Palta, Priya

Abstract Although APOE ε4 is an established risk factor for dementia, it is unclear whether it is associated with elevated risk or earlier symptom onset. Longitudinal study of 10,400 white-race individuals in the ARIC cohort followed from age 60 to incident dementia diagnosis, death, or censoring. All-cause dementia was defined using standardized algorithms incorporating longitudinal cognitive change, proxy report, and hospital or death certificate dementia codes. Death was ascertained via the National Death Index and death certificates. We used a parametric mixture of generalized gamma distributions to simultaneously estimate the distribution of event times and the proportion of individuals who experience each outcome (i.e., dementia and its competing risk, dementia-free death) by APOE ε4 status (≥ 1 allele vs. no alleles). Age-adjustment was through use of age as the time scale. APOE ε4 carrier status was associated with a doubling of the overall frequency of dementia incidence to 25% compared to 13% (p < 0.001) in non- ε4 carriers. The distributions of time to dementia was modified by APOE ε4 status (p=0.007): median time to dementia onset among APOE ε4 carriers was 81.9 years compared to 83.3 years in non-APOE ε4 carriers (p = 0.005). No differences in results were found by sex. APOE ε4 carrier status is associated with both elevated risk and earlier time to dementia onset. These findings clarify the causal role of APOE in dementia etiology, could help better identify at-risk subgroups, and may help facilitate better research recruitment.

Introduction: Stiffening of the aorta is associated with increased pulse pressure and transmission of pulsatile energy into the cerebral circulation. An association between increased aortic stiffening with intracranial atherosclerotic disease (ICAD) has not been widely studied. We tested the hypothesis that loss of aortic elasticity (i.e. higher aortic stiffness) is associated with a higher presence of ICAD. Methods: ARIC-NCS participants (n=1412; mean age: 76 years; 42% male; 30% Black) with measures of aortic stiffness and vascular brain magnetic resonance imaging (MRI) 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). cfPWV was discretized into high vs. low aortic stiffness based on the upper 25 th percentile, 13.4 m/s. Brain MRI was performed on 3.0 Tesla scanners using a standardized protocol that included an MR angiography (MRA) and high isotropic resolution vessel MRI. Presence of ICAD was defined as eccentric wall thickening with or without luminal stenosis on MRA. We first examined the functional form relationship between continuous measures of cfPWV and ICAD. Comparing those with high vs. low aortic stiffening, we estimated the prevalence odds of ICAD using logistic regression. Models were adjusted for age, sex, race-center, education, smoking, heart rate, blood-pressure lowering medication, diabetes, LDL-cholesterol, and minutes/week of physical activity. Sampling weights were used for generalizability to the full ARIC cohort at visit 5. We tested for effect modification by race, sex, diabetes, central systolic blood pressure, and use of blood pressure-lowering medication. Results: The mean cfPWV was higher among participants with ICAD (12.6 ± 3.2 m/s) compared to those without ICAD (11.2 ± 2.9 m/s). cfPWV was associated with ICAD in a monotonic, linear fashion (p<0.05). The presence of ICAD was 50.6% among participants with high aortic stiffness (cfPWV above the upper 25th percentile; n=354) compared to 30.2% among participants with low aortic stiffness (n=1058). Compared to participants with low aortic stiffness, those with high aortic stiffness had two-fold higher odds of ICAD (odds ratio (OR): 1.97, 95% confidence interval (CI): 1.68, 2.33). No statistically significant modification of this association was observed. Results were robust to exclusions for prevalent stroke (n=43) and prevalent cardiovascular disease (n=153). Conclusions: Aortic stiffness, a highly prevalent trait among older men and women, is associated with ICAD presence quantified by magnetic resonance angiography. Aortic stiffness, its risk factors and the factors associated with the preservation of aortic elasticity, may play a role in modifying the risk of intracranial atherosclerosis.

