Midlife cumulative deficit frailty predicts Alzheimer's disease-related plasma biomarkers in older adults.

BACKGROUND: The study explores whether frailty at midlife predicts mortality and levels of biomarkers associated with Alzheimer's disease and related dementias (ADRD) and neurodegeneration by early old age. We also examine the heritability of frailty across this age period. METHODS: Participants were 1,286 community-dwelling men from the Vietnam Era Twin Study of Aging at average ages 56, 62 and 68, all without ADRD at baseline. The cumulative deficit frailty index (FI) comprised 37 items assessing multiple physiological systems. Plasma biomarkers at age 68 included beta-amyloid (Aß40, Aß42), total tau (t-tau) and neurofilament light chain (NfL). RESULTS: Being frail doubled the risk of all-cause mortality by age 68 (OR = 2.44). Age 56 FI significantly predicted age 68 NfL (P = 0.014), Aß40 (P = 0.001) and Aß42 (P = 0.023), but not t-tau. Age 62 FI predicted all biomarkers at age 68: NfL (P = 0.023), Aß40 (P = 0.002), Aß42 (P = 0.001) and t-tau (P = 0.001). Age 68 FI scores were associated with age 68 levels of NfL (P = 0.027), Aß40 (P < 0.001), Aß42 (P = 0.001) and t-tau (P = 0.003). Genetic influences accounted for 45-48% of the variance in frailty and significantly contributed to its stability across 11 years. CONCLUSIONS: Frailty during one's 50s doubled the risk of mortality by age 68. A mechanism linking frailty and ADRD may be through its associations with biomarkers related to neurodegeneration. Cumulative deficit frailty increases with age but remains moderately heritable across the age range studied. With environmental factors accounting for about half of its variance, early interventions aimed at reducing frailty may help to reduce risk for ADRD.

A twin analysis to estimate genetic and environmental factors contributing to variation in weighted gene co-expression network module eigengenes.

Multivariate network-based analytic methods such as weighted gene co-expression network analysis are frequently applied to human and animal gene-expression data to estimate the first principal component of a module, or module eigengene (ME). MEs are interpreted as multivariate summaries of correlated gene-expression patterns and network connectivity across genes within a module. As such, they have the potential to elucidate the mechanisms by which molecular genomic variation contributes to individual differences in complex traits. Although increasingly used to test for associations between modules and complex traits, the genetic and environmental etiology of MEs has not been empirically established. It is unclear if, and to what degree, individual differences in blood-derived MEs reflect random variation versus familial aggregation arising from heritable or shared environmental influences. We used biometrical genetic analyses to estimate the contribution of genetic and environmental influences on MEs derived from blood lymphocytes collected on a sample of N = 661 older male twins from the Vietnam Era Twin Study of Aging (VETSA) whose mean age at assessment was 67.7 years (SD = 2.6 years, range = 62-74 years). Of the 26 detected MEs, 14 (56%) had statistically significant additive genetic variation with an average heritability of 44% (SD = 0.08, range = 35%-64%). Despite the relatively small sample size, this demonstration of significant family aggregation including estimates of heritability in 14 of the 26 MEs suggests that blood-based MEs are reliable and merit further exploration in terms of their associations with complex traits and diseases.

The genetic and environmental etiology of novel frequency-driven regional parcellations of abnormal white matter.

The prevalence of white matter disease increases with age and is associated with cerebrovascular disease, cognitive decline, and risk for dementia. MRI measures of abnormal signal in the white matter (AWM) provide estimates of damage, however, regional patterns of AWM may be differentially influenced by genetic or environmental factors. With our data-driven regional parcellation approach, we created a probability distribution atlas using Vietnam Era Twin Study of Aging (VETSA) data (n = 475, mean age 67.6 years) and applied a watershed algorithm to define separate regional parcellations. We report biometrical twin modeling for five anatomically distinct regions: (1) Posterior, (2) Superior frontal and parietal, (3) Anterior and inferior frontal with deep areas, (4) Occipital, and (5) Anterior periventricular. We tested competing multivariate hypotheses to identify unique influences and to explain sources of covariance among the parcellations. Family aggregation could be entirely explained by additive genetic influences, with additive genetic variance (heritability) ranging from 0.69 to 0.79. Most genetic correlations between parcellations ranged from moderate to high (rg = 0.57-0.85), although two were small (rg = 0.35-0.39), consistent with varying degrees of unique genetic influences. This proof-of-principle investigation demonstrated the value of our novel, data-driven parcellations, with identifiable genetic and environmental differences, for future exploration.

