Trials and Treatments for Vascular Brain Health: Risk Factor Modification and Cognitive Outcomes.

There is robust evidence linking vascular health to brain health, cognition, and dementia. In this article, we present evidence from trials of vascular risk factor treatment on cognitive outcomes. We summarize findings from randomized controlled trials of antihypertensives, lipid-lowering medications, diabetes treatments (including antidiabetic drugs versus placebo, and intensive versus standard glycemic control), and multidomain interventions (that target several domains simultaneously such as control of vascular and metabolic factors, nutrition, physical activity, and cognitive stimulation etc). We report that evidence on the efficacy of vascular risk reduction interventions is promising, but not yet conclusive, and several methodological limitations hamper interpretation. Evidence mainly comes from high-income countries and, as cognition and dementia have not been the primary outcomes of many trials, evaluation of cognitive changes have often been limited. As the cognitive aging process occurs over decades, it is unclear whether treatment during the late-life window is optimal for dementia prevention, yet older individuals have been the target of most trials thus far. Further, many trials have not been powered to explore interactions with modifiers such as age, race, and apolipoprotein E, even though sub-analyses from some trials indicate that the success of interventions differs depending on patient characteristics. Due to the complex multifactorial etiology of dementia, and variations in risk factors between individuals, multidomain interventions targeting several risk factors and mechanisms are likely to be needed and the long-term sustainability of preventive interventions will require personalized approaches that could be facilitated by digital health tools. This is especially relevant during the COVID-19 pandemic, where intervention strategies will need to be adapted to the new normal, when face-to-face engagement with participants is limited and public health measures may create changes in lifestyle that affect individuals' vascular risk profiles and subsequent risk of cognitive decline.

Body mass index in early adulthood and dementia in late life: Findings from a pooled cohort.

INTRODUCTION: To examine the independent association of body mass index (BMI) in early adulthood with dementia incidence among men and women. METHODS: We studied 5104 older adults from the Cardiovascular Health Study (CHS) and the Health, Aging, and Body Composition (Health ABC) study. We imputed early adulthood and midlife BMI using a pooled parent cohort with complete adult lifespan coverage and previously established methods. Dementia was ascertained using criteria such as neuropsychological test battery, medical records, and dementia-related drug use. Pooled logistic regression (PLR) models were used. RESULTS: Compared to women with normal BMI in early adulthood, the odds of dementia were higher among both overweight (odds ratio [OR] = 1.8; 95% confidence interval [CI] = 1.31 to 2.54) and obese (OR = 2.45; 95% CI = 1.47 to 4.06) women, independent of mid- and late-life BMI. Similar relationship was observed in men. CONCLUSIONS: With the growing obesity epidemic among US adults, efforts aimed at reducing dementia may need to begin obesity prevention and treatment early in the life course.

Ten-Year Prevalence of Cognitive Impairment Diagnoses and Associated Medical and Psychiatric Conditions in a National Cohort of Older Female Veterans.

OBJECTIVE: Veterans are at risk for dementia because of elevated general risk factors and exposure to military risk factors; however, few studies have focused on female veterans despite their growing numbers. We sought to characterize the 10-year prevalence of cognitive impairment (i.e., mild cognitive impairment and dementia) and associated conditions in older female veterans. METHODS: Data were extracted from Veterans Health Administration medical records of 168,111 female veterans aged 65 and older. Cognitive impairment (CI) diagnoses were defined using International Classification of Diseases, Ninth Revision (ICD-9) codes or dementia medication prescriptions. Medical comorbidities and psychiatric conditions were determined using ICD-9 codes occurring within 2years of CI diagnosis or the last recorded medical encounter for veterans without CI. RESULTS: Ten-year prevalence was 1.8% (3,075) for mild cognitive impairment (MCI) diagnoses and 8.1% (13,653) for dementia diagnoses. Prevalence increased with age (MCI age 65: 1.4%; age 85+: 2.7%; dementia age 65: 2.5%; age 85+: 17.7%); 37.3% had dementia subtype diagnoses, with Alzheimer's disease being the most prevalent (72.7%). 47.7% of veterans with CI had at least one medical comorbidity, whereas 22.5% had at least one psychiatric condition. CONCLUSION: Few studies have characterized the prevalence of cognitive impairment in female veterans despite the expected increases in CI and impending demographic shifts in the military. The high prevalence of medical and psychiatric conditions in female veterans with CI highlights their healthcare burden and emphasizes the need for further investigations into the prevention, treatment, and care of cognitive impairment in this understudied population.

