Probable chronic pain, brain structure, and Alzheimer's plasma biomarkers in older men.

Chronic pain leads to tau accumulation and hippocampal atrophy in mice. In this study, we provide one of the first assessments in humans, examining the associations of probable chronic pain with hippocampal volume, integrity of the locus coeruleus (LC)-an upstream site of tau deposition-and Alzheimer's Disease-related plasma biomarkers. Participants were mostly cognitively unimpaired men. Probable chronic pain was defined as moderate-to-severe pain in 2+ study waves at average ages 56, 62, and 68. At age 68, 424 participants underwent structural magnestic resonance imaging (MRI) of hippocampal volume and LC-sensitive MRI providing an index of LC integrity (LC contrast-to-noise ratio). Analyses adjusted for confounders including major health conditions, depressive symptoms, and opioid use. Models showed that men with probable chronic pain had smaller hippocampal volume and lower rostral-middle-but not caudal-LC contrast-to-noise ratio compared to men without probable chronic pain. Men with probable chronic pain also had higher levels of plasma total tau, beta-amyloid-42, and beta-amyloid-40 compared to men without probable chronic pain. These findings suggest that probable chronic pain is associated with tau accumulation and reduced structural brain integrity in regions affected early in the development of Alzheimer's Disease. PERSPECTIVE: Probable chronic pain was associated with plasma biomarkers and brain regions that are affected early in Alzheimer's disease (AD). Reducing pain in midlife and elucidating biological mechanisms may help to reduce the risk of AD in older adults.

A Traitlike Dimension of Subjective Memory Concern Over 30 Years Among Adult Male Twins.

Importance: Subjective memory concern has long been considered a state-related indicator of impending cognitive decline or dementia. The possibility that subjective memory concern may itself be a heritable trait is largely ignored, yet such an association would substantially confound its use in clinical or research settings. Objective: To assess the heritability and traitlike dimensions of subjective memory concern and its clinical correlates. Design, Setting, and Participants: This longitudinal twin cohort study was conducted from 1967 to 2019 among male adults with a mean (SD) age of 37.75 (2.52) years to follow-up at mean ages of 56.15 (2.72), 61.50 (2.43), and 67.35 (2.57) years (hereafter, 38, 56, 62, and 67 years, respectively) in the Vietnam Era Twin Study of Aging. The study included a national community-dwelling sample with health, education, and lifestyle characteristics comparable to a general sample of US men in this age cohort. Participants were monozygotic and dizygotic twins randomly recruited from the Vietnam Era Twin Registry. Data were analyzed from May 2021 to December 2022. Main Outcomes and Measures: Measures included subjective memory concern at 4 time points; objective memory, depressive symptoms, and anxiety at the last 3 time points; negative emotionality (trait neuroticism) at age 56 years; polygenic risk scores (PRSs) for neuroticism, depression, and Alzheimer disease; APOE genotype; and parental history of dementia. Primary outcomes were heritability and correlations between subjective memory concern and other measures. Results: The sample included 1555 male adults examined at age 38 years, 520 at age 56 years (due to late introduction of subjective memory concern questions), 1199 at age 62 years, and 1192 at age 67 years. Phenotypically, subjective memory concerns were relatively stable over time. At age 56 years, subjective memory concern had larger correlations with depressive symptoms (r, 0.32; 95% CI, 0.21 to 0.42), anxiety (r, 0.36; 95% CI, 0.18 to 0.51), and neuroticism (r, 0.34; 95% CI, 0.26 to 0.41) than with objective memory (r, -0.24; 95% CI, -0.33 to -0.13). Phenotypic results were similar at ages 62 and 67 years. A best-fitting autoregressive twin model indicated that genetic influences on subjective memory concern accumulated and persisted over time (h2 = 0.26-0.34 from age 38-67 years). At age 56 years, genetic influences for subjective memory concern were moderately correlated with genetic influences for anxiety (r, 0.36; 95% CI, 0.18 to 0.51), negative emotionality (r, 0.51; 95% CI, 0.44-0.57), and depressive symptoms (r, 0.20; 95% CI, 0.10 to 0.29) as well as objective memory (r, -0.22; 95% CI, -0.30 to -0.14). Similar genetic correlations were seen at ages 62 and 67 years. The neuroticism PRS was associated with subjective memory concern at age 38 years (r, 0.10; 95% CI, 0.03. to 0.18) and age 67 years (r, 0.09; 95% CI, 0.01 to 0.16). Subjective memory concern was not associated with any Alzheimer disease risk measures. Conclusions and Relevance: This cohort study found stable genetic influences underlying subjective memory concern dating back to age 38 years. Subjective memory concern had larger correlations with affect-related measures than with memory-related measures. Improving the utility of subjective memory concern as an indicator of impending cognitive decline and dementia may depend on isolating its statelike component from its traitlike component.

