Neighborhood disadvantage in later life is associated with poorer cognition and increased vulnerability to dementia. Cognitive reserve (CR), an individual's total cognitive resources, may foster cognitive resilience against dementia in the face of neighborhood disadvantage. However, whether the neighborhood disadvantage-cognition association varies across older adults remains understudied and its moderators remain underexplored. We examined associations between late midlife neighborhood disadvantage and five domain-specific cognitive functions as well as the moderating role of young adult CR on these associations. In 1149 community-dwelling men age 61-73 living across the United States, we assessed neighborhood-level socioeconomic disadvantage using the area deprivation index and cognitive performance in executive function, episodic memory, processing speed, verbal fluency, and visual-spatial ability. General cognitive ability assessed at average age 20 was used as a measure of young adult CR. Years of education was included as another potential moderator for comparison. Greater late midlife neighborhood disadvantage was associated with poorer executive function (β = -.09, p < .05) and processing speed (β = -.12, p < .05). Moreover, those with higher young adult CR showed a weaker association between neighborhood disadvantage and executive function (β = .07, p < .02). The same moderation effect was not observed for years of education. Findings are consistent with the idea that neighborhood disadvantage negatively associates with executive function, albeit less so among those with higher young adult CR. Fostering cognitive development to enhance CR earlier in life may buffer against environmental threats to later-life executive function, which is among the earliest cognitive functions affected in aging, and may, in turn, decrease vulnerability to dementia.

INTRODUCTION:Educational attainment (EA) is negatively associated with body mass index (BMI), but less is known about the association between EA and adult BMI change. We analysed the role of genetic and environmental factors in the associations between EA and BMI trajectory components over adulthood. DATA AND METHODS:Pooled data from 59,490 twins aged 31-99 years (49% women) across 11 cohorts with EA and repeated measures of BMI were used. BMI trajectory components (baseline BMI and BMI change per decade) were estimated using linear mixed-effects (LME) and delta slope methods. EA was derived by regressing years of education on birth year and cohort. Associations between EA and BMI trajectories were evaluated with LME models in both cohort-specific and pooled data. Genetic and environmental contributions were evaluated using structural equation modelling. RESULTS:EA was more strongly negatively associated with baseline BMI and BMI change (mean of 1.31 and 1.32 kg/m2 per decade in men and women, respectively) in women (β = -0.14 kg/m², 95% CI: -0.15 to -0.12; β = -0.02 kg/m²/decade, 95% CI: -0.03 to -0.01, respectively) than in men (β = -0.07, 95% CI: -0.08 to -0.06; β = -0.01, 95% CI: -0.02 to -0.001, respectively). The associations between baseline BMI and EA were explained by genetic factors in men (rA = -0.10) and by both genetic (rA = -0.17) and unique environmental factors (rE = -0.07) in women. For BMI change, the associations with EA were explained by genetic factors (rA = -0.04 in men; -0.06 in women). CONCLUSION:Individuals with higher EA tend to have lower baseline BMI and slower BMI increases across adulthood. These associations are primarily genetically mediated.

INTRODUCTION:Evidence regarding the association between physical activity (PA) and Alzheimer's disease (AD)-related biomarkers is scarce and inconsistent. METHODS:At ages 56 and 67, 564 men from the Vietnam Era Twin Study of Aging reported their PA during the preceding week from which metabolic equivalent of energy expenditure (MET) hours were determined. At age 67 we assayed plasma AD-related biomarkers (phosphorylated tau [p-tau]217, neurofilament light chain [NfL], amyloid beta (Aβ)42/40 ratio, and glial fibrillary acidic protein [GFAP]). We used generalized estimating equations to test whether PA at ages 56 or 67 was associated with these biomarkers at 67. RESULTS:Age 56 MET hours were inversely associated with NfL and GFAP at 67 (NfL: B = -0.10, 95% confidence interval [CI]: -0.17 to -0.03, GFAP: B = -0.08, 95% CI: -0.15 to -0.01) but were not significantly associated with p-tau217 or Aβ42/40 ratio. DISCUSSION:Our NfL and GFAP results suggest that midlife PA may reduce risk for neurodegeneration in older age via amyloid-independent mechanisms.

