Objective Women have >50% greater lifetime risk of dementia than men but the role of female-specific endocrine milieu is not well-understood. This study evaluates associations between indicators of estrogen exposure from women9s reproductive period and dementia risk in a large diverse population. Methods We evaluated 15,754 female members (29.9% nonwhite) of Kaiser Permanente with clinical examinations and health survey data from 1964 to 1973 and were members as of January 1, 1996. In midlife (mean age 51.1 years), women reported age at menarche and menopause and hysterectomy status. Reproductive span was calculated as menopause age minus menarche age. Dementia diagnoses were abstracted from January 1, 1996 to September 30, 2017 medical records (mean age at start of dementia follow-up 76.5 years). Cox proportional hazard models evaluated associations between aspects of reproductive span and dementia risk adjusting for demographics and life course health indicators. Results Forty-two percent of women developed dementia. Compared to menarche at age 13.0 (mean menarche age), menarche at ≥16 was associated with 23% greater dementia risk (adjusted hazard ratio [HR] 1.23; 95% confidence interval [CI] 1.01–1.50) adjusting for demographics and life course health indicators. Natural menopause at age <47.4 (mean menopause age) was associated with 19% elevated dementia risk (HR 1.19; 95% CI 1.07–1.31). Reproductive spans <34.4 years (mean duration) were associated with 20% elevated dementia risk (HR 1.20; 95% CI 1.08–1.32). Hysterectomies were associated with 8% elevated dementia risk (HR 1.08; 95% CI 1.01–1.16). Conclusion In this large prospective cohort study, endocrine events signaling less estradiol exposure (i.e., later age at menarche, younger age at menopause, shorter reproductive span, and hysterectomies) were associated with elevated risk of dementia.

OBJECTIVE: In children with type 1 diabetes (T1D), severe hypoglycemia (SH) is associated with poorer cognition, but the association of SH with cognitive function in late life is unknown. Given the increasing life expectancy in people with T1D, understanding the role of SH in brain health is crucial. RESEARCH DESIGN AND METHODS: We examined the association between SH and cognitive function in 718 older adults with T1D from the Study of Longevity in Diabetes (SOLID). Subjects self-reported recent SH (previous 12 months) and lifetime history of SH resulting in inpatient/emergency department utilization. Global and domain-specific cognition (language, executive function, episodic memory, and simple attention) were assessed. The associations of SH with cognitive function and impaired cognition were evaluated via linear and logistic regression models, respectively. RESULTS: Thirty-two percent of participants (mean age 67.2 years) reported recent SH and 50% reported lifetime SH. Compared with those with no SH, subjects with a recent SH history had significantly lower global cognition scores. Domain-specific analyses revealed significantly lower scores on language, executive function, and episodic memory with recent SH exposure and significantly lower executive function with lifetime SH exposure. Recent SH was associated with impaired global cognition (odds ratio [OR] 3.22, 95% CI 1.30, 7.94) and cognitive impairment on the language domain (OR 3.15, 95% CI 1.19, 8.29). CONCLUSIONS: Among older adults with T1D, recent SH and lifetime SH were associated with worse cognition. Recent SH was associated with impaired global cognition. These findings suggest a deleterious role of SH on the brain health of older patients with T1D and highlight the importance of SH prevention.

OBJECTIVE Individuals with type 1 diabetes have experienced an increase in life expectancy; yet, it is unknown what level of glycemic control is ideal for maintaining late-life brain health. We investigated the association of long-term glycemic control with dementia in older individuals with type 1 diabetes. RESEARCH DESIGN AND METHODS We followed 3,433 members of a health care system with type 1 diabetes, ages ≥50 years, from 1996 to 2015. Repeated measurements of hemoglobin A_1c (HbA_1c), dementia diagnoses, and comorbidities were ascertained from health records. Cox proportional hazards models were fit to evaluate the association of time-varying glycemic exposure with dementia, with adjustment for age, sex, race/ethnicity, baseline health conditions, and frequency of HbA_1c measurement. RESULTS Over a mean follow-up of 6.3 years, 155 individuals (4.5%) were diagnosed with dementia. Patients with ≥50% of HbA_1c measurements at 8–8.9% (64–74 mmol/mol) and ≥9% (≥75 mmol/mol) had 65% and 79% higher risk of dementia, respectively, compared with those with <50% of measurements exposed (HbA_1c 8–8.9% adjusted hazard ratio [aHR] 1.65 [95% CI 1.06, 2.57] and HbA_1c ≥9% aHR 1.79 [95% CI 1.11, 2.90]). By contrast, patients with ≥50% of HbA_1c measurements at 6–6.9% (42–52 mmol/mol) and 7–7.9% (53–63 mmol/mol) had a 45% lower risk of dementia (HbA_1c 6–6.9% aHR 0.55 [95% CI 0.34, 0.88] and HbA_1c 7–7.9% aHR 0.55 [95% CI 0.37, 0.82]). CONCLUSIONS Among older patients with type 1 diabetes, those with majority exposure to HbA_1c 8–8.9% and ≥9% had increased dementia risk, while those with majority exposure to HbA_1c 6–6.9% and 7–7.9% had reduced risk. Currently recommended glycemic targets for older patients with type 1 diabetes are consistent with healthy brain aging.