Microglia specific deletion of miR-155 in Alzheimer's disease mouse models reduces amyloid-ß pathology but causes hyperexcitability and seizures.

Alzheimer's Disease (AD) is characterized by the accumulation of extracellular amyloid-ß (Aß) as well as CNS and systemic inflammation. Microglia, the myeloid cells resident in the CNS, use microRNAs to rapidly respond to inflammatory signals. MicroRNAs (miRNAs) modulate inflammatory responses in microglia, and miRNA profiles are altered in Alzheimer's disease (AD) patients. Expression of the pro-inflammatory miRNA, miR-155, is increased in the AD brain. However, the role of miR-155 in AD pathogenesis is not well-understood. We hypothesized that miR-155 participates in AD pathophysiology by regulating microglia internalization and degradation of Aß. We used CX3CR1CreER/+ to drive-inducible, microglia-specific deletion of floxed miR-155 alleles in two AD mouse models. Microglia-specific inducible deletion of miR-155 in microglia increased anti-inflammatory gene expression while reducing insoluble Aß1-42 and plaque area. Yet, microglia-specific miR-155 deletion led to early-onset hyperexcitability, recurring spontaneous seizures, and seizure-related mortality. The mechanism behind hyperexcitability involved microglia-mediated synaptic pruning as miR-155 deletion altered microglia internalization of synaptic material. These data identify miR-155 as a novel modulator of microglia Aß internalization and synaptic pruning, influencing synaptic homeostasis in the setting of AD pathology.

Associations Between Ambient Air Pollution and Cognitive Abilities from Midlife to Early Old Age: Modification by APOE Genotype.

BACKGROUND: Fine particulate matter (PM2.5) and nitrogen dioxide (NO2) measures of ambient air pollution are associated with accelerated age-related cognitive impairment, and Alzheimer's disease and related dementias (ADRD). OBJECTIVE: We examined associations between air pollution, four cognitive factors, and the moderating role of apolipoprotein E (APOE) genotype in the understudied period of midlife. METHODS: Participants were ∼1,100 men in the Vietnam Era Twin Study of Aging. Baseline cognitive assessments were from 2003 to 2007. Measures included past (1993-1999) and recent (3 years prior to baseline assessment) PM2.5 and NO2 exposure, in-person assessment of episodic memory, executive function, verbal fluency, and processing speed, and APOE genotype. Average baseline age was 56 years with a 12-year follow-up. Analyses adjusted for health and lifestyle covariates. RESULTS: Performance in all cognitive domains declined from age 56 to 68. Higher PM2.5 exposures were associated with worse general verbal fluency. We found significant exposure-by-APOE genotype interactions for specific cognitive domains: PM2.5 with executive function and NO2 with episodic memory. Higher PM2.5 exposure was related to worse executive function in APOE ɛ4 carriers, but not in non-carriers. There were no associations with processing speed. CONCLUSION: These results indicate negative effects of ambient air pollution exposure on fluency alongside intriguing differential modifications of cognitive performance by APOE genotype. APOE ɛ4 carriers appeared more sensitive to environmental differences. The process by which air pollution and its interaction with genetic risk for ADRD affects risk for later life cognitive decline or progression to dementia may begin in midlife.

Rostral-middle locus coeruleus integrity and subjective cognitive decline in early old age.

