Association of Adherence to a MIND-Style Diet With the Risk of Cognitive Impairment and Decline in the REGARDS Cohort.

BACKGROUND AND OBJECTIVES: Diet may influence the development of cognitive impairment and affect cognitive decline, but whether this relationship varies between Black American and White American people is unclear. This study examined the association of Mediterranean-Dietary Approaches to Stop Hypertension Intervention for Neurodegenerative Delay (MIND) and incident cognitive impairment and cognitive trajectories in a biracial prospective cohort study. METHODS: Using data derived from the Food Frequency Questionnaire in the REasons for Geographic and Racial Differences in Stroke study, we compared MIND diet adherence with incident cognitive impairment and cognitive trajectory in Black participants and White participants. Logistic regression was used to model MIND diet score (continuous variable and using tertiles) and incident cognitive impairment after adjusting for age, sex, race, region, education, income, total energy, hypertension history, dyslipidemia, diabetes, estimated glomerular filtration rate, ischemic heart conditions, atrial fibrillation, and lifestyle factors including sedentary, obesity, and smoking. Mixed-effects models were used to examine the association between cognitive trajectory and MIND diet adherence. RESULTS: Dietary data to calculate the MIND diet score and cognitive data were available on 14,145 participants with a mean age of 64 years (SD 9.0 years) that was 56.7% female. Greater MIND diet adherence was associated with a decreased incidence of cognitive impairment (odds ratio [OR] 0.96, 95% CI 0.93-0.99, p = 0.02) after adjusting for all covariates. In the fully adjusted model, greater MIND diet adherence was associated with decreased risk of cognitive impairment in female participants (OR 0.92, 95% CI 0.89-0.96, p < 0.001) but not in male participants (OR 1.01, 95% CI 0.97-1.06, p = 0.64). In all models, greater MIND diet adherence was associated with decreased risk of cognitive decline. MIND diet adherence was a better predictor of cognitive decline in Black participants (ß = 0.04, SE = 0.007, p < 0.001) than in White participants (ß = 0.03, SE = 0.004, p < 0.001). DISCUSSION: Greater MIND diet adherence was associated with decreased risk of cognitive impairment in female participants but not male participants, with no difference between Black participants and White participants. However, MIND diet adherence was a better predictor of cognitive trajectory in Black participants than in White participants.

General cognitive ability in high school, attained education, occupational complexity, and dementia risk.

INTRODUCTION: We address the extent to which adolescent cognition predicts dementia risk in later life, mediated by educational attainment and occupational complexity. METHODS: Using data from Project Talent Aging Study (PTAS), we fitted two structural equation models to test whether adolescent cognition predicts cognitive impairment (CI) and Ascertain Dementia 8 (AD8) status simultaneously (NCognitive Assessment = 2477) and AD8 alone (NQuestionnaire = 6491) 60 years later, mediated by education and occupational complexity. Co-twin control analysis examined 82 discordant pairs for CI/AD8. RESULTS: Education partially mediated the effect of adolescent cognition on CI in the cognitive assessment aample and AD8 in the questionnaire sample (Ps < 0.001). Within twin pairs, differences in adolescent cognition were small, but intrapair differences in education predicted CI status. DISCUSSION: Adolescent cognition predicted dementia risk 60 years later, partially mediated through education. Educational attainment, but not occupational complexity, contributes to CI risk beyond its role as a mediator of adolescent cognition, further supported by the co-twin analyses. HIGHLIGHTS: Project Talent Aging Study follows enrollees from high school for nearly 60 years. General cognitive ability in high school predicts later-life cognitive impairment. Low education is a risk partially due to its association with cognitive ability.

Childhood Maltreatment and Dementia Risk Factors in Midlife: A Prospective Investigation.