Aiding alternatives assessment with an uncertainty-tolerant hazard scoring method.

This research developed a single-score system to simplify and clarify decision-making in chemical alternatives assessment, accounting for uncertainty. Today, assessing alternatives to hazardous constituent chemicals is a difficult task-rather than comparing alternatives by a single definitive score, many independent toxicological variables must be considered at once, and data gaps are rampant. Thus, most hazard assessments are only comprehensible to toxicologists, but business leaders and politicians need simple scores to make decisions. In addition, they must balance hazard against other considerations, such as product functionality, and they must be aware of the high degrees of uncertainty in chemical hazard data. This research proposes a transparent, reproducible method to translate eighteen hazard endpoints into a simple numeric score with quantified uncertainty, alongside a similar product functionality score, to aid decisions between alternative products. The scoring method uses Clean Production Action's GreenScreen as a guide, but with a different method of score aggregation. It provides finer differentiation between scores than GreenScreen's four-point scale, and it displays uncertainty quantitatively in the final score. Displaying uncertainty also illustrates which alternatives are early in product development versus well-defined commercial products. This paper tested the proposed assessment method through a case study in the building industry, assessing alternatives to spray polyurethane foam insulation containing methylene diphenyl diisocyanate (MDI). The new hazard scoring method successfully identified trade-offs between different alternatives, showing finer resolution than GreenScreen Benchmarking. Sensitivity analysis showed that different weighting schemes in hazard scores had almost no effect on alternatives ranking, compared to uncertainty from data gaps.

Early adult to midlife cardiovascular risk factors and cognitive function.

BACKGROUND: Studies have linked midlife and late-life cardiovascular risk factors (CVRFs) to cognitive function, yet little is known about CVRF exposure in early adulthood and subsequent cognitive function. In addition, most studies rely on single assessments of CVRFs, which may not accurately reflect long-term exposure. We sought to determine the association between cumulative exposure to CVRFs from early to middle adulthood and cognitive function at midlife. METHODS AND RESULTS: In a prospective study of 3381 adults (age, 18-30 years at baseline) with 25 years of follow-up, we assessed cognitive function at year 25 (2010-2011) with the Digit Symbol Substitution Test, Stroop Test, and Rey Auditory Verbal Learning Test analyzed with standardized z scores. The primary predictor was 25-year cumulative exposure estimated by areas under the curve for resting systolic and diastolic blood pressures, fasting blood glucose, and total cholesterol. Higher cumulative systolic and diastolic blood pressures and fasting blood glucose were consistently associated with worse cognition on all 3 tests. These associations were significant primarily for exposures above recommended guidelines; cognitive test z scores were between 0.06 and 0.30 points less, on average, for each 1-SD increase in risk factor area under the curve after adjustment for age, race, sex, and education (P<0.05 for all). Fewer significant associations were observed for cholesterol. CONCLUSIONS: Cumulative exposure to CVRFs from early to middle adulthood, especially above recommended guidelines, was associated with worse cognition in midlife. The meaning of this association and whether it warrants more aggressive treatment of CVRFs earlier in life require further investigation.

Alcohol consumption patterns and cognitive impairment in older women.

OBJECTIVE: Few studies have investigated changes in alcohol consumption and risk of cognitive impairment among oldest old adults. METHODS: In a prospective study of 1309 women ≥65 years old, alcohol use was assessed at repeated visits and used to estimate average change in alcohol consumption over 16 years. Clinically significant cognitive impairment (mild cognitive impairment and dementia) was assessed at year 20. RESULTS: Compared with the reference group (slight decrease in alcohol consumption by 0-0.5 drinks/week, 60.4%), increasing consumption over time (>0 drinks/week) was not associated with risk of cognitive impairment (5.0%, odds ratio [OR]: 1.00, 95% confidence interval [CI]: 0.54-1.85). Decreasing consumption by >0.5 drinks/week was associated with increased risk (34.5%, OR: 1.34, 95% CI: 1.05-1.70). Adjustment for age, education, diabetes, smoking, BMI, and physical activity attenuated the magnitude of the effect slightly and resulted in borderline statistical significance. CONCLUSION: Women in their ninth and tenth decade of life who decrease alcohol use may be at risk of cognitive impairment.