Large-scale genome-wide association studies (GWAS) and rare variant association studies (RVAS) from population biobanks provide valuable resources for gene discovery in complex human traits. We present an analysis of the All of Us Research Program v8 release, which includes whole genome sequencing data and harmonized phenotypic information of 392,030 participants after quality control, enabling a unified investigation of rare and common variants across a spectrum of human traits and diseases. We build an extensive phenome- and genome-wide ("All by All") computational framework to perform GWAS and RVAS on 3,602 phenotypes and identify 49,863 approximately independent, high-quality single-variant and gene-level associations. Meta-analyses of All of Us and UK Biobank, with sample sizes as large as 786,871 participants, further enhance statistical power and find 193 pLoF gene-phenotype associations that are not significant in either cohort alone, including 22 associations not highlighted by previous studies. We also present a public interactive browser that integrates association results for common and rare variants to facilitate interpretation and rapid querying of summary statistics, along with supporting documentation, and a Featured Workspace in the All of Us Researcher Workbench. Our framework will apply to iterative data releases as All of Us grows, empowering researchers worldwide to uncover insights into the functional effects of genetic components on complex traits and diseases.

OBJECTIVES:Early-life rural-urban residence has been linked to differences in later-life cognitive functioning and dementia risk. However, the contextual pathways underlying these associations, particularly emergent associations later in life, remain underexplored. We examined the associations between young adult urbanicity and domain-specific cognition in older adulthood and whether late midlife neighborhood socioeconomic disadvantage may mediate such associations. METHODS:Participants were 881 community-dwelling men aged 61-73 from across the United States. Young adult urbanicity (rural, suburban, and urban) was assessed at a mean age of 20 based on the Rural-Urban Continuum Codes. Late midlife neighborhood disadvantage was indexed by the area deprivation index (ADI), and cognitive performance in older adulthood was assessed in five domains: executive function, episodic memory, processing speed, verbal fluency, and visual-spatial ability. RESULTS:Compared to those in rural areas, participants who resided in urban areas during young adulthood had lower late midlife ADI (β = -0.85, p < .05), and better executive function (β = 0.19), processing speed (β = 0.24), and verbal fluency (β = 0.30) (ps < .05) in older adulthood. ADI partially mediated these associations, such that urban residence was associated with lower ADI, which was then associated with better performance in these three domains (indirect effects: βs = 0.02 to 0.03). DISCUSSION:Late midlife neighborhood disadvantage represents a contextual pathway linking early-life rural-urban residence to cognitive function in older adulthood. Reducing socioeconomic disadvantage through health policies and interventions at both the community-level early in life and the neighborhood-level later in life may help reduce the risk of cognitive impairment and dementia.

