Alzheimer’s Disease-Related Neuropathology Among Patients with Medication Treated Type 2 Diabetes in a Community-Based Autopsy Cohort

Article type: Research Article

Authors: Barthold, Douglas^{a; b; *} | Gibbons, Laura E.^{c; g} | Marcum, Zachary A.^{a; b} | Gray, Shelly L.^{a; b} | Dirk Keene, C.^d | Grabowski, Thomas J.^e | Postupna, Nadia^d | Larson, Eric B.^{f; g; 1} | Crane, Paul K.^{g; 1}

Affiliations: [a] The Comparative Health Outcomes, Policy, and Economics (CHOICE) Institute, Department of Pharmacy, University of Washington, Seattle, WA, USA | [b] The Plein Center for Geriatric Pharmacy Research, Education, and Outreach, School of Pharmacy, University of Washington, Seattle, WA, USA | [c] General Internal Medicine, Data Management and Statistics Core, Alzheimer’s Disease Research Center, University of Washington, Seattle, WA, USA | [d] Laboratory Medicine and Pathology, School of Medicine, University of Washington, Seattle, WA, USA | [e] Departments of Radiology and Neurology, UW School of Medicine, Alzheimer’s Disease Research Center, University of Washington, Seattle, WA, USA | [f] Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA | [g] Department of Medicine, UW School of Medicine, University of Washington, Seattle, WA, USA

Correspondence: [*] Correspondence to: Douglas Barthold, UW Department of Pharmacy, 1959 Pacific St NE, Box 357630, Seattle, WA 98107, USA. Tel.: +1 781 264 3267; E-mail: barthold@uw.edu.

Note: [1] These authors contributed equally and should be considered co-senior authors on this work.

Abstract: Background:Diabetes is a risk factor for Alzheimer’s disease and related dementias (ADRD). Epidemiologic evidence shows an association between diabetes medications and ADRD risk; cell and mouse models show diabetes medication association with AD-related neuropathologic change (ADNC). Objective:This hypothesis-generating analysis aimed to describe autopsy-measured ADNC for individuals who used diabetes medications. Methods:Descriptive analysis of ADNC for Adult Changes in Thought (ACT) Study autopsy cohort who used diabetes medications, including sulfonylureas, insulin, and biguanides; total N = 118. ADNC included amyloid plaque distribution (Thal phasing), neurofibrillary tangle (NFT) distribution (Braak stage), and cortical neuritic plaque density (CERAD score). We also examined quantitative measures of ADNC using the means of standardized Histelide measures of cortical PHF-tau and Aβ1–42. Adjusted analyses control for age at death, sex, education, APOE genotype, and diabetes complication severity index. Results:Adjusted analyses showed no significant association between any drug class and traditional neuropathologic measures compared to nonusers of that class. In adjusted Histelide analyses, any insulin use was associated with lower mean levels of Aβ1–42 (–0.57 (CI: –1.12, –0.02)) compared to nonusers. Five years of sulfonylureas and of biguanides use was associated with lower levels of Aβ1–42 compared to nonusers (–0.15 (CI: –0.28, –0.02), –0.31 (CI: –0.54, –0.07), respectively). Conclusion:Some evidence exists that diabetes medications are associated with lower levels of Aβ1–42, but not traditional measures of neuropathology. Future studies are needed in larger samples to build understanding of the mechanisms between diabetes, its medications, and ADRD, and to potentially repurpose existing medications for prevention or delay of ADRD.

Keywords: Alzheimer’s disease, dementia, diabetes treatments, neuropathology

DOI: 10.3233/JAD-210059

Journal: Journal of Alzheimer's Disease, vol. 83, no. 3, pp. 1303-1312, 2021