Objectives

To examine the effects of age and race on the association of apolipoprotein E (APOE) genotypes with cognitive decline in a population sample.

Design

Longitudinal study of 18 years' duration.

Setting

Biracial urban US population sample.

Participants

There were a total of 5807 participants, 60% African American (AA) and 40% European American (EA).

Measurements

A composite cognitive function based on individual tests of episodic memory, perceptual speed, and the Mini-Mental State Examination.

Results

The frequencies of APOE ε2/ε3 (14% vs 12%), ε2/ε4 (4% vs 2%), ε3/ε4 (29% vs 22%), and ε4/ε4 (4% vs 2%) genotypes were higher among AAs than EAs. After adjusting for demographic factors, the rate of decline in global cognition was twice as high among participants with the APOE ε4/ε4 genotype compared to participants with the APOE ε3/ε3 genotype (0.097 vs 0.048 SD units [SDUs] per year; P < .0001). This doubling was not different between AAs (0.091 vs 0.045 SDUs per year) and EAs (0.118 vs 0.059 SDUs per year) (P_interaction = .63). The APOE ε3/ε4 genotype was associated with a higher rate of decline with age (P_interaction = .021), while the APOE ε2/ε4 genotype (P_interaction = .016) and the APOE ε2/ε3 genotype (P_interaction = .043) were associated with a lower rate of decline with higher age. The APOE ε2/ε2 genotype was associated with a lower rate of decline in episodic memory, while the APOE ε2/ε4 was associated with a higher rate of decline in episodic memory and perceptual speed.

Conclusions

The association of the APOE genotypes with cognitive decline was not different between AAs and EAs. However, individuals with different APOE genotypes showed a lower or a higher rate of decline with age. J Am Geriatr Soc 67:734-740, 2019.

Introduction

The trends in prevalence and incidence of Alzheimer's disease (AD) dementia remain uncertain.

Methods

A sample of 2794 participants with a clinical diagnosis for AD dementia were included.

Results

The 2010 census standardized prevalence of AD dementia was 14.5% (95% CI = 13.7-15.3), and annual incidence was 2.3% (1.7-2.9). Both prevalence and incidence showed substantial variation over time, but no secular trends. The prevalence of AD dementia did not change significantly from 14.6% (95% CI = 13.0, 16.2) in 1994-1997 to 14.7% (95% CI = 13.2, 16.2) in 2010-2012 (P = .84). The annual incidence of AD dementia was 2.8% (95% CI = 2.2, 3.2) in 1998-2000 and 2.2% (95% CI = 1.6, 2.8) in 2004-2006 (P = .20) and remained steady in 2010-2012. The prevalence and incidence among African Americans were approximately twice than those among European Americans.

Conclusions

The prevalence and incidence of AD dementia showed substantial variation between 1994 and 2012, but no secular trend.

Objective

To examine the association of blood pressure (BP) with incident Alzheimer's disease (AD) dementia.

Methods

This work is based on a longitudinal, cohort study of 18 years, the Chicago Health and Aging Project (CHAP) performed in 2,137 participants (55% black) with systolic BP measured around 8.1 years before incident AD dementia.

Results

The association of BP with risk of AD dementia was U-shaped, with the lowest risks of AD dementia near the center of the systolic BP (SBP) and diastolic BP (DBP) distributions, and modestly elevated risk at lower BPs, and greater risk at higher BPs. The degree of U-shape and the range of lowest risk (threshold ranges) varied with antihypertensive medication use and presence of the APOE ε4 allele. The U-shape was most prominent for the subgroup not taking antihypertensive medications and having an APOE ε4 allele. At higher BPs, those having the APOE ε4 allele and not receiving antihypertensive medication were at greater risk of AD dementia than other groups: The risk of incident AD dementia increased by 100% (relative risk [RR] = 2.00; 95% confidence interval [CI] = 1.70, 2.31) for every 10 mm Hg increase in SBP above 140 mm Hg. For DBP, the risk of incident of AD dementia increased by 57% (RR = 1.57; 95% CI = 1.33, 1.86) for every 5 mm Hg increase in DBP above 76 mm Hg.

Interpretation

The BP risk of AD dementia association is U-shaped, with elevated risk at lower and higher BPs. People having the APOE ε4 allele and not receiving antihypertensive medication with higher BPs have notably elevated risk of AD dementia. Ann Neurol 2018;83:935-944.

Background

Studies that have investigated the association between markers of inflammation and risk of dementia are conflicting. Therefore, the researchers conducted a systematic review and meta-analysis of observational studies with the hypothesis that an increased level of peripheral proinflammatory markers would be associated with risk of all-cause dementia or Alzheimer's disease (AD).

Methods

The researchers conducted a literature search of observational studies indexed in the PubMed and PsycInfo databases. Selected studies included those with at least one peripheral inflammatory biomarker and its association with risk of all-cause dementia or AD. Random effects models were used to generate pooled hazard ratios (HRs) comparing the top versus bottom quantile of inflammatory marker level. Heterogeneity was assessed using the I (2) statistic.