Background The process by which aging leads to increased risk for Alzheimer’s disease and related dementias is not entirely understood, but one hypothesized contributor is the occurrence of low-grade inflammation in older age. Associations between peripheral C-reactive protein (CRP), a marker of systemic inflammation, and brain structure have been widely studied, but fewer studies have examined CRP in relation to diffusion measures, particularly using newer techniques such as restriction spectrum imaging (RSI). In the current study, we examined how high sensitivity CRP (hsCRP) relates to diffusion metrics and global brain tissue volumes among a group of older adult men. Methods We analyzed a sample of 372 cognitively unimpaired men from VETSA, who were assessed at average age 67 for plasma hsCRP and underwent diffusion and structural brain imaging. Linear mixed models examined associations of hsCRP with global and regional measures of restricted normalized directional (RND) and free normalized isotropic (FNI) diffusion in white matter and hindered normalized total diffusion (HNT) and FNI diffusion in gray matter derived from RSI. Similarly, the relationship of hsCRP to global and regional fractional anisotropy (FA) in white matter and mean diffusivity (MD) in white and gray matter was examined. Finally, we examined hsCRP relationships with global gray and white matter volumes as well as global abnormal white matter (AWM; white matter hyperintensities), to attempt quasi-replication of previous findings. Results Higher hsCRP was associated with lower global white matter RND, with several tract-level associations. hsCRP was also associated with greater entorhinal cortex FNI. Conventional DTI metrics showed no associations with hsCRP. In structural analyses, higher hsCRP was associated with lower global gray matter volume but not white matter volume or abnormalities. Conclusion In this sample of older males, higher hsCRP was associated with differences in white matter microstructure measured using multi-shell RSI metrics and with lower global gray matter volume. Conventional DTI metrics showed few associations with hsCRP. These findings suggest that systemic inflammation may be reflected in subtle differences in brain microstructure and macrostructure and highlight the potential value of more sensitive multi-shell diffusion approaches for detecting inflammation-related brain differences in aging populations.

OBJECTIVE:Poor social relations of older adults have been linked to cognitive decline, dementia risk, morbidity, and mortality. We investigated how characteristic ways people relate to romantic partners (adult attachment) might function as risk/protective factors for overall health or dementia risk. Specifically, we evaluated whether attachment anxiety and/or attachment avoidance at midlife predicted cumulative deficit frailty (CDF) and mild cognitive impairment (MCI) in early old age. METHOD:Participants were 1,608 men in the Vietnam Era Twin Study of Aging. Participants' attachment was assessed at a mean age of 56 (starting 2003) and health mediators at a mean age of 62 (2009-2014; e.g., perceived stress, doctor visits, smoking, alcohol consumption, and social isolation). Outcomes at a mean age of 68 (2016-2019) included CDF based on a 37-item scale and MCI. Structural equation modeling assessed associations between attachment, mediators, and outcomes. RESULTS:The effect of attachment anxiety on CDF was indirect, mediated by perceived stress, doctor visits, and smoking at age 62 (total indirect effect: β = .147, p < .001). Its effect on MCI was also indirect, mediated by its association with perceived stress (total indirect effect (β = .090, p = .001). Attachment avoidance did not predict CDF, but it directly predicted MCI (β = .134, p = .033). CONCLUSIONS:Attachment anxiety and attachment avoidance predict frailty and cognitive function through different pathways in older adults. Viewing others as trustworthy and dependable in midlife may be protective against frailty and dementia risk in old age. Focusing on improving the quality of interpersonal relationships may thus help to reduce risk. (PsycInfo Database Record (c) 2026 APA, all rights reserved).

Objective: Studies investigating resting-state functional connectivity of the amygdala and hippocampus have produced inconsistent findings. The authors' objective was to conduct the largest systematic comparison of alterations in functional connectivity of the amygdala and hippocampus in individuals with posttraumatic stress disorder (PTSD) using a multicohort mega-analysis with uniform processing steps and parameters across all cohorts. Methods: Resting-state functional MRI data from 1,017 PTSD patients and 1,702 control participants from 32 international sites were centrally preprocessed with HALFpipe and analyzed using the Image-Based Meta- and Mega-Analysis (IBMMA) package for neuroimaging processing. Group-level seed-based whole-brain analyses were completed for the right and left amygdala and hippocampus. Additional correlation analyses were conducted between PTSD norm-severity scores and resting-state functional connectivity (rs-FC). Results: Compared to control participants, individuals with PTSD showed stronger rs-FC between the left amygdala seed and right hippocampus and amygdala and the left and right lingual gyri. Greater PTSD total norm-severity scores were significantly associated with rs-FC between the left amygdala and right hippocampus/amygdala and rs-FC between the right amygdala and left hippocampus/amygdala. Conclusions: Greater connectivity between subcortical threat centers involved in fear processing, memory, and extinction learning characterizes the resting state in PTSD. Future directions include investigating how different interventions, such as brain stimulation, neurofeedback, and psychotherapy, might modulate the aberrant neural networks in PTSD.