BACKGROUND: Previous studies have linked childhood adversities to dementia risk, yet most studies are cross-sectional in design and utilize retrospective self-reports to assess childhood experiences. These design characteristics make it difficult to establish temporal order and draw firm conclusions. OBJECTIVES: Using a longitudinal design, we sought to determine whether childhood maltreatment predicts dementia risk factors in middle adulthood. METHODS: Data have been obtained from a prospective cohort design study of children with documented cases of childhood maltreatment (ages 0-11 years at case identification) and demographically matched controls who were followed up and interviewed in middle adulthood. Outcomes were assessed through a medical examination and interview, and 807 of the cases that included blood collection at mean age 41. Dementia risk were investigated using 11 potentially modifiable risk factors. RESULTS: Compared to controls, individuals with histories of childhood maltreatment had a higher risk of low educational attainment, low social contact, smoking, and clinical depression, and a higher total number of dementia risk factors. In general, childhood maltreatment predicted a higher risk of dementia for females, males, and Black and White participants. Black maltreated participants had a greater risk for traumatic brain injury compared to Black controls. Physical abuse, sexual abuse, and neglect, each predicted a higher number of dementia risk factors in mid-life. CONCLUSION: These findings provide evidence that childhood maltreatment increases the risk for dementia in mid-life and has a demonstrable impact lasting over 30 years. Reducing the prevalence of mid-life dementia risk factors could reduce the risk of later-life dementia.

Linking Air Pollution Exposure to Blood-Based Metabolic Features in a Community-Based Aging Cohort with and without Dementia.

BACKGROUND: Long-term exposure to air pollution has been associated with changes in levels of metabolites measured in the peripheral blood. However, most research has been conducted in ethnically homogenous, young or middle-aged populations. OBJECTIVE: To study the relationship between the plasma metabolome and long-term exposure to three air pollutants: particulate matter (PM) less than 2.5µm in aerodynamic diameter (PM2.5), PM less than 10µm in aerodynamic diameter (PM10), and nitrogen dioxide (NO2) in an ethnically diverse, older population. METHODS: Plasma metabolomic profiles of 107 participants of the Washington Heights and Inwood Community Aging Project in New York City, collected from 1995-2015, including non-Hispanic white, Caribbean Hispanic, and non-Hispanic Black older adults were used. We estimated the association between each metabolic feature and predicted annual mean exposure to the air pollutants using three approaches: 1) A metabolome wide association study framework; 2) Feature selection using elastic net regression; and 3) A multivariate approach using partial-least squares discriminant analysis. RESULTS: 79 features associated with exposure to PM2.5 but none associated with PM10 or NO2. PM2.5 exposure was associated with altered amino acid metabolism, energy production, and oxidative stress response, pathways also associated with Alzheimer's disease. Three metabolites were associated with PM2.5 exposure through all three approaches: cysteinylglycine disulfide, a diglyceride, and a dicarboxylic acid. The relationship between several features and PM2.5 exposure was modified by diet and metabolic diseases. CONCLUSIONS: These relationships uncover the mechanisms through which PM2.5 exposure can lead to altered metabolic outcomes in an older population.

Rural versus Urban Residence in Adulthood and Incident Cognitive Impairment.

INTRODUCTION: Rural versus urban living is a social determinant of cognitive health. We estimated the association of rural versus urban residence in the USA with incident cognitive impairment (ICI) and assessed effect heterogeneity by sociodemographic, behavioral, and clinical factors. METHODS: The Reasons for Geographic and Racial Differences in Stroke Study (REGARDS) is a population-based prospective observational cohort of 30,239 adults, 57% female, 36% Black, aged 45+ years, sampled from 48 contiguous states in the USA in 2003-2007. We analyzed 20,878 participants who at baseline were cognitively intact with no history of stroke and had ICI assessed on average 9.4 years later. We classified participants' home addresses at baseline as urban (population ≥50,000), large rural (10,000-49,999), or small rural (≤9,999) by Rural-Urban Commuting Area codes. We defined ICI as ≥1.5 SD below the mean on at least 2 of the following tests: word list learning, word list delayed recall, and animal naming. RESULTS: Participants' home addresses were 79.8% urban, 11.7% large rural, and 8.5% small rural. ICI occurred in 1,658 participants (7.9%). Small rural residents had higher odds of ICI than urban residents, adjusted for age, sex, race, region, and education (OR = 1.34 [95% CI: 1.10, 1.64]), and after further adjustment for income, health behaviors, and clinical characteristics (OR = 1.24 [95% CI: 1.02, 1.53]). Former smoking versus never, nondrinking versus light alcohol drinking, no exercise versus ≥4 times/week, CES-D depressive symptom score of 2 versus 0, and fair versus excellent self-rated health had stronger associations with ICI in small rural areas than in urban areas. For example, in urban areas, lack of exercise was not associated with ICI (OR = 0.90 [95% CI: 0.77, 1.06]); however, lack of exercise combined with small rural residence was associated with 1.45 times the odds of ICI compared with ≥4 bouts of exercise/week in urban areas (95% CI: 1.03, 2.03). Overall, large rural residence was not associated with ICI; however, black race, hypertension, and depressive symptoms had somewhat weaker associations with ICI, and heavy alcohol drinking a stronger association with ICI, in large rural areas than in urban areas. CONCLUSION: Small rural residence was associated with ICI among USA adults. Further research to better understand why rural residents are at higher risk for developing ICI and mechanisms to ameliorate that risk will support efforts to advance rural public health.

