Genetic variants associated with risk of Alzheimer's disease contribute to cognitive change in midlife: The Atherosclerosis Risk in Communities Study.

Alzheimer's disease (AD) is the most common form of dementia and is characterized by impairment in memory, behavioral changes, and gradual loss of autonomy. Since there is a long latent period prior to diagnosis, the aim of this study was to determine whether twenty single nucleotide polymorphisms identified in genome-wide association analyses of AD are associated with cognitive change in 8,320 white and 2,039 African-American middle-aged adults enrolled in the prospective Atherosclerosis Risk in Communities (ARIC) study. Cognition was evaluated using the Delayed Word Recall Test (DWRT; verbal memory), Digit Symbol Substitution Test (DSST; processing speed), and Word Fluency Test (WFT; executive function). General linear models were used to assess mean differences in 6-year change in test scores among individuals categorized by genotype after adjusting for age, gender, and years of education. Addition of the minor allele for rs670139 (MS4A4E), rs9331896 (CLU), and rs12155159 (NME8) was nominally associated with change on the DWRT, DSST, and WFT, respectively, in whites. The ZCWPW1 (rs1476679) and CDS33 (rs3865444) variants were nominally associated with change on the DWRT and WFT in African-Americans. For rs670139 and rs9331896 the association was only significant in individuals bearing at least one APOE ϵ4 allele in stratified analyses. An unweighted genetic risk score aggregating the risk alleles for 15 polymorphisms was not associated with change in cognitive function. Although the AD-associated genetic variants appear to have small effects on early cognitive change, replication will be required to establish whether there is a discernible influence on cognitive status in midlife. © 2016 Wiley Periodicals, Inc.

Spousal Cognitive Status and Risk for Declining Cognitive Function and Dementia: The Atherosclerosis Risk in Communities Study.

Objectives: We investigated the relationship between the cognitive status of participants' spouses and participants' own cognitive outcomes, controlling for mid-life factors. Methods: Participants (n = 1845; baseline age 66-90 years) from the prospective Atherosclerosis Risk in Communities Study were followed from 2011 to 2019. We used linear regression and Cox proportional hazard models to estimate whether spouses of people with MCI/dementia had lower cognitive functioning and elevated risk of incident dementia. Results: Having a spouse with MCI/dementia was associated with a deficit in cognitive function (b = -0.09 standard deviations; 95% CI = -0.18, 0.00). Adjustment for mid-life risk factors attenuated this association (b = -0.02 standard deviations; 95% CI = -0.10, 0.06). We observed no significant relationship between spousal MCI/dementia status and incident dementia (hazard ratio = 0.97; 95% CI = 0.69, 1.38). Discussion: Spousal cognitive status is not associated with poor cognitive outcomes independent of mid-life factors.

Is an MRI-derived anatomical measure of dementia risk also a measure of brain aging?

Machine learning methods have been applied to estimate measures of brain aging from neuroimages. However, only rarely have these measures been examined in the context of biologic age. Here, we investigated associations of an MRI-based measure of dementia risk, the Alzheimer's disease pattern similarity (AD-PS) scores, with measures used to calculate biological age. Participants were those from visit 5 of the Atherosclerosis Risk in Communities Study with cognitive status adjudication, proteomic data, and AD-PS scores available. The AD-PS score estimation is based on previously reported machine learning methods. We evaluated associations of the AD-PS score with all-cause mortality. Sensitivity analyses using only cognitively normal (CN) individuals were performed treating CNS-related causes of death as competing risk. AD-PS score was examined in association with 32 proteins measured, using a Somalogic platform, previously reported to be associated with age. Finally, associations with a deficit accumulation index (DAI) based on a count of 38 health conditions were investigated. All analyses were adjusted for age, race, sex, education, smoking, hypertension, and diabetes. The AD-PS score was significantly associated with all-cause mortality and with levels of 9 of the 32 proteins. Growth/differentiation factor 15 (GDF-15) and pleiotrophin remained significant after accounting for multiple-testing and when restricting the analysis to CN participants. A linear regression model showed a significant association between DAI and AD-PS scores overall. While the AD-PS scores were created as a measure of dementia risk, our analyses suggest that they could also be capturing brain aging.

Standing Blood Pressure and Risk of Falls, Syncope, Coronary Heart Disease, and Mortality.