OBJECTIVES: Abnormal tau, a hallmark Alzheimer's disease (AD) pathology, may appear in the locus coeruleus (LC) decades before AD symptom onset. Reports of subjective cognitive decline are also often present prior to formal diagnosis. Yet, the relationship between LC structural integrity and subjective cognitive decline has remained unexplored. Here, we aimed to explore these potential associations. METHODS: We examined 381 community-dwelling men (mean age = 67.58; SD = 2.62) in the Vietnam Era Twin Study of Aging who underwent LC-sensitive magnetic resonance imaging and completed the Everyday Cognition scale to measure subjective cognitive decline along with their selected informants. Mixed models examined the associations between rostral-middle and caudal LC integrity and subjective cognitive decline after adjusting for depressive symptoms, physical morbidities, and family. Models also adjusted for current objective cognitive performance and objective cognitive decline to explore attenuation. RESULTS: For participant ratings, lower rostral-middle LC contrast to noise ratio (LCCNR) was associated with significantly greater subjective decline in memory, executive function, and visuospatial abilities. For informant ratings, lower rostral-middle LCCNR was associated with significantly greater subjective decline in memory only. Associations remained after adjusting for current objective cognition and objective cognitive decline in respective domains. CONCLUSIONS: Lower rostral-middle LC integrity is associated with greater subjective cognitive decline. Although not explained by objective cognitive performance, such a relationship may explain increased AD risk in people with subjective cognitive decline as the LC is an important neural substrate important for higher order cognitive processing, attention, and arousal and one of the first sites of AD pathology.

MRI-assessed locus coeruleus integrity is heritable and associated with multiple cognitive domains, mild cognitive impairment, and daytime dysfunction.

INTRODUCTION: The locus coeruleus (LC) undergoes extensive neurodegeneration in early Alzheimer's disease (AD). The LC is implicated in regulating the sleep-wake cycle, modulating cognitive function, and AD progression. METHODS: Participants were 481 men (ages 62 to 71.7) from the Vietnam Era Twin Study of Aging. LC structural integrity was indexed by neuromelanin-sensitive magnetic resonance imaging (MRI) contrast-to-noise ratio (LCCNR ). We examined LCCNR , cognition, amnestic mild cognitive impairment (aMCI), and daytime dysfunction. RESULTS: Heritability of LCCNR was .48. Participants with aMCI showed greater daytime dysfunction. Lower LCCNR was associated with poorer episodic memory, general verbal fluency, semantic fluency, and processing speed, as well as increased odds of aMCI and greater daytime dysfunction. DISCUSSION: Reduced LC integrity is associated with widespread differences across cognitive domains, daytime sleep-related dysfunction, and risk for aMCI. These findings in late-middle-aged adults highlight the potential of MRI-based measures of LC integrity in early identification of AD risk.

Interaction between Alcohol Consumption and Apolipoprotein E (ApoE) Genotype with Cognition in Middle-Aged Men.

OBJECTIVE: Heavy alcohol consumption is associated with poorer cognitive function in older adults. Although understudied in middle-aged adults, the relationship between alcohol and cognition may also be influenced by genetics such as the apolipoprotein (ApoE) ε4 allele, a risk factor for Alzheimer's disease. We examined the relationship between alcohol consumption, ApoE genotype, and cognition in middle-aged adults and hypothesized that light and/or moderate drinkers (≤2 drinks per day) would show better cognitive performance than heavy drinkers or non-drinkers. Additionally, we hypothesized that the association between alcohol use and cognitive function would differ by ApoE genotype (ε4+ vs. ε4-). METHOD: Participants were 1266 men from the Vietnam Era Twin Study of Aging (VETSA; M age = 56; range 51-60) who completed a neuropsychological battery assessing seven cognitive abilities: general cognitive ability (GCA), episodic memory, processing speed, executive function, abstract reasoning, verbal fluency, and visuospatial ability. Alcohol consumption was categorized into five groups: never, former, light, moderate, and heavy. RESULTS: In fully adjusted models, there was no significant main effect of alcohol consumption on cognitive functions. However, there was a significant interaction between alcohol consumption and ApoE ε4 status for GCA and episodic memory, such that the relationship of alcohol consumption and cognition was stronger in ε4 carriers. The ε4+ heavy drinking subgroup had the poorest GCA and episodic memory. CONCLUSIONS: Presence of the ε4 allele may increase vulnerability to the deleterious effects of heavy alcohol consumption. Beneficial effects of light or moderate alcohol consumption were not observed.

Posttraumatic stress symptom persistence across 24 years: association with brain structures.

