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The apolipoprotein E (APOE) genotype is a driver of cognitive decline and dementia. We used causal mediation methods to characterize pathways linking the APOE genotype to late-life cognition through Alzheimer's disease (AD) and non-AD neuropathologies.We analyzed autopsy data from 1671 individuals from the Religious Orders Study, Memory and Aging Project, and Minority Aging Research Study (ROS/MAP/MARS) studies with cognitive assessment within 5 years of death and autopsy measures of AD (amyloid beta (Aβ), neurofibrillary tangles), vascular (athero/arteriolo-sclerosis, micro-infarcts/macro-infarcts), and non-AD neurodegenerative neuropathologies (TAR DNA protein 43 [TDP-43], Lewy bodies, amyloid angiopathy, hippocampal sclerosis).The detrimental effect of APOE ε4 on cognition was mediated by summary measures of AD and non-AD neurodegenerative neuropathologies but not vascular neuropathologies; effects were strongest in individuals with dementia. The protective effect of APOE ε2 was partly mediated by AD neuropathology and stronger in women than in men.The APOE genotype influences cognition and dementia through multiple neuropathological pathways, with implications for different therapeutic strategies targeting people at increased risk for dementia.Both apolipoprotein E (APOE) ε2 and APOE ε4 effects on late-life cognition are mediated by AD neuropathology. The estimated mediated effects of most measures of AD neuropathology were similar. Non-Alzheimer's disease (AD) neurodegenerative pathologies mediate the effect of ε4 independently from AD. Non-AD vascular pathologies did not mediate the effect of the APOE genotype on cognition. The protective effect of APOE ε2 on cognition was stronger in women.

Accumulating data suggest that cerebrovascular disease contributes to Alzheimer’s disease pathophysiology and progression toward dementia. Cerebral amyloid angiopathy is a form of cerebrovascular pathology that results from the build-up of β-amyloid in the vessel walls. Cerebral amyloid angiopathy commonly co-occurs with Alzheimer’s disease pathology in the ageing brain and increases the risk of Alzheimer’s disease dementia. In the present study, we examined whether cerebral amyloid angiopathy influences tau deposition and cognitive decline independently or synergistically with parenchymal β-amyloid burden. Secondly, we examined whether tau burden mediates the association between cerebral amyloid angiopathy and cognitive decline. We included data from autopsied subjects recruited from one of three longitudinal clinical–pathological cohort studies: the Rush Memory and Aging Project, the Religious Orders Study and the Minority Aging Research Study. Participants completed annual clinical and cognitive evaluations and underwent brain autopsy. Cerebral amyloid angiopathy pathology was rated as none, mild, moderate or severe. Bielschowsky silver stain was used to visualize neuritic β-amyloid plaques and neurofibrillary tangles. We used linear regression and linear mixed models to test independent versus interactive associations of cerebral amyloid angiopathy and neuritic plaque burden with tau burden and longitudinal cognitive decline, respectively. We used causal mediation models to examine whether tau mediates the association between cerebral amyloid angiopathy and cognitive decline. The study sample included 1722 autopsied subjects (age at baseline = 80.2 ± 7.1 years; age at death = 89.5 ± 6.7 years; 68% females). Cerebral amyloid angiopathy interacted with neuritic plaques to accelerate tau burden and cognitive decline. Specifically, those with more severe cerebral amyloid angiopathy pathology and higher levels of neuritic plaque burden had greater tau burden and faster cognitive decline. We also found that tau mediated the association between cerebral amyloid angiopathy and cognitive decline among participants with higher neuritic plaque burden. In summary, more severe levels of cerebral amyloid angiopathy and higher parenchymal β-amyloid burden interacted to promote cognitive decline indirectly via tau deposition. These results highlight the dynamic interplay between cerebral amyloid angiopathy and Alzheimer’s disease pathology in accelerating progression toward dementia. These findings have implications for Alzheimer’s disease clinical trials and therapeutic development.

