Associations between antidiabetic medications and cerebrospinal fluid biomarkers of Alzheimer's disease

Background: It has been hypothesized that insulin resistance is pivotal in mediating amyloid and tau dysregulations in Alzheimer's disease (AD).

Objective: To investigate the impact of different antidiabetic agents, their daily dosage intake, and treatment duration on cerebrospinal fluid (CSF) AD biomarkers among patients with type 2 diabetes.

Methods: This cross-sectional study selected patients between 50 and 80 years with diabetes and CSF AD biomarkers screened between 2017 and 2023 in the VALCODIS Cohort. CSF biomarkers were total tau (t-tau), phosphorylated tau 181 (p-tau), and amyloid-β 42 (Aβ₄₂). Analytical variables were obtained. Antidiabetic prescriptions were recorded in defined daily doses (DDD), according to the ATC/DDD 2021 system, and years of drug exposure duration before lumbar puncture. Logistic regressions were performed to establish the correlations between drug usage and AD biomarker alteration.

Results: Among patients with diabetes, Insulin consumption was associated with lower odds of abnormal Aβ₄₂ levels (OR 0.36 [95% CI 0.15, 0.76]) and tau pathology (OR 0.49 [95% CI 0.24-0.98]). Metformin was related to lower odds of pathological p-tau when diabetes was uncontrolled, acting on t-tau and t-tau/Aβ₄₂ ratio when it was concomitant with insulin, and patients had controlled diabetes. Lower odds of pathological levels of tau were observed when additional oral antidiabetic drugs were added among metformin users. iSGLT2 was associated with tau pathology.

Conclusions: The impact of antidiabetics on AD-related pathological biomarkers may depend on diabetes management.