Tracing risk for T2D and AD

NEW YORK -- Given their respective pathologies as an endocrine disorder and a neurodegenerative disease, type 2 diabetes and Alzheimer's disease wouldn't seem to have much in common. However, a recent study out of the Icahn School of Medicine at Mount Sinai found that some patients with type 2 diabetes could have genetic risk factors that increase their risk of developing Alzheimer's disease. Dr. Giulio Maria Pasinetti, Saunders Family Chair, professor of Neurology at the Icahn School of Medicine at Mount Sinai and director of Biomedical Training in the Geriatric Research Education and Clinical Centers at J.J. Peters Bronx VA Medical Center, led the team in this work.

It has previously been known that diabetes could play a causative role in Alzheimer's onset and progression -- an increased risk for developing Alzheimer's disease is one of the leading long-term complications of type 2 diabetes -- but any specific mechanisms by which this occurs have not been clarified. Using genome wide association study results, the team examined whether type 2 diabetes and Alzheimer's disease share any genetic etiological factors and the impact those factors could impart on the mechanisms linked to both diseases. Genome wide association studies examine differences at numerous points along the genetic code to see if one or more variations are found more often in a population with a certain trait, such as increased disease risk. Among the differences such studies can detect are single nucleotide polymorphisms (SNPs), small genetic variations that can have significant impact.

As a result, the team found 927 SNPs associated with both diseases. Those genes that are influenced by SNPs shared between the diseases with the same risk allele were identified with an SNP annotation variation (ANNOVAR) software, then Association Protein-Protein Link Evaluator (DAPPLE) software to identify other proteins known to interact with ANNOVAR gene annotations. Of the 927 associated SNPs, 395 SNPs have the same risk for Alzheimer's disease and type 2 diabetes, “suggesting common pathogenic mechanisms underlying the development of both AD and T2D,” the abstract notes.

"We found that gene annotations from ANNOVAR and DAPPLE significantly enriched specific KEGG pathways pertaining to immune responses, cell signaling and neuronal plasticity, cellular processes in which abnormalities are known to contribute to both T2D and AD pathogenesis," the authors noted in the press release. "Thus, our observation suggests that among T2D subjects with common genetic predispositions (e.g., SNPs with consistent risk alleles for T2D and AD), dysregulation of these pathogenic pathways could contribute to the elevated risks for AD in subjects. Interestingly, we found that 532 of the shared T2D/AD GWAS SNPs had divergent risk alleles in the two diseases. For individual shared T2D/AD SNPs with divergent alleles, one of the allelic forms may contribute to one of the diseases (e.g., T2D), but not necessarily to the other (e.g., AD), or vice versa."

"We identified multiple genetic differences in terms of SNPs that are associated with higher susceptibility to develop type 2 diabetes as well as Alzheimer's disease," Pasinetti commented. "Many of these SNPs are traced to genes whose anomalies are known to contribute to T2D and AD, suggesting that certain diabetic patients with these genetic differences are at high risk for developing Alzheimer's. Our data highlights the need for further exploration of genetic susceptibility to Alzheimer's disease in patients with T2D."