BACKGROUND: We assessed the cross-sectional association of physical function measures with cognition in the Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) Cohort. METHODS: Analyses included 1,369 participants (24% Asian, 26% Black, 18% Latino, 32% White). Grip strength was measured using a hand-held dynamometer (kilograms) and gait speed was measured over a 4-meter walk (seconds/meter). The Spanish and English Neuropsychological Assessment Scales (SENAS) was used to evaluate cognitive domains of executive function, semantic memory, and verbal episodic memory. Physical function measures (per standard deviation) were associated with cognitive test z-scores in linear regression models adjusted for demographic, behavioral, and clinical factors. Racial/ethnic differences were tested using interaction terms and stratification. RESULTS: Stronger grip was associated with better executive function [β=0.10(0.05, 0.15)], semantic memory [β=0.13(0.09, 0.18)] and verbal episodic memory [β=0.07(0.02, 0.13)] with no racial/ethnic differences. Faster gait was associated with better executive function [β=0.29(0.22, 0.36)], semantic memory [β=0.23(0.16, 0.30)], and verbal episodic memory [β=0.20(0.13, 0.27)]; however, the association between gait speed and executive function varied by race/ethnicity with the strongest associations in Asians and Whites. CONCLUSION: Across race/ethnicity, grip strength and gait speed were associated with cognition with racial/ethnic differences in the association of gait speed and executive function.

OBJECTIVE We aimed to assess the association between migraine headache and incident dementia. BACKGROUND Migraine is a risk factor for white matter hyperintensities and ischemic stroke, which are both associated with increased risk of dementia. However, it is unknown whether migraine is independently associated with dementia. METHODS History of migraine was ascertained via questionnaire. Adjudicated cases of dementia were identified using cognitive tests, neuropsychological exams, and clinician review of suspected cases. Incident dementia was identified using adjudicated cases, follow-up calls, and surveillance of hospital and death codes. We assessed hazards of incident dementia by migraine status. Sex differences were also examined and stratified results were presented. RESULTS Analysis included 12,495 White and African American participants ages 51-70 with a median follow-up time of 21 years. Prevalence of dementia was 18.5% (1821/9955) among those with no migraine history, 15.8% (196/1243) among those with severe non-migraine heading, and 16.7% (233/1397) among migraineurs. There was no association between migraine and incident dementia [hazard ratio: 1.04 (0.91, 1.20)]. There was also no statistically significant interaction between sex and migraine status on risk of dementia. CONCLUSION Despite evidence of brain abnormalities in migraineurs, there was no association between migraine and incident dementia in this prospective cohort.

Studies examining associations between greenspace and Alzheimer’s disease and related dementia (ADRD) outcomes are rapidly on the rise, yet no known literature reviews have summarized the racialized/ethnic group and geographic variation of those published studies. This is a significant gap given the known disparities in both greenspace access and ADRD risk between racialized/ethnic groups and between developed versus developing countries. In this rapid literature review, we (1) describe the diversity of published greenspace–brain health studies with respect to racialized/ethnic groups and geographic regions; (2) determine the extent to which published studies have investigated racialized/ethnic group differences in associations; and (3) review methodological issues surrounding studies of racialized/ethnic group disparities in greenspace and brain health associations. Of the 57 papers meeting our inclusion criteria as of 4 March 2022, 21% (n = 12) explicitly identified and included individuals who were Black, Hispanic/Latinx, and/or Asian. Twenty-one percent of studies (n = 12) were conducted in developing countries (e.g., China, Dominican Republic, Mexico), and 7% (n = 4) examined racialized/ethnic group differences in greenspace–brain health associations. None of the studies were framed by health disparities, social/structural determinants of health, or related frameworks, despite the known differences in both greenspace availability/quality and dementia risk by racialized/ethnic group and geography. Studies are needed in developing countries and that directly investigate racialized/ethnic group disparities in greenspace—brain health associations to target and promote health equity.