Sleep quality (SQ) is associated with cognitive performance; however, it remains unclear if this association is causal, and consequently, whether SQ is a modifiable risk factor for cognitive aging. Leveraging data from the Vietnam Era Twin Study of Aging (VETSA; N =1036, Mage =67.46, range=61.37-72.13, 304 monozygotic (MZ) pairs, 214 dizygotic (DZ) pairs), we investigated the causal relationship between sleep and cognition, accounting for genetic and shared environmental confounding. Using a Co-Twin Control (CTC) design, we examined whether sleep-cognition associations reflect causal effects versus genetic and environmental confounding, leveraging that MZ twins share 100% of genes while DZ twins share 50%. Measures included sleep quality (Pittsburgh Sleep Quality Index total score), general cognitive ability (GCA), and factor scores across episodic memory, visual-spatial memory, executive function, fluency, and processing speed. SQ-cognition associations were decomposed into between-pair effects (comparing twin pair averages) and within-pair effects (comparing co-twins) to capture familial confounding versus potential causal effects. At the individual level, poorer SQ predicted worse performance (β = -0.02 to -0.03, all ps <.05). Within-pair effects (β = -0.02 to -0.05, all ps <.05) indicated the twin with poorer SQ performed worse, showing stronger effects in DZ (β = -0.02 to -0.06) than MZ twins (β = -0.001 to -0.02), except for processing speed. Weaker within- than between-pair effects suggested partial genetic confounding. Potential causation was observed for SQ-GCA and SQ-visual-spatial relationships as effects persisted regardless of genetic relatedness. SQ-episodic memory and SQ-semantic fluency associations suggested both sources of confounding as effects were only observed in the full sample. The remaining domains suggested genetic confounding as effects dissipated with increasing genetic relatedness. Poorer SQ is associated with worse cognitive performance, though the relationship is complex. In some domains, poorer sleep may causally impact cognition, independent of genetic relatedness, albeit effects are small. In others, associations may reflect sources of confounding, with disrupted sleep and cognition representing symptoms of shared neurodegenerative or pathological processes. These findings emphasize the need for a nuanced approach to determine when sleep interventions may be most effective. NIH/NIA grants R01AG050595 & R01AG076838.

Genetic and environmental factors contribute to weight gain, but how these effects change over adulthood is largely unknown. We examined how genetic factors influence BMI changes from young adulthood to old age and how this change relates to BMI in early adulthood. Data from 16 longitudinal twin cohorts, including 111,370 adults (56

Concerns about memory often increase with age and have been suggested as a precursor to impending memory impairment or dementia. However, subjective memory concern (SMC) has also been shown to reflect an individual’s trait-like tendency to worry about memory, which is more strongly linked to negative affect than to objective memory performance. Despite behavioral evidence supporting a trait-like dimension of SMC, its neuroanatomical underpinnings remain underexplored. In 477 community-dwelling dementia-free men (56–72 years old), we investigated the association between SMC and cortical mean diffusivity (cMD)—a diffusion MRI-based metric of gray matter microstructural integrity—generating a brain-wide map of their association. Self-report trait anxiety and depressive symptoms were collected, along with objective memory scores based on three neuropsychological tasks for which brain maps of their association with cMD were also generated. Finally, we conducted spatial correlational analyses to compare the spatial patterns of these brain association maps to assess whether there were significant spatial resemblances between each. We found that the gray matter integrity correlates of SMC spatially resembled those of depressive symptoms and trait anxiety but not those of objective memory. The spatial correspondences between gray matter integrity correlates of negative affect measures and SMC were significantly stronger than those between SMC and objective memory. Together, these results suggest a neuroanatomical basis of trait-like SMC, which should be distinguished from state-related SMC that may be a precursor of objective memory deficits in research and clinical settings.