Background Central arterial stiffening and increased pulsatility, with consequent cerebral hypoperfusion, may result in structural brain damage and cognitive impairment. Methods and Results We analyzed a cross‐sectional sample of ARIC ‐ NCS (Atherosclerosis Risk in Communities–Neurocognitive Study) participants (aged 67–90 years, 60% women) with measures of cognition (n=3703) and brain magnetic resonance imaging (n=1255). Central arterial hemodynamics were assessed as carotid‐femoral pulse wave velocity and pressure pulsatility (central pulse pressure). We derived factor scores for cognitive domains. Brain magnetic resonance imaging using 3‐Tesla scanners quantified lacunar infarcts; cerebral microbleeds; and volumes of white matter hyperintensities, total brain, and the Alzheimer disease signature region. We used logistic regression, adjusted for demographics, apolipoprotein E ɛ4, heart rate, mean arterial pressure, and select cardiovascular risk factors, to estimate the odds of lacunar infarcts or cerebral microbleeds. Linear regression, additionally adjusted for intracranial volume, estimated the difference in log‐transformed volumes of white matter hyperintensities , total brain, and the Alzheimer disease signature region. We estimated the mean difference in cognitive factor scores across quartiles of carotid‐femoral pulse wave velocity or central pulse pressure using linear regression. Compared with participants in the lowest carotid‐femoral pulse wave velocity quartile, participants in the highest quartile of carotid‐femoral pulse wave velocity had a greater burden of white matter hyperintensities ( P =0.007 for trend), smaller total brain volumes (−18.30 cm 3 ; 95% CI , −27.54 to −9.07 cm 3 ), and smaller Alzheimer disease signature region volumes (−1.48 cm 3 ; 95% CI , −2.27 to −0.68 cm 3 ). These participants also had lower scores in executive function/processing speed (β=−0.04 z score; 95% CI , −0.07 to −0.01 z score) and general cognition (β=−0.09 z score; 95% CI , −0.15 to −0.03 z score). Similar results were observed for central pulse pressure . Conclusions Central arterial hemodynamics were associated with structural brain damage and poorer cognitive performance among older adults.

Abstract Introduction We tested the hypotheses that higher levels of and persistence of midlife leisure‐time physical activity (LTPA) are associated long‐term with lower cognitive decline and less incident dementia. Methods A total of 10,705 participants (mean age: 60 years) had LTPA (no, low, middle, or high) measured in 1987‐1989 and 1993‐1995. LTPA was assessed in relation to incident dementia and 14‐year change in general cognitive performance. Results Over a median follow‐up of 17.4 years, 1063 dementia cases were observed. Compared with no LTPA, high LTPA in midlife was associated with lower incidence of dementia (hazard ratio [95% confidence interval], 0.71 [0.61, 0.86]) and lower declines in general cognitive performance (−0.07 standard deviation difference [−0.12 to −0.04]). These associations were stronger when measured against persistence of midlife LTPA over 6 years. Discussion LTPA is a readily modifiable factor associated inversely with long‐term dementia incidence and cognitive decline.

AbstractIntroductionWe tested the hypothesis that poor sense of smell is associated with lower cognitive function and higher mild cognitive impairment (MCI) prevalence.MethodsOlfaction, measured by the Sniffin' Sticks test, was categorized as olfactory impairment (OI) (score ≤6) or no OI (score >6). MCI was adjudicated based on review of a neuropsychological examination. Linear regression estimated the mean difference in cognitive factor scores, and log‐binomial regression quantified MCI prevalence among participants with versus without OI.ResultsParticipants with OI had lower mean factor scores (memory: −0.27 standard deviation [SD], 95% confidence interval [CI]: −0.35 to −0.19; language: −0.24 SD, 95% CI: −0.30 to −0.17; executive function/processing speed: −0.09 SD, 95% CI: −0.12 to −0.06; and general cognitive performance: −0.25 SD, 95% CI: −0.30 to −0.20). OI was also associated with MCI (n = 204; prevalence ratio = 1.56, 95% CI: 1.37, 1.78).DiscussionAn impaired sense of smell may serve as a readily accessible early marker of neurodegeneration and improve upon the prevailing delayed diagnoses and underascertainment of MCI/dementia.

Background: The association of central arterial stiffness and pressure pulsatility with mild cognitive impairment (MCI) and dementia is not well characterized in the population-based setting. Objective: The aim of this study was to quantify the cross-sectional association of arterial stiffness and pressure pulsatility with MCI and dementia among 4,461 older white and black adults from the population-based Atherosclerosis Risk in Communities Study-Neurocognitive Study. Methods: We used race-stratified multinomial logistic regression to evaluate associations of percentile cut points of carotid-femoral pulse wave velocity, central systolic blood pressure, central pulse pressure, and pulse pressure amplification with MCI and dementia versus no cognitive impairment. Results: Among whites, those with carotid-femoral pulse wave velocity or central systolic blood pressure ≥75th percentile had a higher prevalence of MCI compared to participants <75th percentile (conditional odds ratio (OR); 95% confidence interval (CI): 1.27 (1.02, 1.56) and 1.28 (1.04, 1.57), respectively) and those with central pulse pressure ≥75th percentile had a higher prevalence of MCI (OR 1.27 (95% CI: 1.03, 1.58)) and dementia (OR 1.76 (95% CI: 1.06, 2.92) compared to participants <75th percentile. Also among whites, those with pulse pressure amplification ≤25th percentile had a higher prevalence of dementia compared to participants >25th percentile (OR 1.65; (95% CI: 1.01, 2.70). Weaker associations were seen among black participants. Conclusion: Higher arterial stiffness and pulsatility were associated with MCI and dementia in white participants. Longitudinal characterization of the observed associations is warranted to assess whether arterial stiffness and pressure pulsatility predict MCI and dementia among older adults.