Wu, Aozhou

Objective Midlife vascular risk factors (MVRFs) are associated with incident dementia, as are amyloid β (Aβ) deposition and neurodegeneration. Whether vascular and Alzheimer disease‐associated factors contribute to dementia independently or interact synergistically to reduce cognition is poorly understood. Methods Participants in the Atherosclerosis Risk in Communities–Positron Emission Tomography study were followed from 1987–1989 (45–64 years old) through 2016–2017 (74–94 years old), with repeat cognitive assessment and dementia adjudication. In 2011–2013, dementia‐free participants underwent brain magnetic resonance imaging (with white matter hyperintensity [WMH] and brain volume measurement) and florbetapir (Aβ) positron emission tomography. The relative contributions of vascular risk and injury (MVRFs, WMH volume), elevated Aβ standardized uptake value ratio (SUVR), and neurodegeneration (smaller temporoparietal brain regions) to incident dementia were evaluated with adjusted Cox models. Results In 298 individuals, 36 developed dementia (median follow‐up = 4.9 years). Midlife hypertension and Aβ each independently predicted dementia risk (hypertension: hazard ratio [HR] = 2.57, 95% confidence interval [CI] = 1.16–5.67; Aβ SUVR [per standard deviation (SD)]: HR = 2.57, 95% CI = 1.72–3.84), but did not interact significantly, whereas late life diabetes (HR = 2.50, 95% CI = 1.18–5.28) and Aβ independently predicted dementia risk. WMHs (per SD: HR = 1.51, 95% CI = 1.03–2.20) and Aβ SUVR (HR = 2.52, 95% CI = 1.83–3.47) independently contributed to incident dementia, but WMHs lost significance when MVRFs were included. Smaller temporoparietal brain regions were associated with incident dementia, independent of Aβ and MVRFs (HR = 2.18, 95% CI = 1.18–4.01). Interpretation Midlife hypertension and late life Aβ are independently associated with dementia risk, without evidence for synergy on a multiplicative scale. Given the independent contributions of vascular and amyloid mechanisms, multiple pathways should be considered when evaluating interventions to reduce the burden of dementia. ANN NEUROL 2022;92:607–619

Background: Brain infarcts, white matter hyperintensities (WMH), and brain atrophy appear to contribute to the development of mild cognitive impairment (MCI) and dementia in selected populations, but few prospective studies are available in general populations. Methods: The study included 732 black and white participants, sampled from the original ARIC cohort, who had 3T brain Magnetic Resonance Imaging (MRI) scans, were free of MCI and dementia during 2011-13 (Visit 5), and were evaluated for cognitive impairment during 2016-17 (Visit 6, about 90% complete). We assessed the associations of brain infarcts, WMH, and brain volumes measured on MRI from 2011-2013 with incident MCI and dementia (combined), diagnosed using a computer algorithm based on specified criteria and comprehensive assessment at Visit 6. We used logistic regression, incorporating sampling weights, to evaluate the risk for incident MCI/dementia with adjustment for demographic covariates, major dementia risk factors, and history of cardiovascular diseases. Results: Participants had a median age of 75 (IQR: 71, 79) at Visit 5 (baseline); 62% (453) were female and 33% (242) were African American. There were 156 newly identified cases of MCI or dementia during a median follow-up time of 4.9 (IQR: 3.4, 5.2) years. The presence of any brain infarct was associated with a nonsignificantly higher risk of MCI/dementia (OR: 1.50; 95%CI: 0.87 to 2.58), but the only significant individual association was with cortical infarcts (OR: 1.99; 95%CI: 1.03 to 3.85). WMH volume above the median value was nonsignificantly associated with conversion to MCI/dementia. Smaller Alzheimer’s disease (AD) signature region was an independent predictor for greater risk of MCI/dementia (OR: 1.49; 95%CI: 1.00 to 2.22). A similar but nonsignificant association was observed for total brain volume. Conclusions: Brain infarcts (cortical infarcts) and lower brain volume (AD signature region), measured in community-based older residents, are risk factors for MCI and dementia incidence.

