Metformin Cessation and Dementia Incidence.

Importance: Prior studies suggested that metformin may be associated with reduced dementia incidence, but associations may be confounded by disease severity and prescribing trends. Cessation of metformin therapy in people with diabetes typically occurs due to signs of kidney dysfunction but sometimes is due to less serious adverse effects associated with metformin. Objective: To investigate the association of terminating metformin treatment for reasons unrelated to kidney dysfunction with dementia incidence. Design, Setting, and Participants: This cohort study was conducted at Kaiser Permanente Northern California, a large integrated health care delivery system, among a cohort of metformin users born prior to 1955 without history of diagnosed kidney disease at metformin initiation. Dementia follow-up began with the implementation of electronic health records in 1996 and continued to 2020. Data were analyzed from November 2021 through September 2023. Exposures: A total of 12 220 early terminators, individuals who stopped metformin with normal estimated glomerular filtration rate (eGFR), were compared with routine metformin users, who had not yet terminated metformin treatment or had terminated (with or without restarting) after their first abnormal eGFR measurement. Early terminators were matched with routine users of the same age and gender who had diabetes for the same duration. Main outcomes and measures: The outcome of interest was all-cause incident dementia. Follow-up for early terminators and their matched routine users was started at age of termination for the early terminator. Survival models adjusted for sociodemographic characteristics and comorbidities at the time of metformin termination (or matched age). Mediation models with HbA1c level and insulin usage 1 and 5 years after termination tested whether changes in blood glucose or insulin usage explained associations between early termination of metformin and dementia incidence. Results: The final analytic sample consisted of 12 220 early terminators (5640 women [46.2%]; mean [SD] age at start of first metformin prescription, 59.4 [9.0] years) and 29 126 routine users (13 582 women [46.6%]; mean [SD] age at start of first metformin prescription, 61.1 [8.9] years). Early terminators had 1.21 times the hazard of dementia diagnosis compared with routine users (hazard ratio, 1.21; 95% CI, 1.12 to 1.30). In mediation analysis, contributions to this association by changes in HbA1c level or insulin use ranged from no contribution (0.00 years; 95% CI, -0.02 to 0.02 years) for insulin use at 5 years after termination to 0.07 years (95% CI, 0.02 to 0.13 years) for HbA1c level at 1 year after termination, suggesting that the association was largely independent of changes in HbA1c level and insulin usage. Conclusions and Relevance: In this study, terminating metformin treatment was associated with increased dementia incidence. This finding may have important implications for clinical treatment of adults with diabetes and provides additional evidence that metformin is associated with reduced dementia risk.

Association of Education With Dementia Incidence Stratified by Ethnicity and Nativity in a Cohort of Older Asian American Individuals.

Importance: High education protects against dementia, but returns on educational attainment may be different across sociodemographic groups owing to various social factors. Asian American individuals are a growing and diverse group, but little research has assessed dementia determinants in this population. Objective: To examine the association of education with dementia in a large cohort of Asian American individuals, stratifying by ethnicity and nativity. Design, Setting, and Participants: This cohort study used electronic health record (EHR) and survey data from the Research Program on Genes, Environment, and Health and the California Men's Health Study surveys (2002-2020). Data are from Kaiser Permanente Northern California, an integrated health care delivery system. This study used a volunteer sample who completed the surveys. Participants included Chinese, Filipino, and Japanese individuals who were aged 60 to less than 90 years without a dementia diagnosis in the EHR at the time of the survey (baseline) and who had 2 years of health plan coverage before baseline. Data analysis was performed from December 2021 to December 2022. Exposures: The main exposure was educational attainment (college degree or higher vs less than a college degree), and the main stratification variables were Asian ethnicity and nativity (born in the US or born outside the US). Main Outcomes and Measures: The primary outcome was incident dementia diagnosis in the EHR. Dementia incidence rates were estimated by ethnicity and nativity, and Cox proportional hazards and Aalen additive hazards models were fitted for the association of college degree or higher vs less than a college degree with time to dementia, adjusting for age (timescale), sex, nativity, and an interaction between nativity and college degree. Results: Among 14 749 individuals, the mean (SD) age at baseline was 70.6 (7.3) years, 8174 (55.4%) were female, and 6931 (47.0%) had attained a college degree. Overall, among individuals born in the US, those with a college degree had 12% lower dementia incidence (HR, 0.88; 95% CI, 0.75-1.03) compared with those without at least a college degree, although the confidence interval included the null. The HR for individuals born outside the US was 0.82 (95% CI, 0.72-0.92; P = .46 for the college degree by nativity interaction). The findings were similar across ethnicity and nativity groups except for Japanese individuals born outside the US. Conclusions and Relevance: These findings suggest that college degree attainment was associated with lower dementia incidence, with similar associations across nativity. More work is needed to understand determinants of dementia in Asian American individuals and to elucidate mechanisms linking educational attainment and dementia.

Neighborhood disadvantage and dementia incidence in a cohort of Asian American and non-Latino White older adults in Northern California.

INTRODUCTION: Some evidence suggests that neighborhood socioeconomic disadvantage is associated with dementia-related outcomes. However, prior research is predominantly among non-Latino Whites. METHODS: We evaluated the association between neighborhood disadvantage (Area Deprivation Index [ADI]) and dementia incidence in Asian American (n = 18,103) and non-Latino White (n = 149,385) members of a Northern California integrated health care delivery system aged 60 to 89 at baseline. Race/ethnicity-specific Cox proportional hazards models adjusted for individual-level age, sex, socioeconomic measures, and block group population density estimated hazard ratios (HRs) for dementia. RESULTS: Among non-Latino Whites, ADI was associated with dementia incidence (most vs. least disadvantaged ADI quintile HR = 1.09, 95% confidence interval [CI] = 1.02-1.15). Among Asian Americans, associations were close to null (e.g., most vs. least disadvantaged ADI quintile HR = 1.01, 95% CI = 0.85-1.21). DISCUSSION: ADI was associated with dementia incidence among non-Latino Whites but not Asian Americans. Understanding the potentially different mechanisms driving dementia incidence in these groups could inform dementia prevention efforts.