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Apolipoprotein E4 genotype in combination with poor metabolic profile is associated with reduced cognitive performance in healthy postmenopausal women: implications for late onset Alzheimer's disease.

ABSTRACT: OBJECTIVE:We hypothesized the association of metabolic profile on cognition in postmenopausal women will be greater among ApoE4 carriers compared with noncarriers. METHODS:Metabolic biomarkers and measures of global cognition, executive functions, and verbal memory, collected among postmenopausal females, were used in this analysis. Clustering analyses of metabolic biomarkers revealed three phenotypes: healthy, predominantly hypertensive, and poor metabolic with (borderline normal laboratory values). General linear models tested whether an association of metabolic cluster with cognition differed by ApoE4 genotype. RESULTS:In the total sample of 497 women, verbal memory was lower in the poor metabolic cluster (P?=?0.04). Among ApoE4+ women, performance in all cognitive domains was lowest in the poor metabolic cluster. Differences in executive functions among metabolic clusters were detected only in ApoE4+ women (P value for interaction?=?0.003). CONCLUSIONS:In a general population of postmenopausal women, association between poor metabolic profile with reduction in cognitive performance is more apparent in women who carry an ApoE4 allele. These data indicate a window of opportunity for interventions to reverse the trajectory of the preclinical phase of Alzheimer's disease.

SUBMITTER: Karim R

PROVIDER: S-EPMC7508039 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Apolipoprotein E4 genotype in combination with poor metabolic profile is associated with reduced cognitive performance in healthy postmenopausal women: implications for late onset Alzheimer's disease.

Karim Roksana R Koc Melissa M Rettberg Jamaica R JR Hodis Howard N HN Henderson Victor W VW St John Jan A JA Allayee Hooman H Brinton Roberta D RD Mack Wendy J WJ

Menopause (New York, N.Y.) 20190101 1

<h4>Objective</h4>We hypothesized the association of metabolic profile on cognition in postmenopausal women will be greater among ApoE4 carriers compared with noncarriers.<h4>Methods</h4>Metabolic biomarkers and measures of global cognition, executive functions, and verbal memory, collected among postmenopausal females, were used in this analysis. Clustering analyses of metabolic biomarkers revealed three phenotypes: healthy, predominantly hypertensive, and poor metabolic with (borderline normal ...[more]

PMID: 29975287

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Project description:In addition to being the greatest genetic risk factor for Alzheimer's disease, expression of the ɛ4 allele of apolipoprotein E can lead to cognitive decline during ageing that is independent of Alzheimer's amyloid-β and tau pathology. In human post-mortem tissue and mouse models humanized for apolipoprotein E, we examined the impact of apolipoprotein E4 expression on brain exosomes, vesicles that are produced within and secreted from late-endocytic multivesicular bodies. Compared to humans or mice homozygous for the risk-neutral ɛ3 allele we show that the ɛ4 allele, whether homozygous or heterozygous with an ɛ3 allele, drives lower exosome levels in the brain extracellular space. In mice, we show that the apolipoprotein E4-driven change in brain exosome levels is age-dependent: while not present at age 6 months, it is detectable at 12 months of age. Expression levels of the exosome pathway regulators tumor susceptibility gene 101 (TSG101) and Ras-related protein Rab35 (RAB35) were found to be reduced in the brain at the protein and mRNA levels, arguing that apolipoprotein E4 genotype leads to a downregulation of exosome biosynthesis and release. Compromised exosome production is likely to have adverse effects, including diminishing a cell's ability to eliminate materials from the endosomal-lysosomal system. This reduction in brain exosome levels in 12-month-old apolipoprotein E4 mice occurs earlier than our previously reported brain endosomal pathway changes, arguing that an apolipoprotein E4-driven failure in exosome production plays a primary role in endosomal and lysosomal deficits that occur in apolipoprotein E4 mouse and human brains. Disruption of these interdependent endosomal-exosomal-lysosomal systems in apolipoprotein E4-expressing individuals may contribute to amyloidogenic amyloid-β precursor protein processing, compromise trophic signalling and synaptic function, and interfere with a neuron's ability to degrade material, all of which are events that lead to neuronal vulnerability and higher risk of Alzheimer's disease development. Together, these data suggest that exosome pathway dysfunction is a previously unappreciated component of the brain pathologies that occur as a result of apolipoprotein E4 expression.

Dataset Information

Apolipoprotein E4 genotype in combination with poor metabolic profile is associated with reduced cognitive performance in healthy postmenopausal women: implications for late onset Alzheimer's disease.

Publications

Apolipoprotein E4 genotype in combination with poor metabolic profile is associated with reduced cognitive performance in healthy postmenopausal women: implications for late onset Alzheimer's disease.

Similar Datasets

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