Omega-3 (n-3) polyunsaturated fatty acids (PUFAs), such as docosahexaenoic acid (DHA), have important roles in human nutrition and brain health by promoting neuronal functions, maintaining inflammatory homeostasis, and providing structural integrity. As Alzheimer's disease (AD) pathology progresses, DHA metabolism in the brain becomes dysregulated, the timing and extent of which may be influenced by the apolipoprotein E ε4 (APOE4) allele. Here, we discuss how maintaining adequate DHA intake early in life may slow the progression to AD dementia in cognitively normal individuals with APOE4, how recent advances in DHA brain imaging could offer insights leading to more personalized preventive strategies, and how alternative strategies targeting PUFA metabolism pathways may be more effective in mitigating disease progression in patients with existing AD dementia.
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http://dx.doi.org/10.1016/j.tem.2024.03.003 | DOI Listing |
Background: Alzheimer's disease (AD) is a progressive neurodegenerative disease and the most prevalent type of senile dementia affecting more than 6 million Americans in 2023. Most of these AD cases are sporadic or late-onset AD with unclear etiology. Recent clinical trials on antibody drug clearing Ab plagues in brain show modest benefits of slowing down cognitive decline.
View Article and Find Full Text PDFAlzheimers Dement
December 2024
Weill Cornell Medicine, New York, NY, USA.
Background: The strongest genetic risk factors for AD include the e4 allele of APOE and the R47H point mutation in the TREM2 receptor. TREM2 is required for the induction of a disease-associated microglia (DAM) signature and microglial neurodegenerative phenotype (MGnD) in response to disease pathology, signatures which both include APOE upregulation. There is currently limited information regarding how the TREM2-APOE pathway ultimately contributes to AD risk, and downstream mechanisms of this pathway are unknown.
View Article and Find Full Text PDFAlzheimers Dement
December 2024
Department of Cell Biology and Pathology, New York, NY, USA.
Background: Possession of the APOE4 allele is the strongest genetic risk factor for developing the sporadic form of Alzheimer's disease (AD). Studies investigating APOE4's associated AD risk have largely centered on APOE4's propensity to regulate the deposition of extracellular amyloid beta plaques. More recent attempts to characterize APOE4's role in AD have brought into question the role APOE4 may possess in modulating the pathogenesis of intracellular tau tangles.
View Article and Find Full Text PDFAlzheimers Dement
December 2024
School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
Background: The common APOE2/E3/E4 polymorphism, the strongest risk factor for Alzheimer's disease (AD), is determined by two-site haplotypes at codons 112 (Cys>Arg) and 158 (Arg>Cys), resulting into six genotypes. Due to strong linkage disequilibrium between the two sites, 3 of the 4 expected haplotypes (E2, E3, E4) have been observed and extensively studied in relation to AD risk. Compared to the most common haplotype of E3 (Cys112 - Arg158), E4 (Arg112 - Arg 158) and E2 (Cys112 - Cys158) haplotypes are determined by a single-point mutation at codons 112 and 158, respectively.
View Article and Find Full Text PDFAlzheimers Dement
December 2024
University of Kentucky, Lexington, KY, USA.
Background: Apolipoprotein E (ApoE) exists in three protein isoforms: E2, E3, and E4, which differ by only one or two amino acids. These slight differences profoundly effect protein structure and function, allowing each isoform to differentially impact Alzheimer's Disease (AD) risk. Relative to the most common E3 isoform, E4 dramatically increases risk, while E2 confers a substantial decrease in risk.
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