Lifestyle and health-related risk factors and risk of cognitive aging among older veterans.

Lifestyle and health-related factors are critical components of the risk for cognitive aging among veterans. Because dementia has a prolonged prodromal phase, understanding effects across the life course could help focus the timing and duration of prevention targets. This perspective may be especially relevant for veterans and health behaviors. Military service may promote development and maintenance of healthy lifestyle behaviors, but the period directly after active duty has ended could be an important transition stage and opportunity to address some important risk factors. Targeting multiple pathways in one intervention may maximize efficiency and benefits for veterans. A recent review of modifiable risk factors for Alzheimer's disease estimated that a 25% reduction of a combination of seven modifiable risk factors including diabetes, hypertension, obesity, depression, physical inactivity, smoking, and education/cognitive inactivity could prevent up to 3 million cases worldwide and 492,000 cases in the United States. Lifestyle interventions to address cardiovascular health in veterans may serve as useful models with both physical and cognitive activity components, dietary intervention, and vascular risk factor management. Although the evidence is accumulating for lifestyle and health-related risk factors as well as military risk factors, more studies are needed to characterize these factors in veterans and to examine the potential interactions between them.

Association of Changes in C-Reactive Protein Level Trajectories Through Early Adulthood With Cognitive Function at Midlife: The CARDIA Study.

BACKGROUND AND OBJECTIVES: Late-life inflammation has been linked to dementia risk and preclinical cognitive decline, but less is known about early adult inflammation and whether this could influence cognition in midlife. We aimed to identify inflammation levels through early adulthood and determine association of these trajectories with midlife cognition. METHODS: We used data from the Coronary Artery Risk Development in Young Adults study to identify inflammation trajectories (C-reactive protein [CRP] level <10 mg/L) over 18 years through early adulthood (age range 24-58) in latent class analysis and to assess associations with cognition 5 years after the last CRP measurement (age range 47-63). Six cognitive domains were evaluated from tests of verbal memory, processing speed, executive function, verbal and category fluency, and global cognition; poor cognitive performance was defined as a decline of ≥1 SD less than the mean on each domain. The primary outcome was poor cognitive performance. Logistic regression was used to adjust for demographics, smoking, alcohol use, physical activity, and APOE 4 status. RESULTS: Among 2,364 participants, the mean (SD) age was 50.2 (3.5) years; 55% were female, and 57% were White. Three CRP trajectories emerged over 18 years: lower stable (45%), moderate/increasing (16%), and consistently higher (39%). Compared with lower stable CRP, both consistently higher (adjusted odds ratio [aOR] 1.67, 95% CI 1.23-2.26) and moderately/increasing (aOR 2.04, 95% CI 1.40-2.96) CRP had higher odds of poor processing speed; consistently higher CRP additionally had higher odds of poor executive function (aOR 1.36, 95% CI 1.00-1.88). For memory (moderately/increasing aOR 1.36, 95% CI 1.00-1.88; consistently higher aOR 1.18, 95% CI 0.90-1.54), letter fluency (moderately/increasing aOR 1.00, 95% CI 0.69-1.43; consistently higher aOR 1.05, 95% CI 0.80-1.39), category fluency (moderately/increasing aOR 1.16, 95% CI 0.82-1.63; consistently higher aOR 1.11, 95% CI 0.85-1.45), or global cognition (moderately/increasing aOR 1.16, 95% CI 0.82-1.63; consistently higher aOR 1.11, 95% CI 0.85-1.45), no association was observed. DISCUSSION: Consistently higher or moderate/increasing inflammation starting in early adulthood may lead to worse midlife executive function and processing speed. Study limitations include selection bias due to loss to follow-up and reliance on CRP as the only inflammatory marker. Inflammation is important for cognitive aging and may begin much earlier than previously known.

Retinopathy and cognitive impairment in adults with CKD.