BACKGROUND: ACC/AHA guidelines caution against the use of antihypertensive therapy in the setting of low standing systolic BP (SBP) < 110 mm Hg due to unclear benefits. METHODS: The Atherosclerosis Risk in Communities (ARIC) Study measured supine and standing SBP in adults aged 45-64 years between 1987 and 1989. We used Cox regression to evaluate the associations of low standing SBP (<110 mm Hg) with risk of falls, syncope, coronary heart disease (CHD), and mortality through December 31, 2019. Falls and syncope were ascertained by hospitalization and outpatient claims; CHD events were adjudicated. Associations were examined overall and in strata of hypertension stage, 10-year atherosclerotic cardiovascular disease (ASCVD) risk, age, and sex. RESULTS: Among 12,467 adults followed a median of 24 years (mean age at enrollment 54.1 ±â€…5.8 years, 55% women, 26% Black adults), 3,000 (24%) had a standing SBP < 110 mm Hg. A standing SBP < 110 mm Hg compared to standing SBP ≥ 110 mm Hg was not significantly associated with falls or syncope, and was associated with a lower risk of CHD events and mortality with HRs of 1.02 (95% CI 0.94, 1.11), 1.02 (0.93, 1.11), 0.88 (0.80, 0.97), and 0.91 (0.86, 0.97), respectively. There were no clinically meaningful differences when stratified by hypertension stage, 10-year ASCVD risk, age, and sex. CONCLUSIONS: In this community-based population, low standing SBP was common and not significantly associated with falls or syncope, but was associated with a lower risk of CHD and mortality. These findings do not support screening for low standing BP as a risk factor for adverse events.

Endurance and gait speed relationships with mild cognitive impairment and dementia.

INTRODUCTION: Slower mobility is associated with mild cognitive impairment (MCI) and dementia. We examined the interaction of endurance with gait speed on prevalent MCI and dementia. METHODS: Cross-sectional multinomial regression in the ARIC cohort (n = 2844 participants; 71 to 94 years; 44% men; 18% Black persons) with cognitive status (normal/MCI/dementia), 4 m gait speed, and endurance (2 minute walk [2MW]). RESULTS: Faster gait speed (up to but not above 1 m/s) and better 2MW were separately associated with lower dementia risk. Good performance in both (2MW = 200 m, gait speed = 1.2 m/s) was associated with 99% lower dementia (Relative Prevalence Ratio [RPR] = 0.01 [95% CI: 0.0 to 0.06]) and 73% lower MCI, RPR = 0.27 (0.15 to 0.48) compared to poor performance in both (2MW = 100 m, gait speed = 0.8 m/s). Models incorporating a gait speed-by-2MW interaction term outperformed gait speed-only models (P < .001). DISCUSSION: Gait speed relationships with dementia diminish at faster gait speeds. Combining endurance with gait speed may yield more sensitive markers of MCI and dementia than gait speed alone.

Association Between Thyroid Dysfunction and Incident Dementia in the Atherosclerosis Risk in Communities Neurocognitive Study.

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.

Carotid Intima-Media Thickness and Silent Brain Infarctions in a Biracial Cohort: The Atherosclerosis Risk in Communities (ARIC) Study.

BACKGROUND: Both hypertensive and atherosclerotic processes contribute to common carotid artery intima-media thickness (CCA-IMT). Elevated CCA-IMT may be indicative of subclinical cerebrovascular disease; however, its role in the absence of concomitant carotid artery plaque is uncertain, and few studies have examined associations in Black populations. MATERIALS AND METHODS: At cohort visit 3 (1993-1995) a subset of stroke-free participants (641 Blacks and 702 Whites, mean age 63) from the Atherosclerosis Risk in Communities (ARIC) study was imaged by brain MRI and carotid ultrasound. A CCA-IMT >0.9 mm was considered elevated. Asymptomatic brain lesions ≥3 mm were considered silent brain infarctions (SBI). Subcortical SBI measuring 3 to <20 mm were considered lacunes. Associations between elevated CCA-IMT and SBI were analyzed with Poisson regression. RESULTS: Elevated CCA-IMT was identified in 168 participants (16% of Blacks, 10% of Whites), and SBI were observed in 156 (15% of Blacks, 8% of Whites). Elevated CCA-IMT was strongly related to anterior circulation SBI, posterior circulation SBI, and lacunes. After adjustments, elevated CCA-IMT remained associated with greater number of lacunes in Blacks ([prevalence ratio, PR] = 1.60; 95% confidence interval [CI]: 1.02-2.51), but not Whites (PR = 0.85; 95% CI: 0.35-2.04); P value for interaction = 0.12. Among Black participants without concomitant carotid plaque, elevated CCA-IMT was associated with twice the number of lacunes (PR = 2.00; 95% CI: 1.05-3.82). CONCLUSIONS: In older Black adults, elevated CCA-IMT is independently associated with lipohyalinosis of the cerebral small vessels, irrespective of concomitant carotid plaque and vascular risk factors.

