Gross, Alden L.

AbstractIntroductionMotoric cognitive risk (MCR), a clinical syndrome characterized by slow gait speed and subjective cognitive complaints, has been associated with dementia risk. The neuropathological features underlying MCR remain poorly understood.MethodsThe Atherosclerosis Risk in Communities (ARIC) community‐based cohort study classified participants using standardized criteria as MCR+/– and mild cognitive impairment (MCI)+/– at study baseline (2011–2013). We examined the 5‐year dementia risk and baseline brain structural/molecular abnormalities associated with MCR+ and MCI+ status.ResultsOf 5023 nondemented participants included, 204 were MCR+ and 1030 were MCI+. Both MCR+ and MCI+ participants demonstrated increased dementia risk. The pattern of structural brain abnormalities associated with MCR+ differed from that of MCI+. Whereas MCI+ was associated with comparatively smaller volumes in brain regions vulnerable to Alzheimer's disease pathology, MCR+ status was associated with smaller volumes in frontoparietal regions and greater white matter abnormalities.DiscussionMCR may represent a predementia syndrome characterized by prominent white matter abnormalities and frontoparietal atrophy.

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.

Importance Black individuals are more likely than white individuals to develop dementia. Whether higher blood pressure (BP) levels in black individuals explain differences between black and white individuals in dementia risk is uncertain. Objective To determine whether cumulative BP levels explain racial differences in cognitive decline. Design, Setting, and Participants Individual participant data from 5 cohorts (January 1971 to December 2017) were pooled from the Atherosclerosis Risk in Communities Study, Coronary Artery Risk Development in Young Adults Study, Cardiovascular Health Study, Framingham Offspring Study, and Northern Manhattan Study. Outcomes were standardized as t scores (mean [SD], 50 [10]); a 1-point difference represented a 0.1-SD difference in cognition. The median (interquartile range) follow-up was 12.4 (5.9-21.0) years. Analysis began September 2018. Main Outcomes and Measures The primary outcome was change in global cognition, and secondary outcomes were change in memory and executive function. Exposures Race (black vs white). Results Among 34 349 participants, 19 378 individuals who were free of stroke and dementia and had longitudinal BP, cognitive, and covariate data were included in the analysis. The mean (SD) age at first cognitive assessment was 59.8 (10.4) years and ranged from 5 to 95 years. Of 19 378 individuals, 10 724 (55.3%) were female and 15 526 (80.1%) were white. Compared with white individuals, black individuals had significantly faster declines in global cognition (−0.03 points per year faster [95% CI, −0.05 to −0.01]; P = .004) and memory (−0.08 points per year faster [95% CI, −0.11 to −0.06]; P < .001) but significantly slower declines in executive function (0.09 points per year slower [95% CI, 0.08-0.10]; P < .001). Time-dependent cumulative mean systolic BP level was associated with significantly faster declines in global cognition (−0.018 points per year faster per each 10–mm Hg increase [95% CI, −0.023 to −0.014]; P < .001), memory (−0.028 points per year faster per each 10–mm Hg increase [95% CI, −0.035 to −0.021]; P < .001), and executive function (−0.01 points per year faster per each 10–mm Hg increase [95% CI, −0.014 to −0.007]; P < .001). After adjusting for cumulative mean systolic BP, differences between black and white individuals in cognitive slopes were attenuated for global cognition (−0.01 points per year [95% CI, −0.03 to 0.01]; P = .56) and memory (−0.06 points per year [95% CI, −0.08 to −0.03]; P < .001) but not executive function (0.10 points per year [95% CI, 0.09-0.11]; P < .001). Conclusions and Relevance These results suggest that black individuals’ higher cumulative BP levels may contribute to racial differences in later-life cognitive decline.

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.

Background: High blood pressure (BP), particularly in mid-life, increases the risk for late-life cognitive impairment and dementia (CID). The extent to which Blacks’ and Hispanics’ worse BP control starting in young adulthood contributes to their greater risk of CID compared to Whites is uncertain. Objective: To describe a pooled, multi-ethnic cohort created to determine the associations between BP levels over the life course and CID risk in Blacks, Hispanics, and Whites. Methods: We pooled individual-level data from 35,473 adults (22.6% Blacks, 8.1% Hispanics, 67.3% Whites, 2% Other) with baseline age ≥18 and cognitive assessments across 6 longitudinal cohorts in the United States from 1971 to 2016: Atherosclerosis Risk in Communities Study (ARIC), Coronary Artery Risk Development in Young Adults Study (CARDIA), Cardiovascular Health Study (CHS), Framingham Offspring Study (FOS), Multi-Ethnic Study of Atherosclerosis (MESA), and Northern Manhattan Study (NOMAS). We harmonized cognitive tests across studies into 3 factors representing global cognitive performance, executive function, and memory using statistically appropriate confirmatory factor analysis. Mean (SD) follow up was 17.1 (10.9) years. Results: The mean (SD) baseline age was 54.3 (16.4) years and 19554 (55.1%) participants were female (Table). There were 3193 (9.0%) first incident strokes (2651 ischemic, 348 hemorrhagic, and 117 other or undetermined type) and 15147 (42.7%) deaths. The Table presents mean BPs at the first and last visits by cohort and the pooled sample. From the initial to the last assessment, mean global cognition decreased over time (p<0.001), as did mean executive function (p<0.001) and mean memory scores (p<0.001) in the pooled sample. Conclusion: This will be the first comprehensive, large investigation of the association of BP levels from young adulthood to late-life and CID risk in Blacks, Hispanics, and Whites.

Background: Although inflammation has been implicated in the pathogenesis of Alzheimer’s disease, the effects of systemic inflammation on brain amyloid deposition remain unclear. Objective: We examined the association of midlife and late-life systemic inflammation with late-life brain amyloid levels in a community sample of non-demented older adults from the Atherosclerosis Risk in Communities (ARIC) – PET Study. Methods: 339 non-demented participants (age: 75 [SD 5]) were recruited from the ARIC Study to undergo florbetapir PET (amyloid) imaging. Blood levels of high sensitivity C-reactive protein (CRP), a marker of systemic inflammation, were measured 22 years (Visit 2), 16 years (Visit 4), and up to 2 years before PET imaging (Visit 5). Elevated brain amyloid deposition (standardized uptake value ratio >1.2) was the primary outcome. Results: Our primary analyses found no association of midlife and late-life CRP with late-life brain amyloid levels. However, in secondary stratified analyses, we found that higher midlife (Visit 2) CRP was associated with elevated amyloid among males (OR 1.65, 95% CI: 1.13–2.42), and among white (OR 1.33, 95% CI: 1.02–1.75), but not African American, participants ( p-interactions<0.05). Among male participants, those who maintained high CRP levels (≥3 mg/L) throughout mid- and late-life were most likely to have elevated brain amyloid (OR, 8.81; 95% CI: 1.23, 62.91). Conclusions: Although our primary analysis does not support an association between systemic inflammation and brain amyloid deposition, we found evidence for sex- and race-dependent associations. However, findings from subgroup analyses should be interpreted with caution.