Group-level studies have highlighted the roles of aging, poor sleep, and brain atrophy in cognitive performance (CP) but have overlooked inter-individual variability. We predict CP from feature sets (demographic, subjective/objective sleep parameters, and regional brain morphometry) using multisite ENIGMA-Sleep data (n = 2,372). Linear and non-linear machine learning models were trained on the largest cohort (n = 845), and the best-performing models were validated on independent cohorts. Subsequently, based on the best-performing model on the largest cohort, we characterized feature importance and interactions across all cohorts. We observed that a combination of demographic, sleep, and brain parameters moderately predicted CP, with age emerging as the key predictor. Model explanations further suggested that age was the primary driver of prediction models, while sleep played a smaller role that varied across subgroups. These findings endorsed inter-individual variability and complex interaction between aging, sleep, brain, and CP.

Alzheimer disease (AD) has a strong genetic basis, yet previously derived polygenic risk scores (PRS) are heavily weighted by the APOE locus and perform inconsistently across diverse ancestries. We developed an APOE-independent multi-ancestry AD PRS using genome-wide association study summary statistics from cohorts in the United States, Europe and East Asia that were applied to European ancestry (EA), African American (AA), Caribbean Hispanic (CH), and East Asian cohorts from the Alzheimer's Disease Genetics Consortium. PRS performance was evaluated in the multi-ancestry Alzheimer's Disease Sequencing Project (ADSP) dataset and validated in several additional multi-ancestry cohorts. The PRS was significantly associated with AD in the ADSP EA, AA, CH, and Native American Hispanic groups with adjusted odds ratios (ORs) between 1.14 and 1.52 per standard deviation of the PRS. PRS performance was validated in the replication cohorts (ORs 1.21-1.65). The PRS was also associated with poorer memory, executive function, and language performance; greater AD-related neuropathological burden (including CERAD, Braak stage, and Thal phase scores); reduced hippocampal volume; lower CSF Aβ42; and elevated total tau and phosphorylated tau (p-tau), with stronger p-tau associations observed in women. Longitudinal analyses revealed that individuals in the highest PRS decile exhibited the steepest cognitive decline, particularly among those who progressed to AD. Our findings demonstrate the utility of an ancestry-aware and APOE-independent PRS for advancing understanding of the genetic basis of AD across diverse populations. Associations observed with early biological and cognitive changes and potential sex-specific differences support the incorporation of a PRS in clinical trials and personalized intervention and prevention strategies.

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.

INTRODUCTION:We addressed whether higher education plays a causal role in reducing dementia risk by comparing two indices of cognitive reserve: education and young adult general cognitive ability (GCA). METHODS:We conducted a 52-year survival analysis to examine associations of GCA and education with dementia in 16,619 male conscripts identified in Swedish national health registries born between 1936 and 1958 and with available data for models including midlife occupational complexity, physical activity, and socioeconomic status (SES). RESULTS:Higher GCA was associated with lower dementia risk (hazard ratio = 0.865, 95% confidence interval = 0.756 to 0.990). After accounting for GCA, no other measure contributed significantly to dementia risk. DISCUSSION:Putative reserve effects of education or occupational complexity likely reflect largely downstream effects of prior GCA. From a lifespan perspective on reducing dementia risk, the results may suggest favoring interventions aimed at enhancing cognitive development during childhood when there is substantial brain development as opposed to later-life cognitive training. HIGHLIGHTS:Education and GCA serve as indices of cognitive reserve. Education is a modifiable risk factor that is associated with dementia risk. The effect of higher education on reduced dementia risk is not directly causal. Education is largely a downstream effect of prior level of GCA. Increasing GCA during childhood may be more effective than later cognitive training.

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.

Sex chromosome trisomies (SCTs) are the most common whole-chromosome aneuploidy in humans. Yet, our understanding of the prevalence and associated health outcomes is largely driven by observational studies of clinically diagnosed individuals, resulting in a disproportionate focus on 47,XXY and associated hypogonadism. We analyzed microarray intensity data of sex chromosomes for 1.5 million individuals enrolled in three large cohorts-the Million Veteran Program, FinnGen, and UK Biobank-to identify individuals with 47,XXY, 47,XYY, and 47,XXX. We examined disease conditions associated with each SCT by performing phenome-wide association studies using electronic health records for each cohort, followed by meta-analysis across cohorts. We identified 2,769 individuals with SCTs (47,XXY: 1,319; 47,XYY: 1,108; and 47,XXX: 342), most of whom had no documented clinical diagnosis (47,XXY: 73.8%; 47,XYY: 98.6%; and 47,XXX: 93.6%). The identified phenotypic associations with SCT spanned all examined disease categories except neoplasms. Many associations are shared among three SCT subtypes, particularly for vascular diseases (e.g., chronic venous insufficiency [odds ratio (OR) (95% confidence interval [CI]) for 47,XXY: 4.7 (3.9,5.8), 47,XYY: 5.6 (4.5,7.0), and 47,XXX: 4.6 (2.7,7.6)]; venous thromboembolism [47,XXY: 4.6 (3.7-5.6), 47,XYY: 4.1 (3.3-5.0), and 47,XXX: 8.1 (4.2-15.4)]; and glaucoma [47,XXY: 2.5 (2.1-2.9), 47,XYY: 2.4 (2.0-2.8), and 47,XXX: 2.3 (1.4-3.5)]). A third sex chromosome confers an increased risk for systemic comorbidities, even if the SCT is not documented. SCT phenotypes largely overlap, suggesting that one or more X/Y homolog genes, possibly in the pseudoautosomal region, may underlie pathophysiology and comorbidities across SCTs.

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.