Reserve, resilience and maintenance of episodic memory and other cognitive functions in aging.

We tested if cognitive and brain reserve and maintenance explain individual differences in episodic memory and other cognitive domains from late middle to early older adulthood. We used The Vietnam Era Twin Study of Aging data (n=1604 men) with episodic memory measured at mean ages of 56, 62 and 68 years, and magnetic resonance imaging data for a subsample of participants (n=321). Cognitive reserve -young adult general cognitive ability at a mean age of 20 years and, to a lesser degree, educational attainment- was positively related to episodic memory performance at each assessment, but not to memory change. We found no evidence for the associations of brain reserve or brain maintenance on memory change. Results were highly similar when looking at processing speed, executive function and verbal fluency. In conclusion, higher young adult cognitive reserve was related to better episodic memory in midlife and older adulthood, but it did not confer better cognitive maintenance with respect to memory. This supports the importance of early cognitive development in dementia prevention.

Multimorbidity, Social Engagement, and Age-Related Cognitive Decline in Older Adults from the Rancho Bernardo Study of Healthy Aging.

Background: Multimorbidity is associated with increased rate of cognitive decline with age. It is unknown whether social engagement, which is associated with reduced risk of dementia, modifies associations between multimorbidity and cognitive decline. Objective: To examine the associations of multimorbidity with longitudinal cognitive test performance among community-dwelling older adults, and to determine whether associations differed by levels of social engagement. Methods: We used data from the Rancho Bernardo Study of Healthy Aging, a community-based prospective cohort study. Starting in 1992-1996, participants completed a battery of cognitive function tests at up to 6 study visits over 23.7 (mean = 7.2) years. Multimorbidity was defined as≥2 of 14 chronic diseases. Social engagement was assessed using items based on the Berkman-Syme Social Network Index. Multivariable linear mixed-effects models were used to test associations of multimorbidity and cognitive performance trajectories. Effect measure modification by social engagement was evaluated. Results: Among 1,381 participants (mean age = 74.5 years; 60.8% women; 98.8% non-Hispanic White), 37.1% had multimorbidity and 35.1% had low social engagement. Multimorbidity was associated with faster declines in Mini-Mental State Examination (MMSE; ß= -0.20; 95% CI -0.35, -0.04), Trail-Making Test Part B (ß= 10.02; 95% CI 5.77, 14.27), and Category Fluency (ß= -0.42; 95% CI -0.72, -0.13) after adjustment for socio-demographic and health-related characteristics. Multimorbidity was associated with faster declines in MMSE among those with low compared to medium and high social engagement (p-interaction < 0.01). Conclusions: Multimorbidity was associated with faster declines in cognition among community-dwelling older adults. Higher social engagement may mitigate multimorbidity-associated cognitive decline.

Brain reserve in midlife is associated with executive function changes across 12 years.

We examined how brain reserve in midlife, measured by brain-predicted age difference scores (Brain-PADs), predicted executive function concurrently and longitudinally into early old age, and whether these associations were moderated by young adult cognitive reserve or APOE genotype. 508 men in the Vietnam Era Twin Study of Aging (VETSA) completed neuroimaging assessments at mean age 56 and six executive function tasks at mean ages 56, 62, and 68 years. Results indicated that greater brain reserve at age 56 was associated with better concurrent executive function (r=.10, p=.040) and less decline in executive function over 12 years (r=.34, p=.001). These associations were not moderated by cognitive reserve or APOE genotype. Twin analysis suggested associations with executive function slopes were driven by genetic influences. Our findings suggest that greater brain reserve allowed for better cognitive maintenance from middle- to old age, driven by a genetic association. The results are consistent with differential preservation of executive function based on brain reserve that is independent of young adult cognitive reserve or APOE genotype.

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.

Association Between Traumatic Brain Injury and Cognitive Decline Among Middle-to-Older Aged Men in the Vietnam Era Twin Study of Aging.