Results

Seven studies were identified, combining for a total 5,717 participants, 746 cases of all-cause dementia and 565 cases of AD. An increased level of C-reactive protein was associated with a 45% increased risk of all-cause dementia (HR: 1.45; 95% CI: 1.10, 1.91). Similarly, a higher level of interleukin-6 was associated with a 32% increased risk (HR: 1.32; 95% CI: 1.06, 1.64) of all-cause dementia. For AD alone, the association with C-reactive protein was less pronounced (HR: 1.21; 95% CI: 1.03, 1.42) and interleukin-6 was not associated with risk of AD (HR: 1.06; 95% CI: 0.83, 1.35). No significant heterogeneity was found in any of the meta-analyses (I (2) = 0%-40%, p ≥ .16).

Conclusions

An increased peripheral level of inflammatory markers is associated with a modest increase in risk of all-cause dementia. Evidence for an association with risk of AD alone is limited.

Background

Many studies have evaluated the stress-cognition association, but few have captured the cumulative nature of stress or distinguished the influences of stressors occurring in childhood versus adulthood. Using a lifecourse approach, we investigated whether cumulative stress exposures are associated with poorer cognitive function and faster cognitive decline.

Methods

We used data from the Midlife Development in the United States Study (N = 3,954, mean baseline age: 56 years). We fit marginal structural generalized estimating equations models to estimate the difference in baseline cognitive function per SD increment in the continuous stressor score, and, separately, between persons in each life course stressor profile and those who did not experience high stress in either childhood or adulthood. We also characterized differences in cognitive decline across levels of stress exposures.

Results

Higher cumulative stress exposure was associated with lower executive function (difference per SD in continuous stressor score = -0.12 SD units, 95% CI = -0.16, -0.08) and episodic memory (difference = -0.09 SD units, 95% CI = -0.13, -0.05). Baseline executive function and episodic memory were lower among those with high stress only in childhood, only in adulthood, and both, than among those without high stress in childhood or adulthood. There was little evidence that rate of change in executive function and episodic memory differed across levels of cumulative stress exposures.

Conclusions

These findings offer support to the hypothesis that stress exposures, accumulated over the life course, worsen cognitive performance, but limited support for the hypothesis that these exposures promote cognitive decline.

Objective

To examine the temporal changes in the likelihood of dementia and mild cognitive impairment (MCI) between 1993 and 2012 using a short battery of cognitive tests.

Methods

A cohort of 10,342 participants underwent a short battery of cognitive tests collected during triennial in-home interviews with 2,794 of those evaluated for the clinical diagnosis of dementia and MCI. We used a generalized logit regression model to estimate the likelihood of dementia and MCI, and a quasibinomial regression model to examine the temporal changes in those likelihood scores.

Results

A short battery of cognitive tests-delayed story recall test, Symbol Digit Modalities Test, and the Mini-Mental State Examination-were associated with the clinical diagnosis of dementia and MCI. The classification accuracy of likelihood scores was 0.92 for dementia and 0.85 for MCI. After adjusting for age, race/ethnicity, and education, the likelihood of dementia in the population decreased from 21.6% (95% confidence interval [CI] 20.9%-22.3%) to 18.9% (95% CI 18.1%-19.7%) between 1993-1996 and 2000-2002 and showed no significant decline between 2000-2002 and 2009-2012 (-0.2%, 95% CI -1.1% to 0.7%). The estimated likelihood of MCI remained similar between 1993-1996 and 2009-2012 (29.0%, 95% CI 27.9%-30.1%), but showed a nonsignificant decrease in 2000-2002.

Conclusion

The likelihood scores based on a short battery of cognitive tests can serve as a measure of dementia and MCI in epidemiologic studies. The decline in the likelihood of dementia and MCI over earlier years was not sustained in later years.

Objective

The longitudinal association of the blood biomarkers total tau (t-tau), neurofilament light (Nf-L), and glial fibrillary acidic protein (GFAP) with common sporadic Alzheimer disease (AD) and cognitive decline is not established.

Methods

Using a single molecule array technology, ultrasensitive immunoassays for serum concentrations of t-tau, Nf-L, and GFAP were measured in a population sample of 1,327 participants (60% African Americans and women) who had a clinical evaluation for AD, had completed in-home cognitive assessments, and had undergone 1.5T structural magnetic resonance imaging.

Results

Higher concentrations of serum biomarkers were associated with the development of clinical AD; especially, the time-specific associations were notable: t-tau 8 to 16 years, and Nf-L and GFAP 4 to 8 years prior to clinical AD. Serum biomarkers were associated with faster cognitive decline over 16 years; baseline t-tau > 0.40pg/ml had 30% faster decline, Nf-L > 25.5pg/ml had 110% faster decline, and GFAP > 232pg/ml had 130% faster decline compared to those in the lowest quartile. Participants with baseline GFAP > 232pg/ml showed 160% faster decline in hippocampal volume compared to those with values < 160pg/ml. Additionally, higher baseline t-tau was associated with faster increase in 3rd ventricular volume, and baseline Nf-L and GFAP were associated with faster decline in cortical thickness.

