APOE ε4 (apoE4) polymorphism is the main genetic determinant of sporadic Alzheimer's disease (AD). A dietary approach (Fortasyn) including docosahexaenoic acid, eicosapentaenoic acid, uridine, choline, phospholipids, folic acid, vitamins B12, B6, C, and E, and selenium has been proposed for dietary management of AD. We hypothesize that the diet could inhibit AD-like pathologies in apoE4 mice, specifically cerebrovascular and connectivity impairment. Moreover, we evaluated the diet effect on cerebral blood flow (CBF), functional connectivity (FC), gray/white matter integrity, and postsynaptic density in aging apoE4 mice. At 10-12 months, apoE4 mice did not display prominent pathological differences compared to wild-type (WT) mice. However, 16-18-month-old apoE4 mice revealed reduced CBF and accelerated synaptic loss. The diet increased cortical CBF and amount of synapses and improved white matter integrity and FC in both aging apoE4 and WT mice. We demonstrated that protective mechanisms on vascular and synapse health are enhanced by Fortasyn, independent of apoE genotype. We further showed the efficacy of a multimodal translational approach, including advanced MR neuroimaging, to study dietary intervention on brain structure and function in aging.
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http://dx.doi.org/10.1155/2016/6846721 | DOI Listing |
Commun Biol
January 2025
School of Psychology and Sussex Neuroscience, University of Sussex, Brighton, UK.
Reduced cerebral blood flow occurs early in the development of Alzheimer's disease (AD), but the factors producing this reduction are unknown. Here, we ask whether genetic and lifestyle risk factors for AD-the ε4 allele of the Apolipoprotein (APOE) gene, and physical activity-can together produce this reduction in cerebral blood flow which leads eventually to AD. Using in vivo two-photon microscopy and haemodynamic measures, we record neurovascular function from the visual cortex of physically active or sedentary mice expressing APOE3 and APOE4 in place of murine APOE.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
February 2025
Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA 94158.
The ε4 variant of human apolipoprotein E () is a key genetic risk factor for neurodegeneration in Alzheimer's disease and elevated all-cause mortality in humans. Understanding the factors and mechanisms that can mitigate the harmful effects of has significant implications. In this study, we find that inactivating the VHL-1 (Von Hippel-Lindau) protein can suppress mortality, neural and behavioral pathologies caused by transgenic human in .
View Article and Find Full Text PDFPLoS One
January 2025
Center for Innovation in Brain Science, University of Arizona Health Sciences, Tucson, Arizona, United States of America.
Translational validity of mouse models of Alzheimer's disease (AD) is variable. Because change in weight is a well-documented precursor of AD, we investigated whether diversity of human AD risk weight phenotypes was evident in a longitudinally characterized cohort of 1,196 female and male humanized APOE (hAPOE) mice, monitored up to 28 months of age which is equivalent to 81 human years. Autoregressive Hidden Markov Model (AHMM) incorporating age, sex, and APOE genotype was employed to identify emergent weight trajectories and phenotypes.
View Article and Find Full Text PDFMol Neurodegener
January 2025
Department of Neurobiology and Behavior, Charlie Dunlop School of Biological Sciences, University of California, Irvine, CA, 92697-4545, USA.
Background: Apolipoprotein E ε4 (APOE4) is the strongest genetic risk factor for late-onset Alzheimer's disease (LOAD). A recent case report identified a rare variant in APOE, APOE3-R136S (Christchurch), proposed to confer resistance to autosomal dominant Alzheimer's Disease (AD). However, it remains unclear whether and how this variant exerts its protective effects.
View Article and Find Full Text PDFBiol Sex Differ
January 2025
Department of Neurosurgery, Neurosurgery Research Institute, Institute of Neurology, Fujian Provincial Institutes of Brain Disorders and Brain Sciences, The First Affiliated Hospital, Binhai Branch of National Regional Medical Center, Fujian Medical University, Fuzhou, Fujian, 350005, China.
Background: Apolipoprotein E4 (ApoE4) is associated with an increased risk of Alzheimer's disease (AD), depression, and anxiety, which were reported to improve after the administration of metformin. However, sex influence on the effect of ApoE4 and metformin on cognition and mental health is poorly understood.
Methods: ApoE3-TR and apoE4-TR mice of both sexes were randomly assigned to the normal saline and metformin groups from 13 months to 18 months of age.
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