Orthostatic Hypotension in Middle-Age and Risk of Falls.

BACKGROUND: One-third of older adults fall each year. Orthostatic hypotension (OH) has been hypothesized as an important risk factor for falls, but findings from prior studies have been inconsistent. METHODS: We conducted a prospective study of the association between baseline OH (1987-1989) and risk of falls in the Atherosclerosis Risk in Communities (ARIC) Study. Falls were ascertained during follow-up via ICD-9 hospital discharge codes or Centers for Medicare & Medicaid Services claims data. OH was defined as a drop in systolic blood pressure (SBP) ≥20mm Hg or diastolic blood pressure (DBP) ≥10mm Hg within 2 minutes of moving from the supine to standing position. Changes in SBP or DBP during OH assessments were also examined as continuous variables. RESULTS: During a median follow-up of 23 years, there were 2,384 falls among 12,661 participants (mean age 54 years, 55% women, 26% black). OH was associated with risk of falls even after adjustment for demographic characteristics and other risk factors (hazard ratio (HR): 1.30; 95% confidence interval (CI): 1.10, 1.54; P = 0.002). Postural change in DBP was more significantly associated with risk of falls (HR 1.09 per -5mm Hg change in DBP; 95% CI: 1.05, 1.13; P < 0.001) than postural change in SBP (HR 1.03 per -5mm Hg change in SBP; 95% CI: 1.01, 1.05; P = 0.002). CONCLUSIONS: In a community-based, middle-aged population, OH, and in particular, postural change in DBP, were independent risk factors for falls over 2 decades of follow-up. Future studies are needed to examine OH thresholds associated with increased risk of falls.

Cardiovascular Dysfunction and Frailty Among Older Adults in the Community: The ARIC Study.

BACKGROUND: The contribution of cardiovascular dysfunction to frailty in older adults is uncertain. This study aimed to define the relationship between frailty and cardiovascular structure and function, and determine whether these associations are independent of coexisting abnormalities in other organ systems. METHODS: We studied 3,991 older adults (mean age 75.6±5.0 years; 59% female) from the Atherosclerosis Risk in Communities (ARIC) Study in whom the following six organ systems were uniformly assessed: cardiac (by echocardiography), vascular (by ankle-brachial-index and pulse-wave-velocity), pulmonary (by spirometry), renal (by estimated glomerular filtration rate), hematologic (by hemoglobin), and adipose (by body mass index and bioimpedance). Frailty was defined by the presence of ≥3 of the following: low strength, low energy, slowed motor performance, low physical activity, or unintentional weight loss. RESULTS: Two hundred eleven (5.3%) participants were frail. In multivariable analyses adjusted for demographics, diabetes, hypertension, and measures of other organ system function, frailty was independently and additively associated with left ventricular hypertrophy (odds ratio [OR] = 1.72; 95% confidence interval [CI] = 1.30-2.40), reduced global longitudinal strain (reflecting systolic function; OR = 1.68; 95% CI = 1.16-2.44), and greater left atrial volume index (reflecting diastolic function; OR = 1.60; 95% CI = 1.13-2.27), which together demonstrated the greatest association with frailty (OR = 2.10; 95% CI = 1.57-2.82) of the systems studied. Lower magnitude associations were observed for vascular and pulmonary abnormalities, anemia, and impaired renal function. Cardiovascular abnormalities remained associated with frailty after excluding participants with prevalent cardiovascular disease. CONCLUSIONS: Abnormalities of cardiac structure and function are independently associated with frailty, and together show the greatest association with frailty among the organ systems studied.

Diabetes, hyperglycemia, and the burden of functional disability among older adults in a community-based study.