Background: Midlife vascular risk factors (MVRF) are associated with incident dementia. Similarly, amyloid β(Aβ) and neurodegeneration (e.g.brain volumes), as parts of the Alzheimer’s Disease (AD) ATN framework, are associated with cognition. Whether vascular and AD-associated factors contribute to dementia independently or interact synergistically to reduce cognitive ability is not well understood. Methods: Recruited from 3 U.S. communities, ARIC-PET participants were followed from 1987-89 (45-64 yo) through 2016-17 (74-94 yo). Cognition was evaluated in 2011-13 (ages 69-88), and twice more, every 2-3 years. In 2011-13, nondemented ARIC-PET participants had a brain MRI, with measurement of white matter hyperintensities (WMH) and brain volumes, with florbetapir (Aβ) PET scans in 2012-14; global cortical standardized uptake value ratio (SUVR) was log-transformed and standardized. Dementia was classified by expert review, as well as phone and medical record surveillance. The relative contributions of vascular risk (MVRF, WMH volume) and AD pathology (elevated Aβ SUVR, smaller AD signature region volumes) to incident dementia were evaluated with Cox proportional hazards regression. Results: In 298 individuals, 36 developed dementia. In models with key MVRF, demographics, and Aβ SUVR, hypertension and Aβ each independently predicted dementia risk (per SD of Aβ SUVR: HR 2.57, 95% CI 1.72-3.84; hypertension: HR 2.57, 95% CI 1.16-5.67), but didn’t interact on dementia risk. WMH (per SD: HR 1.51, 95% CI 1.03-2.20) and Aβ SUVR (per SD: HR 2.52, 95% CI 1.83-3.47) each contributed to incident dementia but WMH lost significance when MVRF were added to the model. Smaller AD signature regions were associated with incident dementia, independent of Aβ SUVR, and remained significant after adjustment for MVRF (HR per SD 2.18, 95% CI 1.18-4.01). Conclusions: Midlife hypertension and late-life Aβ independently contribute to dementia risk, but don’t synergize on a multiplicative scale. Neurodegeneration (e.g.smaller AD signature region volume) is also associated with incident dementia, independent of Aβ and MVRF. Multiple pathways leading to dementia should be considered when evaluating risk factors and interventions to reduce the burden of dementia.

Background: A healthy diet may be protective against cognitive decline by mechanisms that involve improved vascular risk factors such as hypertension and dysglycemia, and reduced systemic inflammation. In this population-based study, we hypothesized that midlife diet pattern would be associated with cognitive decline over 21-years. Methods: This study included 13,603 participants in the ARIC population-based cohort recruited from four U.S. sites who were aged 45 to 64 at baseline (1987-89) when diet was measured. Participants recorded diet using a 66-item food frequency questionnaire. Two dietary patterns, called “Meat and Fried” and the “Balanced Diet”, were named after the most representative foods that emerged from constructs derived from a principal component analysis of 30 food groups. A higher diet pattern score represented greater adherence. Cognitive testing, including the digit symbol substitution, the word fluency and delayed word recall tests, were combined to a z-score at each visit (visits 2, 1990-92; 4, 1996-98 and 5, 2011-2013). Test scores for participants not attending subsequent visits were imputed using Multiple Imputation by Chained Equations to account for cohort attrition. Cognitive performance at visit 2 was compared by tertile (T) of each diet pattern. Using mixed effects models with a random slope and intercept , we determined the 21-year change in cognitive function by diet pattern tertile, adjusting for demographics and medical history. Results: At visit 2, adherence to the Meat and Fried pattern was associated with lower cognitive test scores (z-score T3: -0.172, SD 0.985; T1: 0.149, SD 0.981, p-trend <0.001). Adherence to the Balanced Diet was not associated with differences in cognitive performance (z-score T3: 0.013, SD 0.988; T1 -0.036, SD 1.001, p-trend 0.10). 21-year change in cognitive function did not differ by adherence to diet pattern with adjustments (difference of the change in z-score for Meat and Fried, T3 vs. T1: 0.02, [CI -0.05 to 0.08]; Balanced Diet T3 vs. T1: -0.03, [CI -0.09 to 0.02]). Conclusion: Although participants with a diet pattern high in meat and fried foods had lower cognition at time of first assessment, diet patterns at midlife did not carry independent associations with cognitive decline.

Background Antiplatelets, anticoagulants, and statins are commonly prescribed for various indications. The associations between these medications and the risk of intracerebral hemorrhage (ICH) and cerebral microbleeds (CMBs) are unclear. Methods and Results We performed a retrospective study of the ARIC (Atherosclerosis Risk in Communities) study cohort, recruited from 4 US communities in 1987 to 1989 with follow‐up. In 2011 to 2013, a subset (N=1942) underwent brain magnetic resonance imaging with CMB evaluation. Time‐varying and any antiplatelet, anticoagulant, or statin use was evaluated at subsequent study visits in participants not on each medication at baseline. To determine the hazard of ICH and odds of CMB by medication use, logistic and Cox proportional hazard models were built, respectively, adjusting for the propensity to take the medication, concomitant use of other medications, and cognitive, genetic, and radiographic data. Of 15 719 individuals during up to 20 years of follow‐up, 130 participants experienced an ICH. The adjusted hazard of ICH was significantly lower among participants taking an antiplatelet at the most recent study visit before ICH versus nonusers (hazard ratio [HR], 0.53; 95% CI, 0.30–0.92). Statin users had a significantly lower hazard of an ICH compared with nonusers (adjusted HR, 0.13; 95% CI, 0.05–0.34). There was no association of CMB and antiplatelet, anticoagulant, or statin use in adjusted models. Conclusions In this US community‐based study, antiplatelet and statin use were associated with lower ICH hazard, whereas no association was noted between CMBs and antiplatelets, anticoagulants, and statins. Further study is needed to understand the differential roles of these medications in cerebral microhemorrhages and macrohemorrhages.