Traumatic brain injury (TBI) is associated with increased risk of dementia. However, whether TBI is associated with greater cognitive decline over time in specific cognitive domains among older adults is not well understood. This prospective cohort study used data from 1476 male Vietnam Era Twin Study of Aging participants (average age at study entry = 57.9 years, range = 51-71 years; 97.6% non-Hispanic; 92.5% White) collected from 2003 to 2019, who had complete information on prior TBI. Participants completed a comprehensive neuropsychological assessment at up to three visits over up to a 12-year follow-up period during which they also self-reported their history of TBI. Multivariable, linear mixed-effects models were used to assess associations between TBI and cognitive performance trajectories. Effect measure modification by apolipoprotein E (APOE) epsilon 4 (ε4) genotype status was assessed in a subset of participants. Thirty-one percent of participants reported a history of TBI; 29.4% were APOE ε4 carriers. There were no statistically significant associations of TBI with decline in episodic memory, executive function, or processing speed among participants overall. In models stratified by APOE ε4 carrier status, TBI was associated with a larger magnitude of decline in executive function for APOE ε4 carriers (ß = -0.0181; 95% confidence interval [CI] -0.0335, -0.0027) compared to noncarriers (ß = -0.0031; 95% CI -0.0128, 0.0067; P Interaction = 0.03). In sensitivity analyses, TBI earlier in life (before military induction, average age = 20 years) was associated with faster declines in executive function compared to no TBI, irrespective of APOE ε4 status. In this sample of middle-to-older aged men, TBI was associated with faster declines in executive function among APOE ε4 carriers and among those who reported TBI in early life. These findings support the importance of a life course perspective when considering factors that may influence cognitive health in aging.

Testing the causal impact of amyloidosis on total Tau using a genetically informative sample of adult male twins.

INTRODUCTION: The amyloid cascade hypothesis predicts that amyloid-beta (Aß) aggregation drives tau tangle accumulation. We tested competing causal and non-causal hypotheses regarding the direction of causation between Aß40 and Aß42 and total Tau (t-Tau) plasma biomarkers. METHODS: Plasma Aß40, Aß42, t-Tau, and neurofilament light chain (NFL) were measured in 1,035 men (mean = 67.0 years) using Simoa immunoassays. Genetically informative twin modeling tested the direction of causation between Aßs and t-Tau. RESULTS: No clear evidence that Aß40 or Aß42 directly causes changes in t-Tau was observed; the alternative causal hypotheses also fit the data well. In contrast, exploratory analyses suggested a causal impact of the Aß biomarkers on NFL. Separately, reciprocal causation was observed between t-Tau and NFL. DISCUSSION: Plasma Aß40 or Aß42 do not appear to have a direct causal impact on t-Tau. In contrast, Aß aggregation may causally impact NFL in cognitively unimpaired men in their late 60s.

The Association between Exposure to Fine Particulate Matter and MRI-Assessed Locus Coeruleus Integrity in the Vietnam Era Twin Study of Aging (VETSA).

BACKGROUND: Increased exposure to ambient air pollution, especially fine particulate matter ≤2.5µm (PM2.5) is associated with poorer brain health and increased risk for Alzheimer's disease (AD) and related dementias. The locus coeruleus (LC), located in the brainstem, is one of the earliest regions affected by tau pathology seen in AD. Its diffuse projections throughout the brain include afferents to olfactory areas that are hypothesized conduits of cerebral particle deposition. Additionally, extensive contact of the LC with the cerebrovascular system may present an additional route of exposure to environmental toxicants. OBJECTIVE: Our aim was to investigate if exposure to PM2.5 was associated with LC integrity in a nationwide sample of men in early old age, potentially representing one pathway through which air pollution can contribute to increased risk for AD dementia. METHODS: We examined the relationship between PM2.5 and in vivo magnetic resonance imaging (MRI) estimates of LC structural integrity indexed by contrast to noise ratio (LCCNR) in 381 men [mean age=67.3; standard deviation (SD)=2.6] from the Vietnam Era Twin Study of Aging (VETSA). Exposure to PM2.5 was taken as a 3-year average over the most recent period for which data were available (average of 5.6 years prior to the MRI scan). We focused on LCCNR in the rostral-middle portion of LC due to its stronger associations with aging and AD than the caudal LC. Associations between PM2.5 exposures and LC integrity were tested using linear mixed effects models adjusted for age, scanner, education, household income, and interval between exposure and MRI. A co-twin control analysis was also performed to investigate whether associations remained after controlling for genetic confounding and rearing environment. RESULTS: Multiple linear regressions revealed a significant association between PM2.5 and rostral-middle LCCNR (ß=-0.16; p=0.02), whereby higher exposure to PM2.5 was associated with lower LCCNR. A co-twin control analysis found that, within monozygotic pairs, individuals with higher PM2.5 exposure showed lower LCCNR (ß=-0.11; p=0.02), indicating associations were not driven by genetic or shared environmental confounds. There were no associations between PM2.5 and caudal LCCNR or hippocampal volume, suggesting a degree of specificity to the rostral-middle portion of the LC. DISCUSSION: Given previous findings that loss of LC integrity is associated with increased accumulation of AD-related amyloid and tau pathology, impacts on LC integrity may represent a potential pathway through which exposure to air pollution increases AD risk. https://doi.org/10.1289/EHP14344.

