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.

State-Level Indicators of Childhood Educational Quality and Incident Dementia in Older Black and White Adults.

Importance: Higher educational attainment is associated with reduced dementia risk, but the role of educational quality is understudied, presenting a major evidence gap, especially as it may contribute to racial inequities. Objective: To evaluate the association between state-level educational quality during childhood and dementia risk. Design, Setting, and Participants: This cohort study analyzed longitudinal data collected from January 1, 1997, through December 31, 2019 (23-year follow-up period). The sample comprised members of Kaiser Permanente Northern California (KPNC), a large integrated health care delivery system, who completed an optional survey during 1964-1972. Eligible individuals were US born; non-Hispanic Black or non-Hispanic White; aged 65 years or older as of January 1, 1996; were still alive; and did not have a dementia diagnosis or lapse in KPNC membership greater than 90 days between January 1 and December 31, 1996. Exposures: Historical state-level administrative indicators of school quality (school term length, student-teacher ratio, and attendance rates) linked to participants using birth state and birth year (with a 6-year lag) and divided into tertiles using the pooled sample. Main Outcomes and Measures: Dementia diagnoses from electronic health records between 1997 and 2019 were analyzed between March 1 and August 31, 2022. The associations of educational quality with incident dementia were estimated using Cox proportional hazards regression models. Results: Among 21 450 KPNC members who participated in the optional survey, individuals born before availability of educational quality records (n = 87) and missing educational attainment (n = 585) were excluded. The final analytic sample was 20 778 individuals (56.5% women, 43.5% men; mean [SD] age, 74.7 [6.5] years; 18.8% Black; 81.2% White; 41.0% with less than high school education). Among Black individuals, 76.2% to 86.1% (vs 20.8%-23.3% of White individuals) attended schools in states in the lowest educational quality tertiles. Highest (vs lowest) educational quality tertiles were associated with lower dementia risk (student-teacher ratio: hazard ratio [HR], 0.88 [95% CI, 0.83-0.94]; attendance rates: HR, 0.80 [95% CI, 0.73-0.88]; term length: HR, 0.79 [95% CI, 0.73-0.86]). Effect estimates did not differ by race and were not attenuated by adjustment for educational attainment. Conclusions and Relevance: In this cohort study, lower state-average educational quality was more common among Black individuals and associated with higher dementia risk. Differential investment in high-quality education due to structural racism may contribute to dementia disparities.

Participant education, spousal education and dementia risk in a diverse cohort of members of an integrated health care delivery system in Northern California.

OBJECTIVE: The role of spousal education on dementia risk and how it may differ by gender or race/ethnicity is unknown. This study examines the association between one's own education separate from and in conjunction with spousal education and risk of dementia. DESIGN: Cohort. SETTING: Kaiser Permanente Northern California (KPNC), an integrated health care delivery system. PARTICIPANTS: 8835 members of KPNC who were aged 40-55, married and reported own and spousal education in 1964-1973. PRIMARY OUTCOME MEASURE: Dementia cases were identified through medical records from 1 January 1996 to 30 September 2017. METHODS: Own and spousal education was self-reported in 1964-1973 and each was classified as four indicator variables (≤high school, trade school/some college, college degree and postgraduate) and as ≥college degree versus

Incidence of dementia after age 90 in a multiracial cohort.

INTRODUCTION: Little is known about dementia incidence in diverse populations of oldest-old, the age group with highest dementia incidence. METHODS: Incident dementia diagnoses from 1/1/2010 to 9/30/2015 were abstracted from medical records for 2350 members of an integrated health care system in California (n = 1702 whites, n = 375 blacks, n = 105 Latinos, n = 168 Asians) aged ≥90 in 2010. We estimated race/ethnicity-specific age-adjusted dementia incidence rates and implemented Cox proportional hazards models and Fine and Gray competing risk of death models adjusted for demographics and comorbidities in midlife and late-life. RESULTS: Dementia incidence rates (n = 771 cases) were lowest among Asians (89.9/1000 person-years), followed by whites (96.9/1000 person-years), Latinos (105.8/1000 person-years), and blacks (121.5/1000 person-years). Cox regression and competing risk models estimated 28% and 36% higher dementia risk for blacks versus whites adjusting for demographics and comorbidities. DISCUSSION: Patterns of racial/ethnic disparities in dementia seen in younger older adults continue after the age of 90 years, though smaller in magnitude.

Early Midlife Pulmonary Function and Dementia Risk.