BACKGROUND:The impact of chronic pain and opioid use on cognitive decline and mild cognitive impairment (MCI) is unclear. We investigated these associations in early older adulthood, considering different definitions of chronic pain. METHODS:Men in the Vietnam Era Twin Study of Aging (VETSA; n = 1,042) underwent cognitive testing and medical history interviews at average ages 56, 62, and 68. Chronic pain was defined using pain intensity and interference ratings from the SF-36 over 2 or 3 waves (categorized as mild versus moderate-to-severe). Opioid use was determined by self-reported medication use. Amnestic and non-amnestic MCI were assessed using the Jak-Bondi approach. Mixed models and Cox proportional hazards models were used to assess associations of pain and opioid use with cognitive decline and risk for MCI. RESULTS:Moderate-to-severe, but not mild, chronic pain intensity (β = -.10) and interference (β = -.23) were associated with greater declines in executive function. Moderate-to-severe chronic pain intensity (HR = 1.75) and interference (HR = 3.31) were associated with a higher risk of non-amnestic MCI. Opioid use was associated with a faster decline in verbal fluency (β = -.18) and a higher risk of amnestic MCI (HR = 1.99). There were no significant interactions between chronic pain and opioid use on cognitive decline or MCI risk (all p-values > .05). DISCUSSION:Moderate-to-severe chronic pain intensity and interference related to executive function decline and greater risk of non-amnestic MCI; while opioid use related to verbal fluency decline and greater risk of amnestic MCI. Lowering chronic pain severity while reducing opioid exposure may help clinicians mitigate later cognitive decline and dementia risk.

The amyloid cascade hypothesis predicts that amyloid-beta (Aβ) aggregation drives tau tangle accumulation. We tested competing causal and non-causal hypotheses regarding the direction of causation between Aβ40 and Aβ42 and total Tau (t-Tau) plasma biomarkers. Plasma Aβ40, Aβ42, 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 Aβs and t-Tau. No clear evidence that Aβ40 or Aβ42 directly causes t-Tau was observed. Instead, the alternative causal hypotheses also fit the data well. In contrast, exploratory analyses suggested a causal impact of the Aβ biomarkers on NFL. Separately, reciprocal causation was observed between t-Tau and NFL. Plasma Aβ40 or Aβ42 do not appear to have a direct causal impact on t-Tau, though our use of total rather than phosphorylated tau was a limitation. In contrast, Aβ biomarkers appeared to causally impact NFL in cognitively unimpaired men in their late 60 s.

The increasing scale and complexity of neuroimaging datasets aggregated from multiple study sites present substantial analytic challenges, as existing statistical analysis tools struggle to handle missing voxel-data, suffer from limited computational speed and inefficient memory allocation, and are restricted in the types of statistical designs they are able to model. We introduce Image-Based Meta- & Mega-Analysis (IBMMA), a novel software package implemented in R and Python that provides a unified framework for analyzing diverse neuroimaging features, efficiently handles large-scale datasets through parallel processing, offers flexible statistical modeling options, and properly manages missing voxel-data commonly encountered in multi-site studies. IBMMA successfully analyzed a large-n dataset of several thousand participants and revealed findings in brain regions that some traditional software overlooked due to missing voxel-data resulting in gaps in brain coverage. IBMMA has the potential to accelerate discoveries in neuroscience and enhance the clinical utility of neuroimaging findings.

