Diabetic Phenotypes and Late-Life Dementia Risk

Abstract

Background Mendelian Randomization (MR) studies have reported that type 2 diabetes (T2D) was not associated with Alzheimer's Disease (AD). We adopted a modified, mechanism-specific MR design to explore this surprising result. Methods Using inverse-variance weighted MR analysis, we evaluated the association between T2D and AD using data from 39 single nucleotide polymorphisms (SNPs) significantly associated to T2D in DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) and the corresponding associations of each SNP with AD risk obtained from the International Genomics of Alzheimer's Project (IGAP, n=17,008 AD cases and n=37,154 controls). We evaluated mechanism-specific genetic subscores, including beta-cell function, insulin sensitivity, and adiposity, and repeated analyses in 8,501 Health and Retirement Study (HRS) participants for replication and model validation. Results In IGAP, the overall T2D polygenic score did not predict AD (odds ratio (OR) for the T2D polygenic score = 1.01, 95% confidence interval (CI): 0.96, 1.06) but the insulin sensitivity polygenic score predicted higher AD risk (OR=1.17, CI: 1.02, 1.34). In HRS, polygenic scores were associated with T2D risk; the associations between insulin sensitivity genetic polygenic score and cognitive phenotypes were not statistically significant. Conclusion Evidence from polygenic scores suggests insulin sensitivity specifically may affect AD risk, more than T2D overall.

Which Risk Factors Causally Influence Dementia? A Systematic Review of Mendelian Randomization Studies

“…Two studies [ 12, 21 ] examined the causal relationship between type 2 diabetes (T2D) or related phenotypes and odds of AD using the International Genomics of Alzheimer’s Project (IGAP) GWAS results. One of these studies [ 21 ] also investigated the link with dementia probability in the Health and Retirement Study (HRS). Although they selected different sets of SNPs for the T2D GRS (49 [ 12 ] versus 39 [ 21 ] SNPs), neither study [ 12, 21 ] found a significant association with T2D.…”

“…One of these studies [ 21 ] also investigated the link with dementia probability in the Health and Retirement Study (HRS). Although they selected different sets of SNPs for the T2D GRS (49 [ 12 ] versus 39 [ 21 ] SNPs), neither study [ 12, 21 ] found a significant association with T2D. There was also little evidence to support the relationship with T2D related phenotypes, as the nominally significant finding by Walter and colleagues [ 21 ] for insulin sensitivity did not survive Bonferroni multiple testing correction ( p = 0.08).…”

“…Although they selected different sets of SNPs for the T2D GRS (49 [ 12 ] versus 39 [ 21 ] SNPs), neither study [ 12, 21 ] found a significant association with T2D. There was also little evidence to support the relationship with T2D related phenotypes, as the nominally significant finding by Walter and colleagues [ 21 ] for insulin sensitivity did not survive Bonferroni multiple testing correction ( p = 0.08). However, higher fasting glucose was significantly associated with increased odds of AD after excluding one SNP (rs11039149) which is possibly pleiotropically associated with AD [ 12 ] ( Table 3 ).…”

Lack of genetic support for shared aetiology of Coronary Artery Disease and Late-onset Alzheimer’s disease

“…Another study reported null associations between genetically-predicted body mass index with LOAD 33 . Likewise, variants encoding Type-2 diabetes were also unrelated to LOAD 34 .…”

Type 2 Diabetes, Cognition, and Dementia in Older Adults: Toward a Precision Health Approach

“…However, in a follow-up MR study that examined single nucleotide polymorphisms independently according to their specific biological mechanism, Alzheimer’s disease dementia risk correlated negatively with insulin sensitivity only (31), a finding that is not surprising given the wealth of literature that connects insulin dysfunction with Alzheimer’s disease dementia–specific neuropathological changes. In addition, a recent examination of genome-wide association study data found significant overlap between single-nucleotide polymorphisms (SNPs) associated with type 2 diabetes and Alzheimer’s disease, providing initial evidence that the two diseases may indeed share genetic risk.…”