spain. 5. Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Catalonia, Spain; Departament de Ciències Fisiològiques II, Escola de Medicina, Universitat de Barcelona, Barcelona, Catalonia, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain. 6. Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Catalonia, Spain. 7. Barcelonabeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Catalonia, Spain; Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Zaragoza, Spain. Electronic address: jdgispert@fpmaragall.org.
Abstract
INTRODUCTION: Apolipoprotein E (APOE)-ε4 is the major genetic risk factor for Alzheimer's disease. However, the dose-dependent impact of this allele on brain morphology of healthy individuals remains unclear. METHODS: We analyzed gray matter volumes (GMvs) in a sample of 533 healthy middle-aged individuals with a substantial representation of ε4-carriers (207 heterozygotes and 65 homozygotes). RESULTS: We found APOE-ε4 additive GMv reductions in the right hippocampus, caudate, precentral gyrus, and cerebellar crus. In these regions, the APOE genotype interacted with age, with homozygotes displaying lower GMv after the fifth decade of life. APOE-ε4 was also associated to greater GMv in the right thalamus, left occipital gyrus, and right frontal cortex. DISCUSSION: Our data indicate that APOE-ε4 exerts additive effects on GMv in regions relevant for Alzheimer's disease pathophysiology already in healthy individuals. These findings elucidate the mechanisms underlying the increased Alzheimer's disease risk in ε4-carriers, suggesting a dose-dependent disease vulnerability on the brain structure level.
INTRODUCTION:Apolipoprotein E (APOE)-ε4 is the major genetic risk factor for Alzheimer's disease. However, the dose-dependent impact of this allele on brain morphology of healthy individuals remains unclear. METHODS: We analyzed gray matter volumes (GMvs) in a sample of 533 healthy middle-aged individuals with a substantial representation of ε4-carriers (207 heterozygotes and 65 homozygotes). RESULTS: We found APOE-ε4 additive GMv reductions in the right hippocampus, caudate, precentral gyrus, and cerebellar crus. In these regions, the APOE genotype interacted with age, with homozygotes displaying lower GMv after the fifth decade of life. APOE-ε4 was also associated to greater GMv in the right thalamus, left occipital gyrus, and right frontal cortex. DISCUSSION: Our data indicate that APOE-ε4 exerts additive effects on GMv in regions relevant for Alzheimer's disease pathophysiology already in healthy individuals. These findings elucidate the mechanisms underlying the increased Alzheimer's disease risk in ε4-carriers, suggesting a dose-dependent disease vulnerability on the brain structure level.
Authors: Ana B Martínez-Martínez; Elena Torres-Perez; Nicholas Devanney; Raquel Del Moral; Lance A Johnson; Jose M Arbones-Mainar Journal: Neurobiol Dis Date: 2020-02-19 Impact factor: 5.996
Authors: Jie Zhang; Jianfeng Wu; Qingyang Li; Richard J Caselli; Paul M Thompson; Jieping Ye; Yalin Wang Journal: IEEE Trans Med Imaging Date: 2021-07-30 Impact factor: 11.037
Authors: Emily J Van Etten; Pradyumna K Bharadwaj; Georg A Hishaw; Matthew J Huentelman; Theodore P Trouard; Matthew D Grilli; Gene E Alexander Journal: Hippocampus Date: 2021-02-15 Impact factor: 3.753