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Abstract: APOE is the major known genetic risk factor for late-onset Alzheimer''s disease. Though relationships between APOE-encoded apolipoprotein E and β-amyloid are increasingly well described, mounting evidence supports wide-ranging effects of APOE on the brain. Specifically, APOE appears to affect brain network activity and closely related neuroenergetic functions that might be involved in vulnerability to neurodegenerative pathophysiology. These effects highlight the salience of further investigation into the diverse influences of APOE. Therefore, this article reviews the interplay between APOE and neuroenergetics and proposes areas for further investigation. This research might lead to the identification of novel therapeutic targets for the treatment and/or prevention of Alzheimer''s disease. [Copyright &y& Elsevier]

Nutrition has been highlighted as a potential factor in Alzheimer's disease (AD) risk and decline and has been investigated as a therapeutic target. Broad-based combination diet therapies have the potential to simultaneously effect numerous protective and corrective processes, both directly (e.g., neuroprotection) and indirectly (e.g., improved vascular health). Here we administered either normal mouse chow with a broad-based nutritional supplement or mouse chow alone to aged male and female 3xTg mice and wildtype (WT) controls. After approximately 4 months of feeding, mice were given a battery of cognitive tasks and then injected with a radiolabeled glucose analog. Brains were assessed for differences in regional glucose uptake and mitochondrial cytochrome oxidase activity, AD pathology, and inflammatory markers. Supplementation induced behavioral changes in the 3xTg, but not WT, mice, and the mode of these changes was influenced by sex. Subsequent analyses indicated that differential response to supplementation by male and female 3xTg mice highlighted brain regional strategies for the preservation of function. Several regions involved have been shown to mediate responses to steroid hormones, indicating a mechanism for sex-based vulnerability. Thus, these findings may have broad implications for the human response to future therapeutics. [ABSTRACT FROM AUTHOR]

In vivo PET imaging studies of young-adult carriers of the apolipoprotein E ℇ4 allele (APOEℇ4), the major Alzheimer's disease (AD) susceptibility gene, have demonstrated declines in glucose metabolism in brain areas later vulnerable to AD, such as posterior cingulate cortex, decades before the possible onset of symptoms. We have previously shown in postmortem studies that such metabolic declines in AD are associated with brain regional mitochondrial dysfunction. To determine whether young adult at-risk individuals demonstrate similar mitochondrial functional decline, we histochemically assessed postmortem tissues from the posterior cingulate cortex of young-adult carriers and noncarriers of APOEℇ4. At-risk ℇ4 carriers had lower mitochondrial cytochrome oxidase activity than noncarriers in posterior cingulate cortex, particularly within the superficial cortical lamina, a pattern similar to that seen in AD patients. Except for one 34 year-old ℇ4 homozygote, the ℇ4 carriers did not have increased soluble amyloid-β, histologic amyloid-β, or tau pathology in this same region. This functional biomarker may prove useful in early detection and tracking of AD and indicates that mitochondrial mechanisms may contribute to the predisposition to AD before any evidence of amyloid or tau pathology. [ABSTRACT FROM AUTHOR]