Type 2 diabetes is a risk factor for late-onset Alzheimer's disease (AD), and studies suggest that pathogenic effects of diabetes and insulin resistance may be associated with non-APOE4 AD. Therefore, we examined association of the APOE4 allele with diabetes in an AD population. Retrospective and cross-sectional clinical and APOE-genotype data on 465 cases with probable or definite AD previously ascertained by the National Institute of Mental Health Genetics Initiative were analyzed by regression analysis. Dependent variables included presence of APOE4 alleles and AD onset age. Diabetes was the independent variable and covariates included gender, hypertension, and other potentially confounding variables. We also examined for interactions involving weight status as overweight and obesity are independent risk factors for insulin resistance, diabetes and AD. Prevalence of diabetes was 13% among AD cases without an APOE4 allele and 5-6% among AD cases with one or two APOE4 alleles. Odds ratio for diabetes was 0.26 [95% CI: 0.09-0.73; P = 0.011] by APOE4 status after adjusting for all covariates. Diabetes did not associate with AD onset age. Among other independent variables included in the model, APOE4 and diuretic medication treatment were associated with AD onset age. In a subset of cases with body mass index determinations, overweight also exhibited an inverse association with APOE4 and associated with decreased non-APOE4 AD onset age. Pathogenic mechanisms associated with diabetes and overweight are enriched in AD cases without an APOE4 allele.
"Although our study has focused specifically on changes related to diet induced obesity it is difficult not to speculate that the changes observed may be directly relevant to the mechanism of Alzheimer's disease. As already mentioned, mid-life obesity is a well-recognized increased risk factor for developing AD , , , , ,  and several rodent studies using transgenic mouse models of AD have demonstrated that diet-induced obesity paradigms increase Aβ levels in the brain , , . More importantly, caloric restriction of these transgenic models is sufficient to decrease brain Aβ levels and plaque load . "
[Show abstract][Hide abstract] ABSTRACT: Middle age obesity is recognized as a risk factor for Alzheimer's disease (AD) although a mechanistic linkage remains unclear. Based upon the fact that obese adipose tissue and AD brains are both areas of proinflammatory change, a possible common event is chronic inflammation. Since an autosomal dominant form of AD is associated with mutations in the gene coding for the ubiquitously expressed transmembrane protein, amyloid precursor protein (APP) and recent evidence demonstrates increased APP levels in adipose tissue during obesity it is feasible that APP serves some function in both disease conditions.
To determine whether diet-induced obesity produced proinflammatory changes and altered APP expression in brain versus adipose tissue, 6 week old C57BL6/J mice were maintained on a control or high fat diet for 22 weeks. Protein levels and cell-specific APP expression along with markers of inflammation and immune cell activation were compared between hippocampus, abdominal subcutaneous fat and visceral pericardial fat. APP stimulation-dependent changes in macrophage and adipocyte culture phenotype were examined for comparison to the in vivo changes.
Adipose tissue and brain from high fat diet fed animals demonstrated increased TNF-α and microglial and macrophage activation. Both brains and adipose tissue also had elevated APP levels localizing to neurons and macrophage/adipocytes, respectively. APP agonist antibody stimulation of macrophage cultures increased specific cytokine secretion with no obvious effects on adipocyte culture phenotype. These data support the hypothesis that high fat diet-dependent obesity results in concomitant pro-inflammatory changes in brain and adipose tissue that is characterized, in part, by increased levels of APP that may be contributing specifically to inflammatory changes that occur.