BACKGROUND: Poor pulmonary function (PPF) is associated with increased risk of dementia, yet it is unclear if PPF in early adulthood to midlife increases risk, independent of smoking and subsequent vascular disease. OBJECTIVE: This study evaluated the association between multiple markers of PPF in early adulthood to midlife and long-term risk of dementia. METHODS: We evaluated 27,387 members of an integrated health care system with forced expiratory volume in 1, 2 seconds, and vital capacity collected from 1964 to 1973 (mean age=41.8±4.2 y). Associations of PPF with dementia diagnoses from January 1, 1996 to September 30, 2015 were evaluated with Cox proportional hazards models adjusted for demographics, height, body mass index, hypertension, smoking status, diabetes, stroke, and heart failure. RESULTS: In total, 7519 individuals (27%) were diagnosed with dementia. In fully adjusted Cox proportional hazards models, for all PPF measures each liter decrease was associated with a 13% to 14% higher risk of dementia. Compared with the highest quintile, the first quintile of PPF measures were associated with a 24% to 28% increased risk of dementia; second to fourth quintiles showed strong dose-dependent associations. Results were similar when stratified by smoking status. CONCLUSIONS: In this large, diverse cohort, multiple measures of PPF in early adulthood to midlife were associated with dementia risk independent of smoking and vascular comorbidities.

Female sex, early-onset hypertension, and risk of dementia.

OBJECTIVE: To evaluate the association of early-adulthood and mid-adulthood hypertension with dementia in men and women. METHODS: We evaluated 5,646 members of a diverse integrated health care delivery system who had clinical examinations and health survey data from 1964 to 1973 (mean age 32.7 years; early adulthood) and 1978-1985 (mean age 44.3 years; mid-adulthood) and were members as of January 1, 1996 (mean age 59.8 years). Hypertension categories based on measurements of blood pressure (BP) and change in hypertension categories between the 2 examinations (e.g., onset hypertension) were used to predict dementia incidence from January 1, 1996, to September 30, 2015. Cox proportional hazard models were adjusted for demographics, vascular comorbidities, and hypertension treatment; inverse probability weighting accounted for differential attrition between first BP measurement and start of follow-up. RESULTS: A total of 532 individuals (9.4%) were diagnosed with dementia. Early adulthood hypertension was not associated with dementia, though effect estimates were elevated among women. Mid-adulthood hypertension was associated with 65% (95% confidence interval [CI] 1.25-2.18) increased dementia risk among women but not men. Onset of hypertension in mid-adulthood predicted 73% higher dementia risk in women (95% CI 1.24-2.40) compared to stable normotensive. There was no evidence that hypertension or changes in hypertension increased dementia risk among men. CONCLUSIONS: Though midlife hypertension was more common in men, it was only associated with dementia risk in women. Sex differences in the timing of dementia risk factors have important implications for brain health and hypertension management.

Association Between Birth in a High Stroke Mortality State, Race, and Risk of Dementia.

Importance: Birth in a group of predominantly southern US states is robustly linked to increased stroke risk. Given the role of cerebrovascular disease in dementia risk, geographic patterning may also occur for dementia incidence. Objective: To determine whether birth in 9 high stroke mortality states (HSMSs) is associated with dementia in a diverse cohort of individuals living in Northern California. Design, Setting, and Participants: An observational cohort study included 7423 members of Kaiser Permanente Northern California (KPNC), an integrated health care delivery system, with health survey and clinical examination data available. Data were collected between 1964 and 1973 when the individuals were middle-aged and 1996 and 2015 when participants were in later life. Exposures: Self-reported state of birth in an HSMS (top quintile of states for stroke mortality). Main Outcomes and Measures: Dementia diagnoses obtained from electronic health records from January 1, 1996, to October 15, 2015. Place of birth, race, educational level, and midlife vascular risk factors data were collected between 1964 and 1973. Results: Of the 7423 persons included in the analysis, 4049 (54.5%) were women; 1354 (18.2%) were black. The mean (SD) age of study participants at their first visit between 1963 and 1974 was 42.94 (1.73) years and mean (SD) age at the beginning of follow-up for dementia in 1996 was 71.14 (2.72) years. Dementia was diagnosed in 2254 (30.4%) of the participants and was more common among those born in an HSMS than those born outside of one (455 [39.0%] vs 1799 [28.8%]). Birth in an HSMS was 9.6 times more common for black participants (795 [58.7%]) than nonblack participants (371 [6.1%]). Overall, birth in an HSMS was associated with a 28% higher risk of dementia (adjusted hazard ratio [aHR], 1.28; 95% CI, 1.13-1.46) adjusted for age, sex, and race. Compared with nonblack persons born outside of an HSMS, black individuals born in an HSMS had the highest dementia risk (aHR, 1.67; 95% CI, 1.48-1.88), followed by black individuals not born in an HSMS (aHR, 1.48; 95% CI, 1.28-1.72), and nonblack persons born in an HSMS had a 46% increased risk (aHR, 1.46; 95% CI, 1.23-1.74). Cumulative 20-year dementia risks at age 65 years were 30.13% (95% CI, 26.87%-32.93%) and 21.80% (95% CI, 20.51%-22.91%) for individuals born in and outside an HSMS, respectively. Conclusions and Relevance: To our knowledge, this is the first study to date of place of birth and incident dementia and shows increased risk for individuals born in an HSMS, even though all participants subsequently resided in California. Birth in an HSMS was common among black participants. Place of birth has enduring consequences for dementia risk and may be a major contributor to racial disparities in dementia.