BACKGROUND: Retinal microvascular abnormalities have been associated with cognitive impairment, possibly serving as a marker of cerebral small-vessel disease. This relationship has not been evaluated in persons with chronic kidney disease (CKD), a condition associated with increased risk of both retinal pathology and cognitive impairment. STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: 588 participants 52 years or older with CKD in the Chronic Renal Insufficiency Cohort (CRIC) Study. PREDICTOR: Retinopathy graded using the Early Treatment Diabetic Retinopathy Study severity scale and diameters of retinal vessels. OUTCOMES: Neuropsychological battery of 6 cognitive tests. MEASUREMENTS: Logistic regression models were used to evaluate the association of retinopathy, individual retinopathy features, and retinal vessel diameters with cognitive impairment (≤1 SD from the mean), and linear regression models were used to compare cognitive test scores across levels of retinopathy, adjusting for age, race, sex, education, and medical comorbid conditions. RESULTS: The mean age of the cohort was 65.3±5.6 (SD) years, 51.9% were nonwhite, and 52.6% were men. The prevalence of retinopathy was 30.1%, and the prevalence of cognitive impairment was 14.3%. Compared with those without retinopathy, participants with retinopathy had an increased likelihood of cognitive impairment on executive function (35.1% vs 11.5%; OR, 3.4 [95% CI, 2.0-6.0]), attention (26.7% vs 7.3%; OR, 3.0 [95% CI, 1.8-4.9]), and naming (26.0% vs 10.0%; OR, 2.1 [95% CI, 1.2-3.4]) after multivariable adjustment. Increased level of retinopathy also was associated with lower cognitive performance on executive function and attention. Microaneurysms were associated with cognitive impairment on some domains, but there were no significant associations with other retinal measures after multivariable adjustment. LIMITATIONS: Unknown temporal relationship between retinopathy and impairment. CONCLUSIONS: In adults with CKD, retinopathy is associated with poor performance on several cognitive domains, including executive function and attention. Evaluation of retinal microvascular abnormalities may be a promising tool for identifying patients with CKD who are at increased risk of cognitive impairment.

Constricting Life Space and Likelihood of Neurodegenerative Disease in Community-Dwelling Older Men.

Importance: Life space is a measure of the frequency, range, and independence of movement through the environment. There is increasing interest in life space as a holistic measure of function in older adults, but the association between change in life space and incident neurodegenerative disease is unknown. Objective: To evaluate the association between change in life space and cognitive decline or incident neurodegenerative disease over 7 years among community-dwelling older men. Design, Setting, and Participants: In this cohort study, logistic regression analyses were used to examine the association of baseline and change in life space with change in cognition unadjusted and adjusted for demographics, cardiovascular risk factors, depression, gait speed, and physical activity. Mixed linear effects models were used to evaluate the association between change in life space and change in cognition. Men were recruited from 6 US sites to participate in a prospective, community-based cohort study of aging and followed-up from 2007 to 2014. Individuals with prevalent dementia or Parkinson disease (PD) at baseline were excluded. Data were analyzed from May 2022 to September 2023. Exposure: Life space, assessed using the University of Alabama at Birmingham Life Space Assessment and divided into tertiles. Main Outcomes and Measures: Participants completed the Modified Mini-Mental State (3MS) Test, and Trail-Making Test Part B at baseline and 7 years later. At follow-up, participants were asked about a new physician diagnosis of dementia and PD. Results: A total of 1684 men (mean [SD] age, 77.1 [4.2] years) were recruited and over 7 years of follow-up, 80 men (4.8%) developed dementia and 23 men (1.4%) developed PD. Mean (SD) life space score was 92.9 (18.7) points and mean (SD) change was -9.9 (22.3) points over follow up. In the adjusted model, each 1-SD decrement in life space was associated with increased odds of dementia (odds ratio [OR], 1.59; 95% CI, 1.28-1.98) but not PD (OR, 1.48; 95% CI, 0.97-2.25). For each 1-SD decrement in life space, men worsened by 20.6 (95% CI, 19.8-21.1) seconds in their Trails B score (P < .001) and declined by 1.2 (95% CI, 1.0-1.3) points in their 3MS score (P < .001) over 7 years. Conclusions and Relevance: In this study of 1684 men followed up over 7 years, change in life space was associated with faster cognitive decline and increased likelihood of neurodegenerative illness. Future studies should examine the role of clinician assessments or wearable electronics in tracking life space in older adults at risk of cognitive decline and neurodegenerative illness.

Methods to Evaluate Changes in Mitochondrial Structure and Function in Cancer.