Posttraumatic stress disorder (PTSD) is known to persist, eliciting early medical co-morbidity, and accelerated aging. Although PTSD diagnosis has been found to be associated with smaller volume in multiple brain regions, posttraumatic stress (PTS) symptoms and their associations with brain morphometry are rarely assessed over long periods of time. We predicted that persistent PTS symptoms across ~24 years would be inversely associated with hippocampal, amygdala, anterior cingulate volumes, and hippocampal occupancy (HOC = hippocampal volume/[hippocampal volume + inferior lateral ventricle volume]) in late middle age. Exploratory analyses examined prefrontal regions. We assessed PTS symptoms in 247 men at average ages 38 (time 1) and 62 (time 2). All were trauma-exposed prior to time 1. Brain volumes were assessed at time 2 using 3 T structural magnetic resonance imaging. Symptoms were correlated over time (r = 0.46 p < .0001). Higher PTS symptoms averaged over time and symptoms at time 1 were both associated with lower hippocampal, amygdala, rostral middle frontal gyrus (MFG), and medial orbitofrontal cortex (OFC) volumes, and a lower HOC ratio at time 2. Increased PTS symptomatology from time 1 to time 2 was associated with smaller hippocampal volume. Results for hippocampal, rostral MFG and medial OFC remained significant after omitting individuals above the threshold for PTSD diagnosis. Even at sub-diagnostic threshold levels, PTS symptoms were present decades after trauma exposure in parallel with highly correlated structural deficits in brain regions regulating stress responsivity and adaptation.

Age-Related Differences in Motivational Integration and Cognitive Control.

Motivational incentives play an influential role in value-based decision-making and cognitive control. A compelling hypothesis in the literature suggests that the motivational value of diverse incentives are integrated in the brain into a common currency value signal that influences decision-making and behavior. To investigate whether motivational integration processes change during healthy aging, we tested older (N = 44) and younger (N = 54) adults in an innovative incentive integration task paradigm that establishes dissociable and additive effects of liquid (e.g., juice, neutral, saltwater) and monetary incentives on cognitive task performance. The results reveal that motivational incentives improve cognitive task performance in both older and younger adults, providing novel evidence demonstrating that age-related cognitive control deficits can be ameliorated with sufficient incentive motivation. Additional analyses revealed clear age-related differences in motivational integration. Younger adult task performance was modulated by both monetary and liquid incentives, whereas monetary reward effects were more gradual in older adults and more strongly impacted by trial-by-trial performance feedback. A surprising discovery was that older adults shifted attention from liquid valence toward monetary reward throughout task performance, but younger adults shifted attention from monetary reward toward integrating both monetary reward and liquid valence by the end of the task, suggesting differential strategic utilization of incentives. These data suggest that older adults may have impairments in incentive integration and employ different motivational strategies to improve cognitive task performance. The findings suggest potential candidate neural mechanisms that may serve as the locus of age-related change, providing targets for future cognitive neuroscience investigations.

Body mass trajectories and cortical thickness in middle-aged men: a 42-year longitudinal study starting in young adulthood.

Evidence strongly suggests that being overweight or obese at midlife confers significantly higher risk for Alzheimer's disease and greater brain atrophy later in life. Few studies, however, examine associations between longitudinal changes in adiposity during early adulthood and later brain morphometry. Measures of body mass index (BMI) were collected in 373 men from the Vietnam Era Twin Study of Aging at average ages 20, 40, 56, and 62 years, yielding 2 BMI trajectories. We then examined associations between BMI phenotypes (trajectories, continuous BMI, obese/nonobese), cortical thickness, and white matter measures from structural magnetic resonance imaging at mean age 62 (time 4, range 56-66 years). Those on the obesity trajectory (N = 171) had a thinner cortex compared with the normal/lean trajectory (N = 202) in multiple frontal and temporal lobe bilateral regions of interest: superior, inferior, middle temporal gyri, temporal pole, fusiform gyrus, banks of the superior temporal sulcus, frontal pole, pars triangularis, caudal and rostral middle frontal gyri (all p < 0.05, false discovery rate corrected). Frontal lobe thinness tended to occur mainly in the right hemisphere. Results were similar for obese versus nonobese adults at age 62. There were no significant differences for white matter volume or abnormalities. Taken in the context of other research, these associations between brain structures and excess BMI at midlife suggest potential for increased risk for cognitive decline in later life.