Females show a disproportionate burden of Alzheimer’s disease pathology and higher Alzheimer’s disease dementia prevalences compared to males, yet the mechanisms driving these vulnerabilities are unknown. There is sexual dimorphism in immunological functioning, and neuroimmune processes are implicated in Alzheimer’s disease genesis. Using neuropathology indicators from human brain tissue, we examined the mediational role of microglial activation on the relationship between amyloid and tau and how it differs by sex. 187 decedents (64% female; 89 mean age at death; 62% non-demented) from the Rush Memory and Aging Project completed neuropathological evaluations with brain tissue quantified for microglial activation, amyloid-β and tau. Proportion of morphologically activated microglia was determined via immunohistochemistry (HLA-DP-DQ-DR) and morphological staging (stage I, II or III). Amyloid-β and tau burden were quantified via immunohistochemistry (M00872 or AT8, respectively). Using causal counterfactual modelling, we estimated the mediational effect of microglial activation on the amyloid-β to tau relationship in the whole sample and stratified by sex (amyloid-β → microglial activation → tau). Alternative models tested the role of microglia activation as the precipitating event (microglial activation → amyloid-β → tau). Microglial activation significantly mediated 33% [95% confidence interval (CI) 10–67] of the relationship between amyloid-β and tau in the whole sample; stratified analyses suggested this effect was stronger and only statistically significant in females. 57% (95% CI 22–100) of the effect of amyloid-β on tau was mediated through microglial activation in females, compared to 19% (95% CI 0–64) in males. Regional analyses suggested that mediational effects were driven by greater cortical versus subcortical microglial activation. Relationships were independent of cerebrovascular disease indices. Alternative models suggested that in females, microglial activation was a significant exposure both preceding the amyloid-β to tau relationship (mediational effect: 50%, 95% CI 23–90) and directly related to tau burden (microglia direct effect: 50%, 95% CI 10–77). By contrast, in males, only the direct effect of microglial activation to tau reached significance (74%, 95% CI 32–100) (mediational effect: 26%, 95% CI 0–68). Our models suggest a reciprocal, bidirectional relationship between amyloid-β and microglial activation that significantly accounts for tau burden in females. By contrast, in males, direct independent (non-mediational) relationships between microglial activation or amyloid-β with tau were observed. Microglial activation may be disproportionately important for Alzheimer’s disease pathogenesis in females. Determining sex-specific vulnerabilities to Alzheimer’s disease development both inform fundamental pathophysiology and support precision health approaches for this heterogeneous disease.

Importance Prior research suggests schooling differences for Black individuals in the US are associated with worse cognitive aging. It is unknown whether age when experiencing school desegregation is associated with differences in late-life cognition in this population. Objective To examine patterns of association between age of school desegregation in grades 1 to 12 and late-life cognition. Design, Setting, and Participants This cohort study analyzed baseline data from the Study of Healthy Aging in African Americans (STAR) cohort collected from 2018 through 2019 in Northern California, primarily in the cities of Richmond and Oakland. Participants were 699 self-identified Black individuals aged 50 years or older who were community-dwelling, long-term members of Kaiser Permanente Northern California and dementia free at baseline. Exposures Participants reported whether they attended a segregated school in grades 1, 6, 9, and 12 and were placed in 1 of 6 transition categories: (1) always attended integrated schools; (2) integrated between grades 1 through 5; (3) integrated between grades 6 through 8; (4) integrated between grades 9 through 12; (5) ever moved from integrated to segregated school; (6) never attended integrated schools. Main Outcomes and Measures Executive function, semantic memory, and verbal episodic memory ascertained via the Spanish and English Neuropsychological Assessment Battery andzstandardized for analyses. Results The mean (SD) age of the 699 participants was 68.5 (8.7) years, and 484 (69.2%) were female. Most participants transitioned from segregated to integrated schools owing to historical timing and cohort geography. Compared with 111 participants who never attended integrated schools (reference group), executive function was better among 50 participants who transitioned to integrated schools between grades 1 and 5 (β = 0.35; 95% CI, 0.08-0.61;P = .01). Semantic memory was better among 435 participants who only attended integrated schools (β = 0.34; 95% CI, 0.14-0.54;P = .001) or among 50 participants who transitioned to integrated schools between grades 1 and 5 (β = 0.43; 95% CI, 0.15-0.72;P = .003). However, no significant differences were found by group for verbal episodic memory function (eg, for 50 participants who transitioned to integrated schools between grades 1 and 5: β = 0.07; 95% CI, −0.22 to 0.35;P = .66). No significant differences were found when testing for potential interactions by sex, Southern birth, or baseline age. Conclusions and Relevance The STAR cohort data indicated that executive function and semantic memory were higher among Black individuals with some integrated school experience. These results suggest that racially segregated schooling experiences, including de facto segregation present today, may be associated with worse late-life cognition.