Mitochondria are regulators of key cellular processes, including energy production and redox homeostasis. Mitochondrial dysfunction is associated with various human diseases, including cancer. Importantly, both structural and functional changes can alter mitochondrial function. Morphologic and quantifiable changes in mitochondria can affect their function and contribute to disease. Structural mitochondrial changes include alterations in cristae morphology, mitochondrial DNA integrity and quantity, and dynamics, such as fission and fusion. Functional parameters related to mitochondrial biology include the production of reactive oxygen species, bioenergetic capacity, calcium retention, and membrane potential. Although these parameters can occur independently of one another, changes in mitochondrial structure and function are often interrelated. Thus, evaluating changes in both mitochondrial structure and function is crucial to understanding the molecular events involved in disease onset and progression. This review focuses on the relationship between alterations in mitochondrial structure and function and cancer, with a particular emphasis on gynecologic malignancies. Selecting methods with tractable parameters may be critical to identifying and targeting mitochondria-related therapeutic options. Methods to measure changes in mitochondrial structure and function, with the associated benefits and limitations, are summarized.

The Metabolic Syndrome Is Associated With Lower Cognitive Performance and Reduced White Matter Integrity in Midlife: The CARDIA Study.

Background: Cardiovascular disease risk factors play a critical role in brain aging. The metabolic syndrome (MetS), a constellation of cardiovascular risk factors, has been associated with poorer cognition in old age; however, it is unclear if it is connected to brain health earlier in life. Methods: We investigated the association of MetS (n = 534, 18.5%) vs. no MetS (n = 2,346, 81.5%) with cognition in midlife within the prospective study, Coronary Artery Risk Development in Young Adults (CARDIA). At midlife (mean age 50), MetS was defined using National Cholesterol Education Program guidelines. At the 5-year follow-up, a cognitive battery was administered including tests of processing speed (Digit Symbol Substitution Test, DSST), executive function (the Stroop Test), verbal memory (Rey Auditory Verbal Learning Test, RAVLT), verbal fluency (category and letter fluency), and global cognitive function (Montreal Cognitive Assessment, MoCA). A sub-sample (n = 453) underwent brain MRI. Results: Participants with MetS had worse performance on tests of verbal fluency, processing speed, executive function, and verbal memory (p < 0.05), but not on global cognition. MetS was also associated with lower frontal, parietal, temporal, and total white matter integrity (p < 0.05), as assessed with fractional anisotropy. Conclusions: MetS is associated with lower cognition and microstructural brain alterations already at midlife, suggesting that MetS should be targeted earlier in life in order to prevent adverse brain and cognitive outcomes.

Long-term television viewing patterns and gray matter brain volume in midlife.

The purpose of this study was to investigate whether long-term television viewing patterns, a common sedentary behavior, in early to mid-adulthood is associated with gray matter brain volume in midlife and if this is independent of physical activity. We evaluated 599 participants (51% female, 44% black, mean age 30.3 ± 3.5 at baseline and 50.2 ± 3.5 years at follow-up and MRI) from the prospective Coronary Artery Risk Development in Young Adults (CARDIA) study. We assessed television patterns with repeated interviewer-administered questionnaire spanning 20 years. Structural MRI (3T) measures of frontal cortex, entorhinal cortex, hippocampal, and total gray matter volumes were assessed at midlife. Over the 20 years, participants reported viewing an average of 2.5 ± 1.7 h of television per day (range: 0-10 h). After multivariable adjustment, greater television viewing was negatively associated with gray matter volume in the frontal (ß = - 0.77; p = 0.01) and entorhinal cortex (ß = - 23.83; p = 0.05) as well as total gray matter (ß = - 2.09; p = 0.003) but not hippocampus. These results remained unchanged after additional adjustment for physical activity. For each one standard deviation increase in television viewing, the difference in gray matter volume z-score was approximately 0.06 less for each of the three regions (p < 0.05). Among middle-aged adults, greater television viewing in early to mid-adulthood was associated with lower gray matter volume. Sedentariness or other facets of television viewing may be important for brain aging even in middle age.

Twenty-Five-Year Change in Cardiac Structure and Function and Midlife Cognition: The CARDIA Study.