Background: Vascular aging is associated with cognitive decline. Aortic stiffness is a hallmark of vascular aging. We tested the hypothesis that greater aortic stiffness is associated with a faster rate of cognitive decline over 5 years among older adults. Methods: A prospective cohort study at the 5th (2011-2013) and 6th (2016-2017) examinations of the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS) was conducted to quantify the association between baseline aortic stiffness and cognitive decline over 5 years. A total of 4639 participants (mean age: 75 years, 41% men, 22% Black) with baseline measures of aortic stiffness and cognitive function were included in the analysis. Aortic stiffness was measured as carotid-femoral pulse wave velocity (cfPWV) using the Omron VP-1000 Plus device and analyzed continuously per 1 standard deviation meter/second (3.20 m/s). Elevated aortic stiffness was defined as the upper 25th percentile of cfPWV (13.39 m/s). Cognitive function was based on ten neuropsychological tests across multiple domains of cognition, including memory, executive function/processing speed, and language. A global cognitive performance factor score was estimated based on all cognitive tests at both visits. Multivariable linear regression was used to examine the associations of each standard deviation (SD) increment in cfPWV and elevated cfPWV with annual cognitive decline over 5 years. Interactions with baseline cognitive status were assessed. To account for attrition (35% over 5 years), multiple imputation by chained equations was used to impute missing global cognitive performance factor scores at visit 6. Results: Each 1 SD increase in cfPWV was associated with 0.008 SD (Beta (β)=-0.008, 95% confidence interval (CI): -0.010, -0.003) annual rate of decline in cognitive function after adjustment for age, sex, education, race-center and ApoE4. With additional adjustment for ever smoking, total weekly physical activity time, mean arterial pressure, diabetes, and body mass index, each SD higher cfPWV was associated with 0.005 SD (β=-0.005, 95% CI: -0.010, -0.001) annual rate of decline in cognitive function. Elevated cfPWV was associated with 0.015 SD (β=-0.015, 95% CI: -0.024, -0.005) annual decline in cognitive function, and with 0.010 SD (β=-0.010, 95% CI: -0.020, 0.0001) annual decline after additional adjustment. Conclusion: Higher aortic stiffness is associated with the rate of decline in global cognitive function among community-dwelling older adults. The hemodynamic sequelae of aortic stiffening may contribute to cognitive decline among older adults.

Introduction: Stiffening of the aorta is associated with greater pulse pressure and transmission of pulsatile energy into the cerebral circulation, which can increase susceptibility to microvascular damage in the brain. We tested the hypothesis that higher aortic stiffness measured in late-life is associated with a greater prevalence odds of dementia measured ~5 years later. Methods: Dementia-free ARIC-NCS participants (n=4753; mean age: 75 years; 42% male; 21% black) with measures of aortic stiffness at the visit 5 (2011-2013) examination were included. Aortic stiffness was measured by carotid-femoral pulse wave velocity (cfPWV) using the VP-1000 Plus device (Omron Co., Japan) and modeled as continuous (per standard deviation (SD)), categorical into distribution-based quartiles, and as elevated vs. non-elevated cfPWV according to the upper 25 th percentile (13.34 m/s). Cognitive status (normal/mild cognitive impairment (MCI)/dementia) was ascertained at the visit 5 and 6 (2016-2017) examinations with expert review by an adjudication committee of in-person cognitive testing. A multivariable logistic regression model estimated the adjusted association of cfPWV with 5-year odds of dementia. Results: Among dementia-free participants, a 1 SD higher cfPWV was associated with a greater odds of dementia (Odds Ratio (OR): 1.19 (95% Confidence Interval (CI): 1.03, 1.39). Elevated cfPWV (upper 25 th percentile) was also associated with a greater odds of dementia (OR: 1.54, 95% CI: 1.08, 2.19) in this sample. This association was stronger among participants who were cognitively normal at visit 5 (n=3758, Table): the multivariable-adjusted OR of dementia = 2.16 (95% CI: 1.35, 3.47) for elevated vs. non-elevated cfPWV. The risk of dementia among those with baseline MCI (n=955) was not associated with cfPWV levels. Results were robust to adjustment for vascular risk factors. Conclusions: Among older adults, especially when MCI is not present, greater central aortic stiffness is associated with dementia risk.