Background Despite growing research on the association between discrimination and disparities in cognitive aging, an evidence gap remains on how the association varies by racial/ethnic group. This study evaluates the associations of experiences of discrimination with cognitive function and whether these associations varied by race/ethnicity and nativity. Method Using the Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) cohort (N = 1 712) with approximately equal groups of Black, White, Latino, and Asian community-dwelling older adults aged 65 years and older, we evaluated the associations between self-reported experiences of everyday and major lifetime discrimination with overall cognitive performance and domain-specific cognition (verbal episodic memory, semantic memory, and executive functioning) across race/ethnicity and nativity. Linear regression models examined the cross-sectional association between self-reported experiences of everyday and major lifetime discrimination with z-standardized coefficients for cognition. We tested for effect modification by race and nativity. All models controlled for age, sex, and education. Results Among KHANDLE participants (mean age: 76 years; SD: 6.8), everyday discrimination was not associated with cognitive scores. Major lifetime discrimination was associated with better average cognitive scores among Black participants but not among other racial/ethnic groups. Major lifetime discrimination was associated with better average cognitive scores among U.S.-born but not among non-U.S.-born individuals. Conclusion Our findings do not imply that discrimination improves cognition, but rather suggest that future research should include more detailed measures on discrimination and unfair treatment that could help disentangle the extent to which relationships are causal or reflect some other underlying factor.

Background Both education and cardiovascular risk factors are strongly associated with dementia risk. However, it is not clear whether these associations persist or vary among individuals with high genetic risk for Alzheimer’s disease. We examined the interactive relationship between lifestyle and genetic dementia risk factors in a prospective cohort study. Methods Our data came from the Atherosclerosis Risk in Communities study participants (n = 13 715; baseline age 45–64; 25% Black; 55% female), who were followed for incident dementia from 1987 through 2017. We used Cox proportional hazard models to estimate the risk of dementia (ascertained through in-person examination, telephone cognitive screeners, and/or hospital and death records) associated with baseline education and cardiovascular risk factors (measured using the American Heart Association’s “Life Simple 7”) among ε4 carriers and non-carriers separately. We also examined differences by race and sex. Results Two thousand two hundred and twenty-six incident dementia cases occurred over a median 25 years of follow-up. Lower educational attainment and poorer cardiovascular health were associated with greater risk of incident dementia. There was an education by apolipoprotein E (APOE) status interaction (p = .005) whereby the association of education and dementia was weaker for ε4 carriers (HR college graduates vs less than high school: 0.71 [0.59–0.84] than non-carriers (0.54 [0.47–0.63]). There was no interaction between APOE status and cardiovascular health on dementia risk. These relationships did not vary significantly by race or sex. Conclusions Education and cardiovascular health were associated with lower dementia risk regardless of APOE genotype, though the protective effects of education were somewhat diminished among ε4 carriers.

Purpose We examined the association of Stroke Belt birth state with late-life cognition in The Study of Healthy Aging in African Americans (STAR). Methods STAR enrolled 764 Black Americans ages 50+ who were long-term Kaiser Permanente Northern California members. Participants completed Multiphasic Health Check-ups (MHC; 1964–1985) where early-life overweight/obesity, hypertension, diabetes, and hyperlipidemia were measured. At STAR (2018), birth state, self-reported early-life socioeconomic status (SES), and executive function, verbal episodic memory, and semantic memory scores were collected. We used linear regression to examine the association between Stroke Belt birth and late-life cognition adjusting for birth year, gender, and parental education. We evaluated early-life SES and cardiovascular risk factors (CVRF) as potential mechanisms. Results Twenty-seven percent of participants were born in the Stroke Belt with a mean age of 69 (standard deviation = 9) at STAR. Stroke Belt birth was associated with worse late-life executive function (β [95% confidence interval]: −0.18 [−0.33, −0.02]) and semantic memory (−0.37 [−0.53, −0.21]), but not verbal episodic memory (−0.04 [−0.20, 0.12]). Adjustment for SES and CVRF attenuated associations of Stroke Belt birth with cognition (executive function [−0.05 {−0.25, 0.14}]; semantic memory [−0.28 {−0.49, −0.07}]). Conclusions Black Americans born in the Stroke Belt had worse late-life cognition than those born elsewhere, underscoring the importance of early-life exposures on brain health.