BACKGROUND AND OBJECTIVE: The goal of this work was to determine whether midlife cardiac structure and function and their 25-year change from early to middle adulthood are associated with lower midlife cognition. METHODS: We studied 2,653 participants from the Coronary Artery Risk Development in Young Adults (CARDIA) study (57% women, 46% Black). Echocardiograms were obtained at year 5, 25, and 30 visits (participant mean age 30, 50, and 55 years) to assess left ventricular (LV) mass (LVM), LV systolic function with LV ejection fraction (LVEF), and LV diastolic function with left atrial volume (LAV) and early peak mitral velocity (E)/early peak mitral annular velocity (e') ratio. LVM and LAV were indexed to body surface area (LVMi and LAVi). At year 30, 5 cognitive domains were measured: global cognition, processing speed, executive function, delayed verbal memory, and verbal fluency. We investigated the association between midlife (year 30) and 25-year change in cardiac structure and function on midlife cognition using linear regressions. RESULTS: Over 25 years, LVMi and LAVi increased with mean change (SD) per year of 0.27 (0.28) g/m2 and 0.42 (0.15) mL/m2, while LVEF decreased by 0.11% (0.02%). After adjustment for demographics and education, 25-year increase (≥1 SD) in LVMi was associated with lower cognition on most tests (p ≤ 0.02); 25-year increase in LAVi was associated with lower global cognition (p = 0.04), but 25-year decrease in LVEF was not associated with cognition. Further adjustment for cardiovascular risk factors led to similar results. In addition, unlike year 30 E/e' ratio and LVEF, higher year 30 LVMi and LAVi were significantly associated with worse cognition on most cognitive tests. DISCUSSION: Midlife cardiac structure and its change from early to middle adulthood are associated with lower midlife cognition even after accounting for confounders. Unlike systolic function, midlife LV diastolic function and its 25-year change were also linked to cognition. Our results provide information linking early to midlife cardiac structure and function to cognition.

Increased risk of dementia in older female US veterans with alcohol use disorder.

AIM: To determine whether alcohol use disorder (AUD) is associated with increased dementia risk among older women veterans. DESIGN: Cohort study. SETTING: United States. PARTICIPANTS: Women veterans with AUD aged ≥ 55 years (n = 2207), receiving care from Veterans Health Administration medical centers from October 2004 to September 2015 with one or more follow-up visit and an age-matched sample of women veterans without AUD (n = 2207). Women at baseline with prevalent dementia or AUD in remission were excluded. MEASUREMENTS: AUD, substance use disorder (SUD), smoking, psychiatric (depression, anxiety, post-traumatic stress disorder, anxiety) and medical comorbidities (diabetes, hypertension, stroke, chronic obstructive pulmonary disorder, traumatic brain disorder) and dementia determined by the International Classification of Diseases, 9th revision, Clinical Modification codes. Cox proportional hazards models were used to determine the association between AUD and dementia risk during follow-up. Sensitivity analyses were performed by excluding women (n = 349) with comorbid SUD and by excluding women (n = 1568) currently smoking. FINDINGS: Veteran women had a mean [standard deviation (SD)] age of 65.0 (5.6) years at baseline. During follow-up (median 4 years, interquartile range: 2-6) 3.7% of women (n = 82) with AUD developed dementia compared with 1.1% (n = 24) without AUD (P < 0.001). After adjustment for demographics, medical and psychiatric conditions and accounting for different Veteran's Integrated Service Networks, the adjusted hazard ratio (aHR) for dementia was 3.12 (95% CI = 1.90-5.12) for women with AUD compared with women without AUD. After removing women with SUD (aHR = 3.53, 95% CI = 2.13-5.85) and women currently smoking (aHR = 3.80, 95% CI = 2.11-6.84), results were similar. CONCLUSIONS: Alcohol use disorder among female US veterans aged more than 55 years appears to be associated with a more than threefold increase of dementia.

The Effect of Sex and Wealth on Population Attributable Risk Factors for Dementia in South Africa.