Amyloid, cerebrovascular disease, and neurodegeneration biomarkers are associated with cognitive trajectories in a racially and ethnically diverse, community-based sample.

We characterized the additive contribution of cerebrovascular biomarkers to amyloid and neurodegeneration biomarkers (AV(N)) when modeling prospective, longitudinal cognitive trajectories within 3 major racial/ethnic groups. Participants (n = 172; age = 69-96 years; 62% women; 31%/49%/20% Non-Hispanic White/Non-Hispanic Black/Hispanic) from the Washington Heights-Inwood Columbia Aging Project were assessed for amyloid (Florbetaben PET), neurodegeneration (cortical thickness, hippocampal volume), and cerebrovascular disease (white matter hyperintensity (WMH), infarcts). Neuropsychological assessments occurred every 2.3 ± 0.6 years for up to 6 visits (follow-up time: 4.2 ± 3.2 years). Linear mixed-effects models were stratified by race/ethnicity groups. Higher amyloid was associated with faster memory decline in all 3 racial/ethnic groups, but was related to faster cognitive decline beyond memory in minoritized racial/ethnic groups. Higher WMH was associated with faster language, processing speed/executive function, and visuospatial ability decline in Non-Hispanic Black participants, while infarcts were associated with faster processing speed/executive function decline in Non-Hispanic White participants. Complementary information from AD, neurodegenerative, and cerebrovascular biomarkers explain decline in multiple cognitive domains, which may differ within each racial/ethnic group. Importantly, treatment strategies exist to minimize vascular contributions to cognitive decline.

FMNL2 regulates gliovascular interactions and is associated with vascular risk factors and cerebrovascular pathology in Alzheimer's disease.

Alzheimer's disease (AD) has been associated with cardiovascular and cerebrovascular risk factors (CVRFs) during middle age and later and is frequently accompanied by cerebrovascular pathology at death. An interaction between CVRFs and genetic variants might explain the pathogenesis. Genome-wide, gene by CVRF interaction analyses for AD, in 6568 patients and 8101 controls identified FMNL2 (p = 6.6 × 10-7). A significant increase in FMNL2 expression was observed in the brains of patients with brain infarcts and AD pathology and was associated with amyloid and phosphorylated tau deposition. FMNL2 was also prominent in astroglia in AD among those with cerebrovascular pathology. Amyloid toxicity in zebrafish increased fmnl2a expression in astroglia with detachment of astroglial end feet from blood vessels. Knockdown of fmnl2a prevented gliovascular remodeling, reduced microglial activity and enhanced amyloidosis. APP/PS1dE9 AD mice also displayed increased Fmnl2 expression and reduced the gliovascular contacts independent of the gliotic response. Based on this work, we propose that FMNL2 regulates pathology-dependent plasticity of the blood-brain-barrier by controlling gliovascular interactions and stimulating the clearance of extracellular aggregates. Therefore, in AD cerebrovascular risk factors promote cerebrovascular pathology which in turn, interacts with FMNL2 altering the normal astroglial-vascular mechanisms underlying the clearance of amyloid and tau increasing their deposition in brain.

Association of Dietary Prebiotic Consumption with Reduced Risk of Alzheimer's Disease in a Multiethnic Population.