Background Increased carotid intima‐media thickness, interadventitial diameter, presence of carotid plaque, and lower distensibility are predictors for cardiovascular disease. These indices likely relate to cerebrovascular disease, and thus may constitute a form of vascular contributions to dementia and Alzheimer disease–related dementia. Therefore, we assessed the relationship of carotid measurements and arterial stiffness with incident dementia in the ARIC (Atherosclerosis Risk in Communities) study. Methods and Results A total of 12 459 ARIC participants with carotid arterial ultrasounds in 1990 to 1992 were followed through 2017 for dementia. Dementia cases were identified using in‐person and phone cognitive status assessments, hospitalization discharge codes, and death certificate codes. Cox proportional hazards models were used to estimate the hazard ratios (HRs) for incident dementia. Participants were aged 57±6 at baseline, 57% were women, and 23% were Black individuals. Over a median follow‐up time of 24 years, 2224 dementia events were ascertained. After multivariable adjustments, the highest quintile of carotid intima‐media thickness and interadventitial diameter in midlife was associated with increased risk of dementia (HR [95% CIs], 1.25 [1.08–1.45]; and 1.22 [1.04–1.43], respectively) compared with its respective lowest quintile. Presence of carotid plaque did not have a significant association with dementia (HR [95% CI], 1.06 [0.97–1.15]). Higher distensibility was associated with lower risk of dementia (HR [95% CI] highest versus lowest quintile, 0.76 [0.63–0.91]). Conclusions Greater carotid intima‐media thickness, interadventitial diameter, and lower carotid distensibility are associated with an increased risk of incident dementia. These findings suggest that both atherosclerosis and carotid stiffness may be implicated in dementia risk.

Background Midlife cardiovascular risk factors (CVRFs) increase risk of dementia. Black Americans experience an elevated prevalence of CVRFs and dementia. However, little is known of how CVRFs prior to midlife affect late-life cognition. We examined CVRFs in adolescence, young adulthood, and midlife with late-life cognition in the Study of Healthy Aging in African Americans (STAR). Method STAR assesses cognitive aging among 764 Black Americans aged ≥50 (mean age = 69; SD = 9; range = 53–95). Participants’ body mass index, blood pressure, glucose, and total cholesterol were collected during Multiphasic Health Checkups (MHC; 1964–1985). At STAR baseline (2018–2019), executive function, verbal episodic memory, and semantic memory were measured using the Spanish and English Neuropsychological Assessment Scales. Linear regression models examined associations between CVRFs and cognition adjusting for demographics and years since MHC. Results At MHC, 36% of participants had 1 CVRF and 26% had ≥2. Twenty-two percent of participants were adolescents (age 12–20), 62% young adults (age 21–34), and 16% midlife adults (age 35–56). Overweight/obesity was not associated with cognition. Hypertension was associated with worse executive function (β [95% CI]: −0.14 [−0.28, −0.0003]) and verbal episodic memory (β [95% CI]: −0.22 [−0.37, −0.07]) compared to normotension. Diabetes was associated with worse executive function (β [95% CI]: −0.43 [−0.83, −0.03]). Having ≥2 CVRFs (vs 0) was associated with worse executive function (β [95% CI]: −0.19 [−0.34, −0.03]) and verbal episodic memory (β [95% CI]: −0.25 [−0.41, −0.08]). Adolescents with hypertension had lower late-life executive function compared to normotensive adolescents (β [95% CI]: −0.39 [−0.67, −0.11]). Young adulthood hypertension (β [95% CI]: −0.29 [−0.49, −0.09]) and midlife hyperlipidemia (β [95% CI]: −0.386 [−0.70, −0.02]) were associated with lower verbal episodic memory. Conclusions Among Black Americans, life-course CVRFs were associated with poorer executive function and verbal episodic memory emphasizing the importance of cardiovascular health on the aging brain.

Background Low socioeconomic status (SES) in early and late life has been associated with lower late-life cognition. Less is known about how changes in SES from childhood to late life are associated with late-life cognition, especially among diverse populations of older adults. Methods In a multi-ethnic sample (n = 1353) of older adults, we used linear regression to test associations of change in comprehensive measures of SES (financial, cultural, and social domains) from childhood to late life with semantic memory, episodic memory, and executive function. We tested whether the association between SES trajectory and late-life cognition differed by populations who resided in the U.S. during childhood or immigrated to the U.S. as adults. Results Participants with low childhood/high late-life financial capital had better semantic memory (β = 0.18; 95% CI: 0.04, 0.32) versus those with low financial capital in both childhood and late life, regardless of childhood residence. We observed a significant interaction in the association of verbal episodic memory and cultural capital by childhood residence (p = 0.08). Participants with a foreign childhood residence had higher verbal episodic memory if they had low childhood/high late-life cultural capital (β = 0.32; 95% CI: 0.01, 0.63), but lower verbal episodic memory if they had high childhood/low late-life cultural capital (β = − 0.40; 95% CI: − 0.94, 0.13). Having high lifecourse social capital was associated with better verbal episodic memory scores among those with a U.S. childhood (β = 0.34; 95% CI: 0.14, 0.55), but lower verbal episodic memory among those with a foreign childhood (β = − 0.10; 95% CI: − 0.51, 0.31). Conclusions High financial and cultural capital in late life is associated with better cognition, regardless of early childhood SES or childhood residence.

