The association between diabetes and Alzheimer’s disease pathophysiology

Background Diabetes is common in persons with dementia and associated with cognitive decline. However, the relation between diabetes and AD pathophysiology is still unclear. Our aim is to assess the association of diabetes diagnosis and blood glucose regulation with CSF AD biomarkers across the AD clinical spectrum, and the potential moderating effects of vascular factors in this relationship. Method As part of the PRIME project, we included individuals from five European memory clinic cohorts with normal cognition (NC, n=419) mild cognitive impairment (MCI, n=363) and dementia (n=151). Inclusion criteria were availability of diabetes diagnosis, fasting blood glucose or HbA1c levels and cerebrospinal fluid (CSF) biomarkers amyloid‐beta42, p‐tau and t‐tau. Center‐specific cut‐offs were used to define biomarker positivity. We performed logistic and linear regression models adjusted for age, education years, gender, cohort, to assess the relation between diabetes and AD biomarkers, as well as the potential influence of hypertension, hypercholesterolemia and BMI on this relationship. Result We included 933 participants in our analysis with an average age of 66.1 years (Table 1). Diabetes was associated with lower odds of being amyloid positive in the total group and in individuals with NC and dementia (Table 2). Diabetes was associated with a lower risk for p‐tau and t‐tau positivity in the total group and in the MCI subgroup. Similar trends were found with HbA1c and blood glucose as predictors. A higher BMI was associated with less t‐tau pathology in persons with diabetes only. Presence of hypertension and hypercholesterolemia did not influence the association between diabetes and AD biomarkers. Additionally, post‐hoc analyses with diagnostic group stratified for amyloid positivity were performed. These analyses indicated that amyloid‐negative demented individuals more often had diabetes than amyloid‐negative NC and MCI individuals (Figure 1). Relative to amyloid‐negative NC, amyloid‐negative demented individuals had higher HbA1c and glucose levels (Figure 2). Amyloid‐positive demented individuals had higher HbA1c levels than amyloid‐positive NC and MCI patients. Conclusion Diabetes and impaired glucose regulation are associated with non‐AD dementia but not with AD‐related cognitive impairments. Surprisingly, amyloid positive individuals with normal cognition less often had diabetes.