Early Cortical Microstructural Changes in Aging Are Linked to Vulnerability to Alzheimer's Disease Pathology.

BACKGROUND: Early identification of Alzheimer's disease (AD) risk is critical for improving treatment success. Cortical thickness is a macrostructural measure used to assess neurodegeneration in AD. However, cortical microstructural changes appear to precede macrostructural atrophy and may improve early risk identification. Currently, whether cortical microstructural changes in aging are linked to vulnerability to AD pathophysiology remains unclear in nonclinical populations, who are precisely the target for early risk identification. METHODS: In 194 adults, we calculated magnetic resonance imaging-derived maps of changes in cortical mean diffusivity (microstructure) and cortical thickness (macrostructure) over 5 to 6 years (mean age: time 1 = 61.82 years; time 2 = 67.48 years). Episodic memory was assessed using 3 well-established tests. We obtained positron emission tomography-derived maps of AD pathology deposition (amyloid-ß, tau) and neurotransmitter receptors (cholinergic, glutamatergic) implicated in AD pathophysiology. Spatial correlational analyses were used to compare pattern similarity among maps. RESULTS: Spatial patterns of cortical macrostructural changes resembled patterns of cortical organization sensitive to age-related processes (r = -0.31, p < .05), whereas microstructural changes resembled the patterns of tau deposition in AD (r = 0.39, p = .038). Individuals with patterns of microstructural changes that more closely resembled stereotypical tau deposition exhibited greater memory decline (ß = 0.22, p = .029). Microstructural changes and AD pathology deposition were enriched in areas with greater densities of cholinergic and glutamatergic receptors (ps < .05). CONCLUSIONS: Patterns of cortical microstructural changes were more AD-like than patterns of macrostructural changes, which appeared to reflect more general aging processes. Microstructural changes may better inform early risk prediction efforts as a sensitive measure of vulnerability to pathological processes prior to overt atrophy and cognitive decline.

Associations of plasma neurofilament light chain with cognition and neuroimaging measures in community-dwelling early old age men.

BACKGROUND: Plasma neurofilament light chain (NfL) is a promising biomarker of neurodegeneration with potential clinical utility in monitoring the progression of neurodegenerative diseases. However, the cross-sectional associations of plasma NfL with measures of cognition and brain have been inconsistent in community-dwelling populations. METHODS: We examined these associations in a large community-dwelling sample of early old age men (N = 969, mean age = 67.57 years, range = 61-73 years), who are either cognitively unimpaired (CU) or with mild cognitive impairment (MCI). Specifically, we investigated five cognitive domains (executive function, episodic memory, verbal fluency, processing speed, visual-spatial ability), as well as neuroimaging measures of gray and white matter. RESULTS: After adjusting for age, health status, and young adult general cognitive ability, plasma NfL level was only significantly associated with processing speed and white matter hyperintensity (WMH) volume, but not with other cognitive or neuroimaging measures. The association with processing speed was driven by individuals with MCI, as it was not detected in CU individuals. CONCLUSIONS: These results suggest that in early old age men without dementia, plasma NfL does not appear to be sensitive to cross-sectional individual differences in most domains of cognition or neuroimaging measures of gray and white matter. The revealed plasma NfL associations were limited to WMH for all participants and processing speed only within the MCI cohort. Importantly, considering cognitive status in community-based samples will better inform the interpretation of the relationships of plasma NfL with cognition and brain and may help resolve mixed findings in the literature.