Background and Aims: South Africa is a middle-income country with high levels of income inequality and a rapidly aging population and increasing dementia prevalence. Little is known about which risk factors for dementia are important and how they differ by social determinants of health as well as key demographic characteristics such as sex and wealth. We sought to calculate the population attributable risks (PARs) for established potentially modifiable risk factors for dementia among these different groups. Methods: We obtained risk factor prevalence from population-based surveys for established dementia risk factors (diabetes, midlife hypertension, midlife obesity, physical inactivity, depression, smoking, low educational attainment, social isolation). We used relative risk estimates reported in previous meta-analyses and estimated PARs using Levin's formula and accounting for communality. We tested for one-way and two-way interactions by sex and wealth using Pearson's χ2. In stratified analyses, we performed tests for trend using logistic regression. Results: The prevalence of established risk factors for dementia ranged from 5% for depression to 64% for low education. After accounting for communality, the risk factors contributing the greatest PAR were low education (weighted PAR 12%, 95% CI 7% to 18%), physical inactivity (9, 5-14%), and midlife hypertension (6, 5-14%). Together, 45% of dementia cases may be attributable to modifiable risk factors (95% CI 25-59%). We found significant interactions (p < 0.005) between sex, wealth, or both (sex * wealth) and each risk factor except social isolation and physical activity. Low education was inversely associated with wealth in both male and female. The PAR for midlife hypertension, obesity, and diabetes was associated with increasing wealth, and was higher in female. In contrast, the PAR for smoking was higher in male (8% vs. 2%) and was associated with increasing wealth among female only. We found that either a strategy of large reductions in selected risk factors with the highest PAR (midlife hypertension, smoking, physical inactivity) or small reductions across all risk factors could potentially reduce dementia cases by as many as 250,000 by 2050. Discussions: The potential impact on dementia risk by decreasing exposure to established dementia risk factors is large and differs by sex and social determinants of health like wealth. Risk factor PAR should inform national and local health policy dementia initiatives in South Africa including which risk factors to target in the whole population and which to target in high-risk groups for maximum public health benefit.

Cardiovascular Risk Factors Across the Life Course and Cognitive Decline: A Pooled Cohort Study.

OBJECTIVE: Cardiovascular risk factors (CVRFs) are associated with increased risk of cognitive decline, but little is known about how early adult CVRFs and those across the life course might influence late-life cognition. To test the hypothesis that CVRFs across the adult life course are associated with late-life cognitive changes, we pooled data from 4 prospective cohorts (n = 15,001, ages 18-95). METHODS: We imputed trajectories of body mass index (BMI), fasting glucose (FG), systolic blood pressure (SBP), and total cholesterol (TC) for older adults. We used linear mixed models to determine the association of early adult, midlife, and late-life CVRFs with late-life decline on global cognition (Modified Mini-Mental State Examination [3MS]) and processing speed (Digit Symbol Substitution Test [DSST]), adjusting for demographics, education, and cohort. RESULTS: Elevated BMI, FG, and SBP (but not TC) at each time period were associated with greater late-life decline. Early life CVRFs were associated with the greatest change, an approximate doubling of mean 10-year decline (an additional 3-4 points for 3MS or DSST). Late-life CVRFs were associated with declines in early late life (<80 years) but with gains in very late life (≥80 years). After adjusting for CVRF exposures at all time periods, the associations for early adult and late-life CVRFs persisted. CONCLUSIONS: We found that imputed CVRFs across the life course, especially in early adulthood, were associated with greater late-life cognitive decline. Our results suggest that CVRF treatment in early adulthood could benefit late-life cognition, but that treatment in very late life may not be as helpful for these outcomes.

HIV and risk of dementia in older veterans.

OBJECTIVE: People living with HIV (PLWH) may be at an increased risk for dementia as they age. Surprisingly, it remains unclear whether PLWH have a higher risk of developing dementia in late life than those without. We explored whether HIV-infection is associated with incident dementia diagnosis in older U.S. veterans accounting for potential confounders and competing risk of death. METHODS: We included 1114 veterans diagnosed with HIV, ages at least 55 years (mean = 62 years, SD = 6), followed in the Veterans Health Administration healthcare system from 2004 to 2015, and a propensity-matched comparison group (n = 1114) without HIV. HIV and dementia diagnoses were determined using electronic medical records. Using Fine-Gray proportional hazards models, we examined whether HIV status was associated with a greater risk of incident dementia. RESULTS: During follow-up (mean = 7 years, SD = 4 from date of HIV diagnosis), 5% of veteran PLWH developed dementia compared with 3% without (P = 0.01). Accounting for the competing risk of death and adjusted for demographics, substance use, education and income, PLWH remained 50% more likely to receive a dementia diagnosis [adjusted hazard ratio (aHR) = 1.50, 95% confidence interval 0.96-2.35]. Although combination antiretroviral therapy (cART) exposure was associated with an increased risk of incident dementia, this was driven by differences in illness severity as captured by CD4 cell count. There was no evidence of a differential effect by cART class. CONCLUSION: In a cohort of older USA veterans, HIV infection increased risk of dementia by 50%, while exposure to cART did not offset this risk. It is critical to understand the mechanisms by which HIV increases risk for developing dementia in later life.

Systolic blood pressure postural changes variability is associated with greater dementia risk.