Interpretation

Serum t-tau, Nf-L, and GFAP predict the development of sporadic AD and cognitive decline, and changes in structural brain characteristics, suggesting their usefulness not only as screening and predictive biomarkers, but also in capturing the pathogenesis of Alzheimer dementia. ANN NEUROL 2020;88:1065-1076.

Bias due to selective mortality is a potential concern in many studies and is especially relevant in cognitive aging research because cognitive impairment strongly predicts subsequent mortality. Biased estimation of the effect of an exposure on rate of cognitive decline can occur when mortality is a common effect of exposure and an unmeasured determinant of cognitive decline and in similar settings. This potential is often represented as collider-stratification bias in directed acyclic graphs, but it is difficult to anticipate the magnitude of bias. In this paper, we present a flexible simulation platform with which to quantify the expected bias in longitudinal studies of determinants of cognitive decline. We evaluated potential survival bias in naive analyses under several selective survival scenarios, assuming that exposure had no effect on cognitive decline for anyone in the population. Compared with the situation with no collider bias, the magnitude of bias was higher when exposure and an unmeasured determinant of cognitive decline interacted on the hazard ratio scale to influence mortality or when both exposure and rate of cognitive decline influenced mortality. Bias was, as expected, larger in high-mortality situations. This simulation platform provides a flexible tool for evaluating biases in studies with high mortality, as is common in cognitive aging research.

Background and objectives

Recent studies suggest the utility of blood biomarkers in detecting changes in neurodegenerative disorders. The objective of our research was to test the hypothesis that the longitudinal changes in total tau (t-tau), neurofilament light chain (Nf-L), and glial fibrillary acidic protein (GFAP) are associated with structural MRI and the development of clinical Alzheimer disease (AD) and cognitive decline.

Methods

Data came from a population-based sample with serum concentrations of t-tau, Nf-L, and GFAP and cognitive characteristics measured over 17 years. The inclusion criteria for this investigation were based on participants with blood samples, cognitive function testing, and clinical diagnosis for AD. The longitudinal changes in the serum biomarkers were examined using linear mixed models for log10-transformed concentrations.

Results

In 1,327 participants (60% Black participants and 60% women, the concentration of t-tau increased annually by 4.8% (95% CI = 4.0-5.6) and Nf-L by 5.9% (95% CI = 5.4-6.4). The longitudinal change in GFAP was higher among Black participants than among White participants (4.4% vs 3.5% per year, p = 0.028). Baseline MRI characteristics were associated with the longitudinal changes in serum biomarkers of clinical AD. Specifically, a higher baseline third ventricular volume was associated with a higher rate of increase in the concentration of t-tau, and white matter hyperintensities predicted a higher rate of increase in Nf-L. The rate of change in concentrations of t-tau, Nf-L, and GFAP was significantly higher among those who developed clinical AD than in those with no cognitive impairment. For each standard deviation unit decline in global cognition, longitudinal change in t-tau increased by 81% (95% CI = 76-86), Nf-L by 113% (95% CI = 105-120), and GFAP by 66% (95% CI = 62-70).

Discussion

Blood biomarkers showed significant longitudinal changes corresponding to cognitive decline, clinical AD, and structural MRI characteristics. Our findings show that longitudinal changes in serum biomarkers were associated with several cognitive endophenotypes.

Classification of evidence

The study found Class II evidence that longitudinal changes in serum t-tau, Nf-L, and GFAP were associated with cognitive decline and the development of clinical AD in people older than 65 years.

Social support during childhood lays the foundation for social relationships throughout the life course and has been shown to predict a wide range of mental and physical health outcomes. Social support measured in late life is prospectively associated with better cognitive aging, but few studies have evaluated social support received earlier in the life course. We quantified the effects of childhood social support, reported retrospectively, on later-life cognitive trajectories and investigated biopsychosocial mechanisms underlying these associations. Latent growth curve models estimated 10-year cognitive trajectories in 8,538 participants (baseline ages 45-93; M_age = 63) in the REasons for Geographic And Racial Differences in Stroke (REGARDS) project. Independent of sociodemographics, childhood socioeconomic status, and household size, greater retrospective childhood social support was associated with better initial episodic memory, but not verbal fluency or cognitive change, in later adulthood. Associations with initial memory level were mediated by sociodemographic and psychosocial variables; specifically, those who reported greater childhood social support reported higher educational attainment and had better physical and emotional health in adulthood, which were each associated with better memory. These results provide support for broad and enduring effects of childhood social support on mental, physical, and cognitive health decades later. (PsycINFO Database Record (c) 2019 APA, all rights reserved).