Influence of young adult cognitive ability and additional education on later-life cognition.

How and when education improves cognitive capacity is an issue of profound societal importance. Education and later-life education-related factors, such as occupational complexity and engagement in cognitive-intellectual activities, are frequently considered indices of cognitive reserve, but whether their effects are truly causal remains unclear. In this study, after accounting for general cognitive ability (GCA) at an average age of 20 y, additional education, occupational complexity, or engagement in cognitive-intellectual activities accounted for little variance in late midlife cognitive functioning in men age 56-66 (n = 1009). Age 20 GCA accounted for 40% of variance in the same measure in late midlife and approximately 10% of variance in each of seven cognitive domains. The other factors each accounted for <1% of the variance in cognitive outcomes. The impact of these other factors likely reflects reverse causation-namely, downstream effects of early adult GCA. Supporting that idea, age 20 GCA, but not education, was associated with late midlife cortical surface area (n = 367). In our view, the most parsimonious explanation of our results, a meta-analysis of the impact of education, and epidemiologic studies of the Flynn effect is that intellectual capacity gains due to education plateau in late adolescence/early adulthood. Longitudinal studies with multiple cognitive assessments before completion of education would be needed to confirm this speculation. If cognitive gains reach an asymptote by early adulthood, then strengthening cognitive reserve and reducing later-life cognitive decline and dementia risk may really begin with improving educational quality and access in childhood and adolescence.

Mediators of the Effect of Childhood Socioeconomic Status on Late Midlife Cognitive Abilities: A Four Decade Longitudinal Study.

BACKGROUND AND OBJECTIVES: Childhood socioeconomic status (cSES) is found to predict later-life cognitive abilities, yet the mechanisms underlying these associations remain unclear. The objective of this longitudinal study was to examine the direct and indirect paths through which cSES influences late midlife cognitive outcomes. RESEARCH DESIGN AND METHODS: Participants were 1,009 male twins in the Vietnam Era Twin Study of Aging (VETSA). At mean ages 20 and 62, participants completed a standardized test for general cognitive ability (GCA). The age 62 cognitive assessment also included in-person tests of processing speed, episodic memory, abstract reasoning, working memory, verbal fluency, visual-spatial ability, and executive functions. At mean age 56, participants were interviewed regarding their own and their parents' education and occupation, and completed questionnaires about cognitive leisure activities and sociodemographic information. Multiple mediation analyses were conducted to examine the direct path effects and indirect path effects of cSES through age 20 GCA, adult SES, and cognitive leisure activities on seven cognitive outcomes at age 62, adjusting for age, ethnicity, and non-independence of observations. RESULTS: Total (direct plus indirect) effects were significant for all measures with the exception of executive functions. Men from lower cSES backgrounds had poorer cognitive functioning in late midlife. The direct effect of cSES was partially mediated for abstract reasoning, and was fully mediated for the remaining six cognitive outcomes. Total indirect effects accounted for at least half of the total effects in each model, with paths through age 20 GCA explaining most of the total indirect effects. DISCUSSION AND IMPLICATIONS: cSES predicted cognitive functioning in late middle age Using multiple mediation models, we show that lower cSES predicts poorer cognition in late midlife primarily through young adult cognitive ability and to a lesser extent through SES in adulthood and engagement in cognitively stimulating activities.

Genetic and Environmental Influences on Verbal Fluency in Middle Age: A Longitudinal Twin Study.

Mounting evidence suggests that measures of phonemic fluency and semantic fluency are differentially associated with other cognitive and health phenotypes, but few studies have examined their shared and unique variance, especially using genetically-informative designs. In this study, 1464 middle-aged twins completed six fluency subtests at up to two time-points (mean age 56 and 62 years). Confirmatory factor analyses supported a two-factor solution: a General Fluency latent factor explained variation in all six subtests and a Semantic-Specific factor accounted for additional variance in semantic subtests. Both factors were explained primarily by genetic influences at both waves (a2 = 0.57-0.76). There was considerable stability of individual differences over 6 years (r = .90 for General Fluency, r = .81 for Semantic-Specific), especially for genetic influences (rg = .94 and 1.0, respectively). These results suggest that semantic fluency can be viewed as a combination of general and semantic-specific variance, but phonemic fluency is captured entirely by the general factor.