BACKGROUND:Traumatic brain injury (TBI) is associated with increased risk of dementia, but it is unclear how earlier life TBI is related to brain health in older age. METHODS:This cross-sectional study compared 517 male Vietnam Era Twin Study of Aging participants with and without a history of TBI (34 % with TBI; median age = 68 [range = 61-72] years). Validated brain age models were used to calculate predicted brain age difference (PBAD and Brain-PAD) scores. A multichannel segmentation approach was used to quantify abnormal white matter signal intensities (AWM). Restriction spectrum imaging (RSI) was used to model multishell diffusion in restricted (intracellular) and free water compartments. Multivariable linear mixed-effects models estimated associations of TBI with PBAD, Brain-PAD, AWM, and RSI outcomes. We assessed moderation in associations of TBI with PBAD, Brain-PAD, AWM, and RSI outcomes by apolipoprotein E epsilon 4 (APOE-ε4) status, depressive and posttraumatic stress symptom severity, and loneliness. RESULTS:PBAD, Brain-PAD, AWM, and global white matter RSI measures did not differ by TBI status but those with history of TBI showed lower restricted diffusion in the inferior longitudinal fasciculus bilaterally and the left inferior occipital fasciculus compared to those without TBI, after adjusting for age and scanner (p-values < 0.05). Results did not differ by APOE-ε4 status, psychiatric symptoms, or loneliness for any primary outcome. CONCLUSIONS:There may be subtle white matter microstructural changes after a TBI event that persist even after over four decades after initial injury. Further research is needed to determine if these differences relate to increased TBI-associated risk of dementia.

Early identification of Alzheimer’s disease (AD) risk prior to irreversible brain damage is critical for improving the success of interventions and treatment. Cortical thickness is a macrostructural measure typically used to assess AD neurodegeneration. However, cortical microstructural changes appear to precede macrostructural atrophy and may improve early identification of AD risk. Currently, whether cortical microstructural neurodegeneration in aging is linked to early vulnerability to AD pathophysiology remains unclear in non-clinical populations, who are precisely the target population for early risk identification. In 194 dementia-free community-dwelling adults, we calculated MRI-derived group-level brain maps of longitudinal changes in cortical mean diffusivity (microstructure) and cortical thickness (macrostructure) over 5-6 years (mean age: Time 1=61.82; Time 2=67.48). We obtained PET-derived group-level brain maps of stereotypical AD pathology deposition (beta-amyloid and tau) and density maps of neurotransmitter receptors (cholinergic, glutamatergic) implicated in AD pathophysiology. An MRI-derived map of cortical organization (sensorimotor-association axis) was used to probe general age-related changes. Spatial correlational analyses were used to compare pattern similarity among maps. We first examined whether changes in cortical microstructure and macrostructure are enriched in regions with increased accumulation of beta-amyloid and tau, and higher density of cholinergic and glutamatergic receptors. We then investigated whether individuals with more AD-like change profiles (spatially similar to beta-amyloid or tau deposition patterns) showed greater memory decline as measured by three well-established neuropsychological tests. Spatial patterns of cortical macrostructural changes only resembled patterns of cortical organization sensitive to general age-related processes (r=-0.31, p<0.05), whereas microstructural changes resembled stereotypical patterns of beta-amyloid (r=0.20, p=0.015) and tau (r=0.41, p=0.015) deposition in AD. Individuals with patterns of microstructural changes that more closely resembled stereotypical tau deposition exhibited greater memory decline (β=0.21, p=0.036). Moreover, microstructural changes and AD pathology deposition were enriched in areas with greater densities of cholinergic and glutamatergic receptors (ps<0.05). Patterns of cortical microstructural neurodegeneration were more AD-like than patterns of macrostructural neurodegeneration, which appeared to reflect more general aging processes. Microstructural changes may therefore better inform early risk prediction efforts as a sensitive measure of vulnerability to pathological processes prior to overt atrophy and cognitive decline.