OBJECTIVE: This study aimed to investigate the association between dietary prebiotic intake and risk for Alzheimer's disease (AD). METHODS: This longitudinal study includes 1,837 elderly (≥65 years) participants of a multi-ethnic community-based cohort study who were dementia-free at baseline and had provided dietary information from food frequency questionnaires. Total daily intake of fructan, one of the best-known prebiotics, was calculated based on consumption frequency and fructan content per serving of 8 food items. The associations of daily fructan intake with AD risk were examined using a Cox proportional hazards model, adjusted for cohort recruitment wave, age, gender, race/ethnicity, education, daily caloric intake, and APOE genotype. Effect modification by race/ethnicity, APOE genotype, and gender was tested by including an interaction term into the Cox models, as well as by stratified analyses. RESULTS: Among 1,837 participants (1,263 women [69%]; mean [SD] age = 76 [6.3] years), there were 391 incident AD cases during a mean follow-up of 7.5 years (13736 person-years). Each additional gram of fructan intake was associated with 24% lower risk for AD ((95% CI)=0.60-0.97; P =0.03). Additional adjusting for smoking, alcohol consumption, and comorbidity index did not change results materially. The associations were not modified by race/ethnicity, gender, and APOE genotype, although stratified analyses showed that fructan intake was significantly associated with reduced AD risk in Hispanics but not in non-Hispanic Blacks or Whites. CONCLUSION: Higher dietary fructan intake is associated with a reduced risk of clinical Alzheimer's disease among older adults.

Baseline Cognitive Impairment in Patients With Asymptomatic Carotid Stenosis in the CREST-2 Trial.

BACKGROUND AND PURPOSE: Studies of carotid artery disease have suggested that high-grade stenosis can affect cognition, even without stroke. The presence and degree of cognitive impairment in such patients have not been reported and compared with a demographically matched population-based cohort. METHODS: We studied cognition in 1000 consecutive CREST-2 (Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial) patients, a treatment trial for asymptomatic carotid disease. Cognitive assessment was after randomization but before assigned treatment. The cognitive battery was developed in the general population REGARDS Study (Reasons for Geographic and Racial Differences in Stroke), involving Word List Learning Sum, Word List Recall, and Word List fluency for animal names and the letter F. The carotid stenosis patients were >45 years old with ≥70% asymptomatic carotid stenosis and no history of prevalent stroke. The distribution of cognitive performance for the patients was standardized, accounting for age, race, and education using performance from REGARDS, and after further adjustment for hypertension, diabetes, dyslipidemia, and smoking. Using the Wald Test, we tabulated the proportion of Z scores less than the anticipated deviate for the population-based cohort for representative percentiles. RESULTS: There were 786 baseline assessments. Mean age was 70 years, 58% men, and 52% right-sided stenosis. The overall Z score for patients was significantly below expected for higher percentiles (P<0.0001 for 50th, 75th, and 95th percentiles) and marginally below expected for the 25th percentile (P=0.015). Lower performance was attributed largely to Word List Recall (P<0.0001 for all percentiles) and for Word List Learning (50th, 75th, and 95th percentiles below expected, P≤0.01). The scores for left versus right carotid disease were similar. CONCLUSIONS: Baseline cognition of patients with severe carotid stenosis showed below normal cognition compared to the population-based cohort, controlling for demographic and cardiovascular risk factors. This cohort represents the largest group to date to demonstrate that poorer cognition, especially memory, in this disease. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02089217.

Epigenetic Aging Biomarkers Associated With Cognitive Impairment in Older African American Adults With Human Immunodeficiency Virus (HIV).

