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Context Type 2 diabetes has been linked with an increased risk of Alzheimer’s disease (AD). Studies on the association between metformin use and AD have reported conflicting results. Objective To investigate whether metformin use modifies the association between diabetes and incident, clinically verified AD. Design Nested case-control study. Setting All community-dwelling people in Finland. Participants Cases were all community-dwelling Finns with AD diagnosed from 2005 to 2011 and with diabetes diagnosed ≥ 3 years before AD (n = 9862). Cases were matched with up to 2 control persons by age, sex, and diabetes duration (n = 19 550). Main outcome measure Cumulative metformin exposure was determined from reimbursed dispensings over a 10- to 16-year period. Adjusted odds ratios (aORs) were calculated using conditional logistic regression to estimate associations, with adjustment for potential confounders. Results A total of 7225 (73.3%) cases and 14528 (74.3%) controls received metformin at least once. Metformin use (ever use) was not associated with incident AD (aOR 0.99; 95% confidence interval [CI], 0.94–1.05). The adjusted odds of AD were lower among people dispensed metformin for ≥ 10 years (aOR 0.85; 95% CI, 0.76–0.95), those dispensed cumulative defined daily doses (DDDs) of &amp;lt; 1825–3650 (aOR 0.91; 95% CI, 0.84–0.98) and &amp;gt; 3650 DDDs (aOR 0.77; 95% CI, 0.67–0.88), and among persons dispensed an average of 2 g metformin daily (aOR 0.89; 95% CI, 0.82–0.96). Conclusion In this large national sample we found no evidence that metformin use increases the risk of AD. Conversely, long-term and high-dose metformin use was associated with a lower risk of incident AD in older people with diabetes.

Metformin and Risk of Alzheimer’s Disease Among Community-Dwelling People With Diabetes: A National Case-Control Study