Background Midlife cardiovascular risk factors (CVRF) increase dementia risk. Less is known about whether CVRF identified before midlife impact late-life cognition in diverse populations. Methods Linear regression models examined hypertension, hyperlipidemia, and overweight/obesity at ages 30 to 59 with late-life executive function, semantic memory, verbal episodic memory, and global cognition in a cohort of Asians, blacks, Latinos, and whites (n=1127; mean age=75.8, range=65 to 98). Models adjusted for age at CVRF, age at cognitive assessment, sex, race/ethnicity, participant education, and parental education. Results Overall, 34% had 1 CVRF at ages 30 to 59; 19% had 2+. Blacks (26%) and Latinos (23%) were more likely to have 2+ CVRF than Asians (14%) or whites (13%). Having 2+ CVRF was associated with lower global cognition [β=-0.33; 95% confidence interval (CI)=-0.45, -0.21], executive function (β=-0.26; 95% CI=-0.39, -0.13), verbal episodic memory (β=-0.34; 95% CI=-0.48, -0.20), and semantic memory (β=-0.20; 95% CI=-0.33, -0.07). Interaction by age (P=0.06) indicated overweight/obesity was negatively associated with executive function at ages 30 to 39 but not at ages 40 to 59. Race/ethnic-specific effects showed disparities in CVRF prevalence impact population disparities in late-life cognition. Conclusion Being overweight/obese in early adulthood and having 2+ CVRF in early adulthood/midlife are modifiable targets to redress racial/ethnic disparities in cognitive impairment and dementia.

Background: Abnormal thyroid hormone levels (high or low) and autoimmunity from autoimmune thyroid disease (AITD) may increase dementia risk. Methods: We examined the associations of thyroid dysfunction or possible AITD in 1990 - 1992 with dementia through 2017 in the Atherosclerosis Risk in Communities (ARIC) Neurocognitive Study. Thyroid dysfunction (subclinical and overt hypo- or hyperthyroidism and euthyroidism) was categorized from serum thyroid-stimulating hormone (TSH) and free thyroxine (FT4) cut-points and AITD from anti-thyroid peroxidase (anti-TPO) antibody positivity. Dementia was identified primarily based on cognitive test performance, neuropsychological examinations and clinician review of suspected cases. Additional cases of dementia were ascertained through telephone interviews or relevant hospital and death certificate codes. Cox regression with multivariable adjustment was used for analysis. Results: After exclusions for missing data, 12,481 participants were included in the analysis (mean index exam age 57 ± 5.7 (44% male, 25% black)), and 2,235 incident dementia cases were identified. AITD was not significantly associated with dementia. Subclinical hypothyroidism was associated with a lower risk of dementia (hazard ratio (HR) (95% confidence interval (CI)): 0.74 (0.60 - 0.92)), while overt hyperthyroidism was associated with a higher risk of dementia (HR (95% CI): 1.40 (1.02 - 1.92)) compared to euthyroid participants. Participants with serum FT4 concentrations above the 95th percentile were at an increased risk of dementia compared to those in the middle 90% of FT4 (HR (95% CI): 1.23 (1.02 - 1.48)). Conclusions: Subclinical hypothyroidism was associated with reduced risk of dementia, whereas overt hyperthyroidism, particularly very elevated FT4, was associated with increased risk of dementia. The association between subclinical hypothyroidism and reduced risk of dementia cannot be explained, but may have been an artifact due to change. By extrapolation, effective treatment of overt hyperthyroidism may modestly reduce dementia risk in older adults. J Endocrinol Metab. 2019;9(4):82-89 doi: https://doi.org/10.14740/jem588