BACKGROUND: Accelerated epigenetic aging using DNA methylation (DNAm)-based biomarkers has been reported in people with human immunodeficiency virus (HIV, PWH), but limited data are available among African Americans (AA), women, and older PWH. METHODS: DNAm was measured using Illumina EPIC Arrays for 107 (69 PWH and 38 HIV-seronegative controls) AA adults ≥60 years in New York City. Six DNAm-based biomarkers of aging were estimated: (1) epigenetic age acceleration (EAA), (2) extrinsic epigenetic age acceleration (EEAA), (3) intrinsic epigenetic age acceleration (IEAA), (4) GrimAge, (5) PhenoAge, and (6) DNAm-estimated telomere length (DNAm-TL). The National Institutes of Health (NIH) Toolbox Cognition Battery (domains: executive function, attention, working memory, processing speed, and language) and Montreal Cognitive Assessment (MoCA) were administered. Participants were assessed for frailty by the Fried criteria. RESULTS: The PWH and control groups did not differ by sex, chronological age, or ethnicity. In total, 83% of PWH had a viral load <50 copies/mL, and 94% had a recent CD4 ≥200 cells/µL. The PWH group had a higher EAA, EEAA, GrimAge, and PhenoAge, and a lower DNAm-TL compared to the controls. IEAA was not different between groups. For PWH, there were significant negative correlations between IEAA and executive function, attention, and working memory and PhenoAge and attention. No associations between biomarkers and frailty were detected. CONCLUSIONS: Evidence of epigenetic age acceleration was observed in AA older PWH using DNAm-based biomarkers of aging. There was no evidence of age acceleration independent of cell type National Institutes of Health composition (IEAA) associated with HIV, but this measure was associated with decreased cognitive function among PWH.

Quality and quantity: The association of state-level educational policies with later life cardiovascular disease.

Education is a powerful predictor of cardiovascular morbidity and mortality. While the majority of the literature has focused on years of educational attainment or degree attainment, fewer studies examine the role of educational quality in the prevention of cardiovascular disease (CVD). We tested the hypothesis that average state-level educational quality was associated with CVD, linking state-level data on educational quality with individual demographic and health data from multiple waves of the National Health and Nutrition Examination Survey (N = 34,770). We examined thirteen CVD-related outcomes-including blood pressure, cholesterol, and heart attack-to understand the multiple pathways through which educational quality may influence CVD. The primary predictor was a composite index of educational quality, combining state-level measures of student-teacher ratios, per-pupil expenditures, and school term length. We fit multivariable models, regressing each outcome on the educational quality composite index and adjusting for individual- and state-level covariates. We also assessed whether the association between state educational quality and CVD differed for less educated individuals. Overall, higher educational quality was associated with less smoking (OR = 0.86, 95%CI: 0.77, 0.97), but there was no statistically significant association for the other 12 outcomes. Interaction tests indicated that less educated individuals benefited less from higher educational quality relative to those with more education for several outcomes. Our study suggests that state-level educational quality is not strongly associated with CVD, and that this null association overall may mask heterogeneous benefits that accrue disproportionately to those with higher levels of education.

Circulating inflammatory biomarkers are related to cerebrovascular disease in older adults.

Objective: This investigation aimed at examining whether circulating inflammatory biomarkers C-reactive protein (CRP), interleukin-6 (IL6), and alpha 1-antichymotrypsin (ACT) were related to cerebrovascular disease (CVD) assessed by MRI. Methods: The study included nondemented elderly participants of a community-based, multiethnic cohort, who received baseline MRI scans and had CRP (n = 508), ACT (435), and IL6 (N = 357) measured by ELISA. Silent brain infarcts and white matter hyperintensities (WMH) were derived from all available MRI scans at baseline, approximately 4.4 years after blood sample collection for inflammatory biomarkers. Repeated assessments of infarcts and WMH, as well as microbleeds assessment, were performed at follow-up MRI visits around 4.5 years later. Cross-sectional and longitudinal relationship between inflammatory biomarkers and CVD were analyzed using appropriate logistic regression models, generalized linear models, or COX models. Results: After adjusting for age, sex, ethnicity, education, APOE genotype, and intracranial volume, 1 SD increase in log10IL6 was associated with infarcts on MRI {odds ratio [OR] (95% confidence interval [CI]) = 1.28 [1.02-1.60], p = 0.033}, and 1 SD increase in log10CRP and log10ACT was associated with microbleeds (OR [95% CI] = 1.46 [1.02-2.09], p = 0.041; and 1.65 [1.11-2.46], p = 0.013; respectively). One SD increase in log10ACT was also associated with larger WMH at the follow-up MRI (b = 0.103, p = 0.012) and increased accumulation of WMH volume (b = 0.062, p = 0.041) during follow-up. The associations remained significant after additional adjustment of vascular risk factors and excluding participants with clinical stroke. Conclusions: Among older adults, increased circulating inflammatory biomarkers were associated with the presence of infarcts and microbleeds, WMH burden, and progression of WMH.

