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.

Sex and ApoE Genotype Differences in Treatment Response to Two Doses of Intranasal Insulin in Adults with Mild Cognitive Impairment or Alzheimer's Disease

“…There has been evidence that ApoE ε4 negative individuals are more sensitive to the cognitive consequences of insulin resistance [15, 24] and that a relationship between insulin resistance and dementia risk may be most commonly observed for adults without an ε4 allele [38, 39]. Our current results further extend this finding to suggest that the ApoE ε4 gene interacts with sex to moderate treatment response.…”

Obesity Accelerates Alzheimer-Related Pathology inAPOE4but notAPOE3Mice

“…Further, levels of senile plaques and neurofibrillary tangles were highest in obese men that were also APOE 4 carriers (Peila et al, 2002). However, several other studies reported that the AD risk associated with obesity and metabolic syndrome is stronger in APOE 3 carriers (Dixit et al, 2005; Leiva et al, 2005; Singh et al, 2006; Profenno and Faraone, 2008). …”

“…Interestingly, APOE 4 carriers can be more sensitive to metabolic consequences associated with obesity (de-Andrade et al, 2000; Kypreos et al, 2009; Niu et al, 2009; Atabek et al, 2012; Zarkesh et al, 2012; Guan et al, 2013). Although some studies do not report an APOE 4 bias in obesity-associated AD risk (Profenno and Faraone, 2008; Luchsinger et al, 2012), others have found that AD risk is increased by obesity (Peila et al, 2002; Ghebranious et al, 2011) and diets high in calories and fatty acids (Luchsinger et al, 2002) only in APOE 4 carriers. Though the human literature suggests a gene-environment interaction between APOE and obesity in regulating development of AD, this question has not been addressed in experimental models.…”

Amyloid precursor protein modulates macrophage phenotype and diet-dependent weight gain

“…Although they may appear as disparate conditions, the risk of Alzheimer’s disease, AD, is increased by middle age obesity, type II diabetes, and cardiovascular/cerebrovascular disease123456789101112131415161718192021, suggesting that a common mechanism of pathophysiology may exist between these conditions. For example, amyloid precursor protein, APP, cleavage to generate the aggregate-prone amyloid beta, Aβ, peptide is a hallmark of the senile plaque pathology of sporadic late onset and early onset AD22.…”