OBJECTIVE: To determine whether orthostatic hypotension (OHYPO) and visit-to-visit blood pressure (BP) postural changes variability are associated with incident dementia. METHODS: We studied 2,131 older adults from the Health, Aging, and Body Composition cohort study. Orthostatic BP was repeatedly assessed over a 5-year baseline period. OHYPO was defined as a fall ≥15 mm Hg in systolic or ≥7 mm Hg in diastolic BP after standing from a sitting position for one-third or more of the visits. Systolic OHYPO and diastolic OHYPO were also examined separately. BP postural changes variability over time was evaluated with several indicators, including SD and coefficient of variation (CV). Incident dementia was determined over 12 years after the baseline period by dementia medication use, ≥1.5 SD decline in Modified Mini-Mental State Examination score, or hospitalization records. RESULTS: Of 2,131 participants (mean age 73 years, 53% female, 39% Black), 309 (14.5%) had OHYPO, 192 (9.0%) had systolic OHYPO, 132 (6.2%) had diastolic OHYPO, and 462 (21.7%) developed dementia. After adjustment for demographics, seated systolic BP (SBP), antihypertensive drugs, cerebrovascular disease, diabetes mellitus, depressive symptoms, smoking, alcohol, body mass index, and presence of 1 or 2 APOE ε4 alleles, systolic OHYPO was associated with greater dementia risk (adjusted hazard ratio [HR] 1.37, 95% confidence interval [CI] 1.01-1.88), unlike diastolic OHYPO and OHYPO. SBP postural changes variability was also associated with higher dementia risk (highest tertile of variability [CV]: adjusted HR 1.35, 95% CI 1.06-1.71). CONCLUSION: Systolic OHYPO and visit-to-visit SBP postural changes variability were associated with greater dementia risk. Our findings raise the question of potential preventive interventions to control orthostatic SBP and its fluctuations.

Association of Late-Onset Unprovoked Seizures of Unknown Etiology With the Risk of Developing Dementia in Older Veterans.

Importance: The incidence of unprovoked seizures and epilepsy increases considerably in late life, with approximately one-third of seizures being of unknown etiology. While individuals with dementia have a high risk of developing unprovoked seizures, it is unknown whether older adults with late-onset unprovoked seizures of unknown etiology (LOSU) are at risk of developing dementia. Objective: To determine whether incident LOSU is associated with a higher risk of dementia among older US veterans. Design, Setting, and Participants: This retrospective multicenter cohort study was conducted using data from US Veterans Health Administration medical centers from October 2001 to September 2015. Data were generated from all veteran inpatient and outpatient encounters that occurred within Veterans Health Administration facilities. A random sample of 941 524 veterans 55 years and older was generated. A total of 649 262 veterans previously diagnosed (using International Classification of Diseases, Ninth Revision, Clinical Modification codes) with dementia, unprovoked seizures, epilepsy, and conditions that could lead to seizures (brain tumors, trauma, infections, stroke, and neurotoxin exposure) as well as veterans without follow-up data were excluded. Data were analyzed from October 2018 to July 2019. Exposures: Late-onset unprovoked seizures of unknown etiology were defined as a new diagnosis of epilepsy or unprovoked seizures without a diagnosis of a secondary cause for seizures. Incident LOSU was assessed during a 5-year baseline period. Main Outcomes and Measures: Veterans were assessed for incident dementia diagnosis during an outcome period. Fine-Gray proportional hazards models were used to determine whether LOSU was associated with greater risk of incident dementia. Models were adjusted for demographic variables, cardiovascular risk factors, depression, and traumatic brain injury. Results: Of the 292 262 included veterans, 282 628 (96.7%) were male, and the mean (SD) age was 73.0 [8.8] years. During the baseline period, 2166 veterans developed LOSU. The mean (SD) follow-up after LOSU was 6.1 (2.9) years. After multivariable adjustment, veterans with LOSU had greater risk of dementia compared with veterans without seizures (hazard ratio, 1.89; 95% CI, 1.62-2.20). A sensitivity analysis imposing a 2-year lag between incident LOSU and dementia diagnosis led to similar results. Conclusions and Relevance: These findings suggest LOSU in older veterans is associated with a 2-fold risk of developing dementia. While seizures are commonly thought to occur in late stages of dementia, these findings suggest unexplained seizures in older adults may be a first sign of neurodegenerative disease.