An Inflammation-related Nutrient Pattern is Associated with Both Brain and Cognitive Measures in a Multiethnic Elderly Population.

BACKGROUND: Accumulating evidence suggests that dietary factors are associated with Alzheimer's disease, cognition, and brain health in older adults. It is however unclear whether inflammation explains this association. OBJECTIVE: To examine whether an inflammation-related nutrient pattern (INP) was associated with neuroimaging and cognitive measures of brain health. METHOD: The current cross-sectional study included 330 non-demented elderly (mean age 79 years at MRI scan) participants in a multi-ethnic, community-based cohort study who had information on nutritional intake (estimated from food frequency questionnaire), circulating C-reactive protein and interleukin- 6 (measured by ELISA), MRI scans, and cognition. Diet and blood samples were collected approximately 5.3 years prior to the MRI and cognitive test visit. We used a reduced rank regression model to derive an INP based on 24 nutrients' relationship with CRP and interleukin-6. We examined the association of the INP with brain and cognitive measures using regression models adjusted for age, sex, race/ethnicity, education, caloric intake, APOE genotype, body mass index, and vascular burden, as well as intracranial volume for the brain MRI measures. RESULTS: The INP was characterized by low intake (effect loading <-0.15) of calcium, vitamins (D, E, A, B1, B2, B3, B5, B6), folate, Ω-3 poly-unsaturated fatty acids, and high intake (>0.15) of cholesterol. As designed, this INP was positively correlated with CRP (Pearson's r=0.25 p=0.005) and interleukin-6 (r=0.30, p<0.0001). Each unit increase in INP was associated with 36.8 cm3 (p=0.023) smaller total brain volume and 0.21 (p=0.038) lower visuospatial z-score. Mediation analysis showed that TGMV (b=0.002, p=0.003) was associated with visuospatial cognitive function, and there was a significant mediation effect by TGMV (indirect effect: -0.049, 95% CI: -0.1121 ~ -0.0131) for the association between INP and visuospatial cognitive score. CONCLUSIONS: Among older adults, a diet with high inflammatory potential is associated with less favorable brain and cognitive health.

Circulating inflammatory biomarkers in relation to brain structural measurements in a non-demented elderly population.

The aim of this investigation was to determine whether circulating inflammatory biomarkers c-reactive protein (CRP), interleukin-6 (IL6), and alpha 1-antichymotrypsin (ACT) were related to structural brain measures assessed by magnetic resonance imaging (MRI). High-resolution structural MRI was collected on 680 non-demented elderly (mean age 80.1years) participants of a community-based, multiethnic cohort. Approximately three quarters of these participants also had peripheral inflammatory biomarkers (CRP, IL6, and ACT) measured using ELISA. Structural measures including brain volumes and cortical thickness (with both global and regional measures) were derived from MRI scans, and repeated MRI measures were obtained after 4.5years. Mean fractional anisotropy was used as the indicator of white matter integrity assessed with diffusion tensor imaging. We examined the association of inflammatory biomarkers with brain volume, cortical thickness, and white matter integrity using regression models adjusted for age, gender, ethnicity, education, APOE genotype, and intracranial volume. A doubling in CRP (b=-2.48, p=0.002) was associated with a smaller total gray matter volume, equivalent to approximately 1.5years of aging. A doubling in IL6 was associated with smaller total brain volume (b=-14.96, p<0.0001), equivalent to approximately 9years of aging. Higher IL6 was also associated with smaller gray matter (b=-6.52, p=0.002) and white matter volumes (b=-7.47, p=0.004). The volumes of most cortical regions including frontal, occipital, parietal, temporal, as well as subcortical regions including pallidum and thalamus were associated with IL6. In a model additionally adjusted for depression, vascular factors, BMI, and smoking status, the association between IL6 and brain volumes remained, and a doubling in ACT was marginally associated with 0.054 (p=0.001) millimeter thinner mean cortical thickness, equivalent to that of approximately 2.7years of aging. None of the biomarkers was associated with mean fractional anisotropy or longitudinal change of brain volumes and thickness. Among older adults, increased circulating inflammatory biomarkers were associated with smaller brain volume and cortical thickness but not the white matter tract integrity. Our preliminary findings suggest that peripheral inflammatory processes may be involved in the brain atrophy in the elderly.