Background and Objectives: The associations of high- and low-density lipoprotein cholesterol (HDL-C and LDL-C) with dementia risk in later life may be complex, and few studies have sufficient data to model non-linearities or adequately adjust for statin use. We evaluated the observational associations of HDL-C and LDL-C with incident dementia in a large and well-characterized cohort with linked survey and electronic health record (EHR) data. Methods: Kaiser Permanente Northern California health plan members aged 55 years and older who completed a health behavior survey between 2002 and 2007, had no history of dementia prior to the survey, and had laboratory measurements of cholesterol within two years after survey completion were followed through December 2020 for incident dementia (Alzheimer’s Disease Related Dementia [ADRD]; Alzheimer’s, vascular, and/or non-specific dementia) based on ICD9 or ICD10 codes in EHRs. We used Cox models for incident dementia with follow-up time beginning 2 years post-survey (after cholesterol measurement) and censoring at end of membership, death, or end of study period. We evaluated non-linearities using b-splines, adjusted for demographic, clinical, and survey confounders, and tested for effect modification by baseline age or prior statin use. Results: 184,367 participants [mean age at survey of 69.5 years, mean HDL-C=53.7 mg/dL (SD = 15.0), LDL-C=108 mg/dL (SD = 30.6)] were included. Higher and lower HDL-C values were associated with elevated ADRD risk compared to the middle quantile: HDL-C in the lowest quintile was associated with an HR of 1.07 (95% CI: 1.03-1.11) and HDL-C in the highest quintile was associated with an HR of 1.15 (95% CI: 1.11-1.20). LDL-C was not associated with dementia risk overall, but statin use qualitatively modified the association. Higher LDL-C was associated with slightly greater risk of ADRD for statin users (53% of the sample, HR per 10 mg/dL increase=1.01, 95% CI: 1.01-1.02) and lower risk for non-users (HR per 10 mg/dL increase=0.98; 95% CI: 0.97-0.99). There was evidence for effect modification by age with linear HDL-C (p=0.003) but not LDL-C (p=0.59). Discussion: Both low and high levels of HDL-C were associated with elevated dementia risk. The association between LDL-C and dementia risk was modest.

OBJECTIVE: Severe hyperglycemia and hypoglycemia (“severe dysglycemia”) are serious complications of type 1 diabetes (T1D). Depression has been associated with severe dysglycemia in type 2 diabetes but has not been thoroughly examined specifically in T1D. We evaluated bidirectional associations between depression and severe dysglycemia among older people with T1D. RESEARCH DESIGN AND METHODS: We abstracted depression and severe dysglycemia requiring emergency room visit or hospitalization from medical health records in 3,742 patients with T1D during the study period (1996–2015). Cox proportional hazards models estimated the associations between depression and severe dysglycemia in both directions, adjusting for demographics, micro- and macrovascular complications, and HbA1c. RESULTS: During the study period, 41% had depression and 376 (11%) and 641 (20%) had hyperglycemia and hypoglycemia, respectively. Depression was strongly associated with a 2.5-fold increased risk of severe hyperglycemic events (hazard ratio [HR] 2.47 [95% CI 2.00, 3.05]) and 89% increased risk of severe hypoglycemic events (HR 1.89 [95% CI 1.61, 2.22]). The association was strongest within the first 6 months (HRhyperglycemia 7.14 [95% CI 5.29, 9.63]; HRhypoglycemia 5.58 [95% CI 4.46, 6.99]) to 1 year (HRhyperglycemia 5.16 [95% CI 3.88, 6.88]; HRhypoglycemia 4.05 [95% CI 3.26, 5.04]) after depression diagnosis. In models specifying severe dysglycemia as the exposure, hyperglycemic and hypoglycemic events were associated with 143% (HR 2.43 [95% CI 2.03, 2.91]) and 74% (HR 1.75 [95% CI 1.49, 2.05]) increased risk of depression, respectively. CONCLUSIONS: Depression and severe dysglycemia are associated bidirectionally among patients with T1D. Depression greatly increases the risk of severe hypoglycemic and hyperglycemic events, particularly in the first 6 months to 1 year after diagnosis, and depression risk increases after severe dysglycemia episodes.

Objectives Evidence on adverse childhood experiences (ACEs) and late-life cognitive outcomes is inconsistent, with little research among diverse racial/ethnic groups. We investigated whether ACE exposures were associated with worse late-life cognition for all racial/ethnic groups and at different ages of exposure. Design Covariate-adjusted mixed-effects linear regression models estimated associations of: (1) total number of ACEs experienced, (2) earliest age when ACE occurred and (3) type of ACE with overall cognition. Setting Kaiser Permanente Northern California members aged 65 years and older, living in Northern California. Participants Kaiser Healthy Aging and Diverse Life Experiences study baseline participants, aged 65 years and older (n=1661; including 403 Asian-American, 338 Latino, 427 Black and 493 white participants). Results Most respondents (69%) reported one or more ACE, most frequently family illness (36%), domestic violence (23%) and parental divorce (22%). ACE count was not adversely associated with cognition overall (β=0.01; 95% CI −0.01 to 0.03), in any racial/ethnic group or for any age category of exposure. Pooling across all race/ethnicities, parent’s remarriage (β=−0.11; 95% CI −0.20 to −0.03), mother’s death (β=−0.18; 95% CI −0.30 to −0.07) and father’s death (β=−0.11; 95% CI −0.20 to −0.01) were associated with worse cognition. Conclusion Adverse childhood exposures overall were not associated with worse cognition in older adults in a diverse sample, although three ACEs were associated with worse cognitive outcomes.