Diabetes and overweight associate with non-APOE4 genotype in an Alzheimer's disease population
ABSTRACT 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.
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- "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. "
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.
Article: Division of Research Annual Report
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ABSTRACT: The cerebral neuropathology of Type 2 diabetes (CNDM2) has not been positively defined. This review includes a description of CNDM2 research from before the 'Pubmed Era'. Recent neuroimaging studies have focused on cerebrovascular and white matter pathology. These and prior studies about cerebrovascular histopathology in diabetes are reviewed. Evidence is also described for and against the link between CNDM2 and Alzheimer's disease pathogenesis. To study this matter directly, we evaluated data from University of Kentucky Alzheimer's Disease Center (UK ADC) patients recruited while non-demented and followed longitudinally. Of patients who had come to autopsy (N = 234), 139 met inclusion criteria. These patients provided the basis for comparing the prevalence of pathological and clinical indices between well-characterized cases with (N = 50) or without (N = 89) the premortem diagnosis of diabetes. In diabetics, cerebrovascular pathology was more frequent and Alzheimer-type pathology was less frequent than in non-diabetics. Finally, a series of photomicrographs demonstrates histopathological features (including clinical-radiographical correlation) observed in brains of persons that died after a history of diabetes. These preliminary, correlative, and descriptive studies may help develop new hypotheses about CNDM2. We conclude that more work should be performed on human material in the context of CNDM2.Biochimica et Biophysica Acta 09/2008; 1792(5):454-69. DOI:10.1016/j.bbadis.2008.08.005 · 4.66 Impact Factor