Two novel loci, COBL and SLC10A2, for Alzheimer's disease in African Americans.

INTRODUCTION: African Americans' (AAs) late-onset Alzheimer's disease (LOAD) genetic risk profile is incompletely understood. Including clinical covariates in genetic analyses using informed conditioning might improve study power. METHODS: We conducted a genome-wide association study (GWAS) in AAs employing informed conditioning in 1825 LOAD cases and 3784 cognitively normal controls. We derived a posterior liability conditioned on age, sex, diabetes status, current smoking status, educational attainment, and affection status, with parameters informed by external prevalence information. We assessed association between the posterior liability and a genome-wide set of single-nucleotide polymorphisms (SNPs), controlling for APOE and ABCA7, identified previously in a LOAD GWAS of AAs. RESULTS: Two SNPs at novel loci, rs112404845 (P = 3.8 × 10-8), upstream of COBL, and rs16961023 (P = 4.6 × 10-8), downstream of SLC10A2, obtained genome-wide significant evidence of association with the posterior liability. DISCUSSION: An informed conditioning approach can detect LOAD genetic associations in AAs not identified by traditional GWAS.

Association of vascular risk factors with cognition in a multiethnic sample.

OBJECTIVES: To examine the relationship between cardiovascular risk factors (CVRFs) and cognitive performance in a multiethnic sample of older adults. METHOD: We used longitudinal data from the Washington Heights-Inwood Columbia Aging Project. A composite score including smoking, stroke, heart disease, diabetes, hypertension, and central obesity represented CVRFs. Multiple group parallel process multivariate random effects regression models were used to model cognitive functioning and examine the contribution of CVRFs to baseline performance and change in general cognitive processing, memory, and executive functioning. RESULTS: Presence of each CVRF was associated with a 0.1 SD lower score in general cognitive processing, memory, and executive functioning in black and Hispanic participants relative to whites. Baseline CVRFs were associated with poorer baseline cognitive performances among black women and Hispanic men. CVRF increase was related to baseline cognitive performance only among Hispanics. CVRFs were not related to cognitive decline. After adjustment for medications, CVRFs were not associated with cognition in Hispanic participants. DISCUSSION: CVRFs are associated with poorer cognitive functioning, but not cognitive decline, among minority older adults. These relationships vary by gender and medication use. Consideration of unique racial, ethnic, and cultural factors is needed when examining relationships between CVRFs and cognition.

A summary risk score for the prediction of Alzheimer disease in elderly persons.

OBJECTIVE: To develop a simple summary risk score for the prediction of Alzheimer disease in elderly persons based on their vascular risk profiles. DESIGN: A longitudinal, community-based study. SETTING: New York, New York. Patients One thousand fifty-one Medicare recipients aged 65 years or older and residing in New York who were free of dementia or cognitive impairment at baseline. MAIN OUTCOME MEASURES: We separately explored the associations of several vascular risk factors with late-onset Alzheimer disease (LOAD) using Cox proportional hazards models to identify factors that would contribute to the risk score. Then we estimated the score values of each factor based on their beta coefficients and created the LOAD vascular risk score by summing these individual scores. RESULTS: Risk factors contributing to the risk score were age, sex, education, ethnicity, APOE epsilon4 genotype, history of diabetes, hypertension or smoking, high-density lipoprotein levels, and waist to hip ratio. The resulting risk score predicted dementia well. According to the vascular risk score quintiles, the risk to develop probable LOAD was 1.0 for persons with a score of 0 to 14 and increased 3.7-fold for persons with a score of 15 to 18, 3.6-fold for persons with a score of 19 to 22, 12.6-fold for persons with a score of 23 to 28, and 20.5-fold for persons with a score higher than 28. CONCLUSIONS: While additional studies in other populations are needed to validate and further develop the score, our study suggests that this vascular risk score could be a valuable tool to identify elderly individuals who might be at risk of LOAD. This risk score could be used to identify persons at risk of LOAD, but can also be used to adjust for confounders in epidemiologic studies.

Sex hormone binding globulin and incident Alzheimer's disease in elderly men and women.