Over 430 million people worldwide experience disabling hearing loss, a condition that becomes more prevalent with age. Although the genetic component to hearing loss has been well established, there has been less data available regarding changes in the genetic contributions to hearing loss over time. We report the pure tone hearing thresholds across 500, 1,000, 2,000, 4,000, and 8,000 Hz from over 1,000 male twins comprising monozygotic (MZ) and dizygotic (DZ) pairs sampled from the United States-based Vietnam Era Twin Study of Aging (VETSA). Twins were tested during three waves, at an average age of 56 at wave 1, an average age of 62 at wave 2, and an average age of 68 at wave 3. Genetically informed structural equation models were used to calculate the genetic contributions. Genetic factors accounted for between 49.4% and 67.7% of the variance in hearing acuity for all frequencies at all three time points. There was no substantial change in the ratio of genetic versus environmental contributions across the three time points, or across individual acoustic frequencies. The stability of hearing acuity over time was moderate to highly attributable to genetic factors. Change in hearing acuity was better explained by unique person-specific environmental factors. These results, from the largest-scale twin study of hearing acuity to date, replicate previous findings that hearing acuity in late life is significantly determined by genetic factors. The unique contribution of the present analysis is that the proportion of hearing acuity attributed to genetics remains relatively consistent across 12 years.

Visual short-term memory binding (VSTMB) requires efficient functional connectivity between cortical regions and is a sensitive behavioral marker of Alzheimer's disease (AD). VSTMB impairments have been detected in individuals with subjective cognitive decline (SCD) who perform normally on standard neuropsychological tests. Research has linked SCD to reduced integrity of the rostral-middle locus coeruleus (LC), an area that accumulates tau in early preclinical AD. Since the LC plays a crucial role in maintaining cortical efficiency, VSTMB may be similarly associated with LC integrity, particularly among those with SCD. Data were from cognitively unimpaired men in the Vietnam Era Twin Study of Aging ( N  = 350; mean age=72.9, SD=2.4) who completed a test of VSTMB, an LC-sensitive MRI scan, and the 39-item Everyday Cognition (ECog) scale; 274 participants also had informant ECog ratings. The VSTMB task employs a change detection paradigm and compares performance in shape-color binding (SCB) versus shape-only (SO) conditions (see Figure 1). Rostral-middle and caudal LC integrity was calculated as a contrast-to-noise ratio (LC-CNR) using a pontine tegmentum reference region. Mixed models regressed VSTMB accuracy across condition (SO, SCB) and set size (2, 3) within person, while testing main effects and interactions with LC-CNR and ECog. Models adjusted for age 20 cognitive ability, current age, depressive symptoms, and state anxiety. Sensitivity analyses adjusted for global performance on standard neuropsychological measures. VSTMB accuracy was lower on the SCB than SO condition (b=-1.08, p  = .001), especially at higher set sizes (b=-1.90, p  < .001). Higher participant-rated, but not informant-rated, SCD was associated with decreasing accuracy on SCB relative to the SO condition (b=-.253, p  = .007). Lower rostral-middle, but not caudal, LC-CNR was associated with poorer SCB accuracy relative to SO condition accuracy (b=7.10, p  = .010). Results remained significant after adjusting for global neuropsychological performance. Subtle losses in cognitive efficiency detected in cognitively unimpaired older adults on a VSTMB task were associated with SCD and LC integrity, even after accounting for performance on traditional neuropsychological tests. Given its role in modulating cortical efficiency through cognitive effort, reduced LC integrity may be associated with SCD when capacity for increasing compensatory effort to perform tasks is exceeded.

Background:Repeated cognitive testing can boost scores due to practice effects (PEs), yet it remains unclear whether PEs persist across multiple follow-ups and long durations. We examined PEs across multiple assessments from midlife to old age in a nonclinical sample. Method:Men (N=1,608) in the Vietnam Era Twin Study of Aging (VETSA) underwent neuropsychological assessment comprising 30 measures across 4 waves (~6-year testing intervals) spanning up to 20 years. We leveraged age-matched replacement participants to estimate PEs at each wave. We compared cognitive trajectories and MCI prevalence using unadjusted versus PE-adjusted scores. Results:Across follow-ups, a range of 7-12 tests (out of 30) demonstrated significant PEs, especially in episodic memory and visuospatial domains. Adjusting for PEs resulted in improved detection of cognitive decline and MCI, with up to 20% higher MCI prevalence. Conclusion:PEs persist across multiple assessments and decades underscoring the importance of accounting for PEs in longitudinal studies.