BACKGROUND: There is a need for continued surveillance of diabetes-related functional disability. In the present study, we examined associations between diabetes, hyperglycemia, and the burden of functional disability in a community-based population. METHODS: A cross-sectional analysis was conducted of 5035 participants who attended Visit 5 (2011-13) of the Atherosclerosis Risk in Communities study. Functional disability was dichotomously defined by any self-reported difficulty performing 12 tasks essential to independent living grouped into four functional domains. Associations of diagnosed diabetes (via self-report) and undiagnosed diabetes and prediabetes (via HbA1c) with functional disability were evaluated using Poisson regression. RESULTS: Participants had a mean age of 75 years, 42 % were male, 22 % were Black, and 31 % had diagnosed diabetes. Those with diagnosed diabetes had a significantly greater burden of functional disability than those without diabetes, even after adjustment for demographics, health behaviors, and comorbidities: prevalence ratios (95 % confidence intervals) were 1.24 (1.15, 1.34) for lower extremity mobility, 1.14 (1.07, 1.21) for general physical activities, 1.33 (1.16, 1.52) for instrumental activities of daily living (ADL), and 1.46 (1.24, 1.73) for ADL (all P < 0.05). The associations of undiagnosed diabetes and prediabetes with disability were not statistically significant (all P > 0.05). CONCLUSIONS: Among older adults, the burden of functional disability associated with diabetes was not entirely explained by known risk factors, including comorbidities. Hyperglycemia below the threshold for the diagnosis of diabetes was not associated with disability. Research into effective strategies for the prevention of functional disability among older adults with diabetes is needed.

Impaired vision and the ability to take medications.

OBJECTIVES: To assess relationships between vision (contrast sensitivity, stereopsis, visual acuity) and a performance-based measure of ability to implement new medications. DESIGN: Cross-sectional analysis; prospective cohort study. SETTING: Community-based. PARTICIPANTS: Three hundred thirty-five participants aged 73 to 82 in Year 3 of the Women's Health and Aging Study II, a representative sample of the two-thirds least-disabled community-dwelling women. MEASUREMENTS: Hopkins Medication Schedule Pillbox Ratio, a joint measure of accuracy and time, and a performance-based measure of ability to implement a prescription. Participants received written and verbal instructions for taking two medications and were directed to place pills in a pillbox accordingly. Vision assessments: contrast sensitivity (Pelli-Robson letter sensitivity chart), stereopsis (Randot Circles), and visual acuity (Early Treatment Diabetic Retinopathy Study eye chart). RESULTS: Forty-four percent (148/335) of women incorrectly placed one or both medications. Each vision measure was positively associated with Pillbox Ratio scores and varied with cognition and time to completion. Better visual acuity, contrast sensitivity, and stereopsis were each associated with better performance in women with poor cognition who filled the pillbox quickly. Additionally, better visual acuity was associated with better performance in participants with good cognition who filled the pillbox slowly; better stereopsis was associated with better performance in participants with poor cognition who filled the pillbox slowly and whose stereoacuity was below normal. CONCLUSION: Visual acuity, contrast sensitivity, and stereopsis should be considered potential risk factors for impaired ability to implement a medication regimen in older adults. Future research should investigate the role of vision, including contrast sensitivity and stereopsis, on performance of other instrumental activities of daily living.

Physical Function, Hyperuricemia, and Gout in Older Adults.

OBJECTIVE: Gout prevalence is high in older adults and those affected are at risk of physical disability, yet it is unclear whether they have worse physical function. METHODS: We studied gout, hyperuricemia, and physical function in 5,819 older adults (age ≥65 years) attending the 2011-2013 Atherosclerosis Risk in Communities Study visit, a prospective US population-based cohort. Differences in lower extremity function (Short Physical Performance Battery [SPPB] and 4-meter walking speed) and upper extremity function (grip strength) by gout status and by hyperuricemia prevalence were estimated in adjusted ordinal logistic regression (SPPB) and linear regression (walking speed and grip strength) models. Lower scores or times signify worse function. The prevalence of poor physical performance (first quartile) by gout and hyperuricemia was estimated using adjusted modified Poisson regression. RESULTS: Ten percent of participants reported a history of gout and 21% had hyperuricemia. There was no difference in grip strength by history of gout (P = 0.77). Participants with gout performed worse on the SPPB test; they had 0.77 times (95% confidence interval [95% CI] 0.65, 0.90, P = 0.001) the prevalence odds of a 1-unit increase in SPPB score and were 1.18 times (95% CI 1.07, 1.32, P = 0.002) more likely to have poor SPPB performance. Participants with a history of gout had slower walking speed (mean difference -0.03; 95% CI -0.05, -0.01, P < 0.001) and were 1.19 times (95% CI 1.06, 1.34, P = 0.003) more likely to have poor walking speed. Similarly, SPPB score and walking speed, but not grip strength, were worse in participants with hyperuricemia. CONCLUSION: Older adults with gout and hyperuricemia are more likely to have worse lower extremity, but not upper extremity, function.