It has been suggested that low levels of estradiol and testosterone increase dementia risk. However, results of the existing observational studies examining associations of endogenous sex hormones with cognition and dementia are conflicting. A possible explanation for these inconsistent findings could be the involvement of sex hormone-binding globulin (SHBG) in regulating sex hormone levels. In the present study, we examined whether SHBG levels were associated with development of AD and overall dementia in a cohort of elderly men and women free of dementia at baseline. We observed that in both men and women higher levels of SHBG were associated with an increased risk for AD and overall dementia. These results were independent of vascular risk factors and bioactive hormone levels. Whether SHBG is causally related to dementia or whether it is a surrogate marker for rate of biological aging and increased risk or for preclinical stage of dementia has to be elucidated.

Relation of diabetes to mild cognitive impairment.

BACKGROUND: Type 2 diabetes mellitus is an important risk factor for Alzheimer disease and is more prevalent in elderly minority persons compared with non-Hispanic white persons. OBJECTIVE: To determine whether diabetes is related to a higher risk of mild cognitive impairment (MCI), a transitional stage between normal cognition and Alzheimer disease, in a multiethnic cohort with a high prevalence of diabetes. DESIGN: Longitudinal cohort study. SETTING: Northern Manhattan in New York, NY. PARTICIPANTS: We studied persons without prevalent MCI or dementia at baseline and with at least 1 follow-up interval. Of 1772 participants with a complete neuropsychological evaluation, 339 (19.1%) were excluded because of prevalent dementia, 304 were excluded because of prevalent MCI (17.2%), and 211 were excluded because of loss to follow-up (11.9%), resulting in a final sample of 918 participants for longitudinal analyses. MAIN OUTCOME MEASURES: We related diabetes defined by self-report to incident all-cause MCI, amnestic MCI, and nonamnestic MCI. We conducted multivariate analyses with proportional hazards regression adjusting for age, sex, years of education, ethnic group, apolipoprotein E (APOE) epsilon4 allele, hypertension, low-density lipoprotein level, current smoking, heart disease, and stroke. RESULTS: A total of 334 persons had incident MCI, 160 (47.9%) had amnestic MCI, and 174 (52.1%) had nonamnestic MCI. Diabetes was related to a significantly higher risk of all-cause MCI and amnestic MCI after adjustment for all covariates. Diabetes was also related to a higher risk of nonamnestic MCI, but this association was appreciably attenuated after adjustment for socioeconomic variables and vascular risk factors. The risk of MCI attributable to diabetes was 8.8% for the whole sample and was higher for African American persons (8.4%) and Hispanic persons (11.0%) compared with non-Hispanic white persons (4.6%), reflecting the higher prevalence of diabetes in minority populations in the United States. CONCLUSION: Diabetes is related to a higher risk of amnestic MCI in a population with a high prevalence of this disorder.

Elevated sex-hormone binding globulin in elderly women with Alzheimer's disease.

BACKGROUND: Hormone levels change significantly with increasing age. These changes may be related to, or be associated with, the emergence of age-related diseases, such as Alzheimer's disease (AD). METHODS: Five hundred and seventy-six women over the age of 65 were studied from the Washington Heights-Inwood Columbia Aging Project (WHICAP). These women were selected from a group of healthy Medicare beneficiaries that were aged 65 and older living in the geographically defined area of northern Manhattan in New York City. Serum levels of estrone (E1), estradiol (E2), total testosterone (TT), dehydroepiandosterone (DHEA), luteinizing hormone (LH), follicle stimulating hormone (FSH), and sex-hormone binding globulin (SHBG) were measured. RESULTS: Significant differences were found between patients with AD and controls only in the level of SHBG, which was 20% higher in patients compared to controls (68.5nmol/l versus 54.7nmol/l, P<0.001). We also estimated levels of total E2 because after menopause, E2 is largely derived from E1. AD patients had significantly lower levels of estimated E2 (AD 0.46 versus controls 0.49, P<0.01). Differences remained significant after adjusting for age, ethnic group, education, and body mass index (BMI). CONCLUSIONS: A marked increase in SHBG levels was found in AD patients. SHBG normally responds to circulating testosterone and estrogen, therefore, elevated SHBG suggests an abnormal increase in its production and regulation. Further work is needed to clarify the cause and consequences of this observation.