PLoS ONE 01/2012; 7(1):e30378. DOI:10.1371/journal.pone.0030378 · 3.23 Impact Factor
"Surprisingly few studies have addressed the association between the APOE polymorphism and risk of diabetes. However, our marginally significant inverse association with E4 genotypes and past history of diabetes was consistent with a mouse model demonstrating that APOE deficiency abrogates insulin resistance  and with the observations in humans that the E4 genotypes were associated with a decreased risk and E2 genotypes with an increased risk of diabetes [57, 58]. On the other hand, the associations between the FAPB2 polymorphism and diabetes remain inconsistent  despite the fact that the polymorphism has been associated with postprandial glucose and insulin levels [26, 34, 35]. "
[Show abstract][Hide abstract] ABSTRACT: Dysfunctional lipid metabolism plays a central role in pathogenesis of major chronic diseases, and genetic factors are important determinants of individual lipid profiles. We analyzed the associations of two well-established functional polymorphisms (FABP2 A54T and APOE isoforms) with past and family histories of 1492 population samples. FABP2-T54 allele was associated with an increased risk of past history of myocardial infarction (odds ratio (OR) = 1.51). Likewise, the subjects with APOE4, compared with E2 and E3, had a significantly increased risk of past history myocardial infarction (OR = 1.89). The OR associated with APOE4 was specifically increased in women for past history of myocardial infarction but decreased for gallstone disease. Interactions between gender and APOE isoforms were also significant or marginally significant for these two conditions. FABP2-T54 allele may be a potential genetic marker for myocardial infarction, and APOE4 may exert sex-dependent effects on myocardial infarction and gallbladder disease.
"The distinct difference in hippocampal insulin responses across apolipoprotein E-epsilon-4 genotype in AD suggests that these two sub-populations might exhibit fundamental differences in brain insulin sensitivity in AD. It is interesting to note that apolipoprotein E-epsilon-4 negative AD are at increased risk for type 2 diabetes and overweight, (Profenno & Faraone, 2008) providing evidence of peripheral insulin signaling disparities across apolipoprotein E-epsilon-4 genotype. Although the biochemical reasons for this genetic-based difference in insulin brain responses cannot be determined from our study, apolipoprotein E- epsilon-4 genotype in AD nevertheless appears to be an important consideration when assessing insulin effects on both memory and brain activity in AD, and might be an important factor if insulin-based AD treatment is considered in the future. "
[Show abstract][Hide abstract] ABSTRACT: Background: Several studies have demonstrated that insulin delivered by nasal spray acutely improves cognitive performance in early Alzheimer's disease. Furthermore, the apolipoprotein E-episilon-4 allele, a known AD risk factor, appears to influence those cognitive responses in a dose dependent manner, with carriers exhibiting impaired cognitive performance at higher insulin doses. The neural correlates of this phenomenon are however presently undefined. Hippocampal neurons are known to express insulin receptors in high densities, and neuronal insulin signaling is thought to modulate long-term potentiation mechanisms, suggesting that insulin might act at the hippocampus to generate cognitive enhancement. How the apolipoprotein E-epsilon-4 allele might interact with hippocampal insulin responses is not clear however. Methods: We studied the effects of a single 40IU dose of insulin aspart on hippocampal activation in 10 cognitively intact and 18 early AD subjects in a double-blind, counterbalanced, crossover memory encoding BOLD-based functional MRI study. We also assessed the effects of insulin on non-cognitive brain function with an fMRI motor task, and mean cerebral blood flow with arterial spin-labeled MRI. Last, insulin's effect on cognitive performance was assessed. We hypothesized AD subjects would demonstrate insulin-related increases in hippocampal activation, and that insulin-related changes would be greatest in apolipoprotein E-epsilon-4 negative AD. We further hypothesized insulin-related increases in mean cerebral blood flow in all subjects. Results: We observed an apolipoprotein E-epsilon-4 based interaction in insulin-related changes in hippocampal activation in AD, with carriers exhibiting decreased activation with insulin. Mean cerebral blood flow did not change significantly with insulin administration. Cognitive performance increased in the apolipoprotein E-epsilon-4 negative AD subjects after insulin administration. Conclusions: There is growing body of research indicating that faulty insulin signaling might be a component of AD neuropathology. The results herein are the first description of the neural correlates of insulin-related cognitive enhancement in AD, and provide direct evidence that insulin might serve an important neuromodulatory role in AD. Insulin also appears to modulate non-cognitive functions in a manner similar to hippocampal activity, suggesting that insulin might have wide spread effects on brain physiology, while the arterial spin-labeled MRI results suggest that insulin's effects are independent of cerebral blood flow. Our results furthermore underscore the importance of the apolipoprotein E-epsilon-4 allele in brain insulin responses.
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