Sex chromosome trisomies (SCT) are the most common whole chromosome aneuploidy in humans. Yet, our understanding of the prevalence and associated health outcomes is largely driven by observational studies of clinically diagnosed cases, resulting in a disproportionate focus on 47,XXY and associated hypogonadism. We analyzed microarray intensity data of sex chromosomes for 1.5 million individuals enrolled in three large cohorts-Million Veteran Program, FinnGen, and UK Biobank-to identify individuals with 47,XXY, 47,XYY, and 47,XXX. We examined disease conditions associated with SCTs by performing phenome-wide association studies (PheWAS) using electronic health records (EHR) data for each cohort, followed by meta-analysis across cohorts. Association results are presented for each SCT and also stratified by presence or absence of a documented clinical diagnosis for 47,XXY. We identified 2,769 individuals with (47,XXY: 1,319; 47,XYY: 1,108; 47,XXX: 342), most of whom had no documented clinical diagnosis (47,XXY: 73.8%; 47,XYY: 98.6%; 47,XXX: 93.6%). The identified phenotypic associations with SCT spanned all PheWAS disease categories except neoplasms. Many associations are shared among three SCT subtypes, particularly for vascular diseases (e.g., chronic venous insufficiency (OR [95% CI] for 47,XXY 4.7 [3.9,5.8]; 47,XYY 5.6 [4.5,7.0]; 4 7,XXX 4.6 [2.7,7.6], venous thromboembolism (47,XXY 4.6 [3.7-5.6]; 47,XYY 4.1 [3.3-5.0]; 47,XXX 8.1 [4.2-15.4]), and glaucoma (47,XXY 2.5 [2.1-2.9]; 47,XYY 2.4 [2.0-2.8]; 47,XXX 2.3 [1.4-3.5]). A third sex chromosome confers an increased risk for systemic comorbidities, even if the SCT is not documented. SCT phenotypes largely overlap, suggesting one or more X/Y homolog genes may underlie pathophysiology and comorbidities across SCTs.

Multisite chronic pain is a risk factor for Alzheimer’s disease, but its relationship with Alzheimer’s pathology remains unclear. This study examines the association between multisite chronic pain and single-site chronic pain with cognitive decline and post-mortem Alzheimer’s biomarkers in older adults. We conducted a longitudinal and prospective observational study using data from 3459 participants without dementia at baseline in the Religious Orders Study and Rush Memory and Aging Project. Participants (mean age = 77.94, SD = 7.93 years) were followed for an average of 8.53 years (SD = 5.74), with cognitive assessments and post-mortem biomarker analyses in a subset of brain donors (n range from 863 to 987 based on assay quality and tissue preservation). Cognitive function was measured using repeated assessments of five cognitive domains and a global composite score. Chronic pain was classified based on self-reported pain, determined by the number of joint sites affected during the first two assessments: Multisite chronic pain was defined as chronic pain in more than one site, single-site chronic pain as chronic pain in one site, and no chronic pain as no chronic pain sites. Brain beta-amyloid (Aβ) load and tau tangle density were assessed post-mortem, ∼10 months after the last clinical evaluation. This was assessed as a global measure across eight Alzheimer’s-affected brain regions, as well as specifically in the entorhinal cortex and hippocampus. Apolipoprotein-ɛ4 genotype was determined from blood and tissue samples. Compared to individuals with single-site (n = 506) or no chronic pain (n = 2599), participants with multisite chronic pain (n = 354) showed steeper declines in global cognition, episodic memory and working memory—especially among those with higher apolipoprotein-ɛ4 load—and were more likely to develop Alzheimer’s dementia. Multisite chronic pain was also linked to increased Aβ deposition in the entorhinal cortex and hippocampus, particularly in apolipoprotein-ɛ4 carriers. Compared to people with no chronic pain, single-site chronic pain did not differ on rate of cognitive decline, Alzheimer’s dementia risk or post-mortem Alzheimer’s biomarkers. Multisite, but not single-site, chronic pain is linked to steeper cognitive decline and increased Aβ deposition, particularly in individuals with elevated Alzheimer’s genetic risk. These findings suggest that reducing pain may mitigate the risk of cognitive decline and dementia.

INTRODUCTION:An earlier age of menopause (AOM) is hypothesized to increase vulnerability to the neuropathological processes of dementia, which begin in midlife. METHODS:We tested this hypothesis in a sample of 10,832 women from the Swedish Twin Registry, stratified by menopause etiology. RESULTS:Survival models showed that a U-shaped association was present for women whose menopause occurred spontaneously. Sensitivity analyses conducted in hormone naïve, apolipoprotein E ε4+, and AOM restricted subsamples showed largely analogous patterns of results. DISCUSSION:Supporting conclusions from basic research, our results suggest that estrogens (proxied here by AOM) influence several biological pathways mediating dementia disease processes. In line with trends in hormone research across the past century, our findings challenge the oversimplified "more-is-better" perspective on hormone exposure and highlight the need for cross-disciplinary approaches to better understand the interacting endocrine and biopsychosocial factors that underlie the association between AOM and dementia pathogenesis. HIGHLIGHTS:We found a U-shaped association of timing of spontaneous menopause and dementia risk. We also found a negative linear association of age of induced menopause and dementia risk. Restriction to a hormone-naïve sample did not alter the pattern of results. Conducted exploration of the impact of common survival model parameter choices on results.

A polygenic score (PGS) for Alzheimer's disease (AD) was derived recently from data on genome-wide significant loci in European ancestry populations. We applied this PGS to populations in 17 European countries and observed a consistent association with the AD risk, age at onset and cerebrospinal fluid levels of AD biomarkers, independently of apolipoprotein E locus (APOE). This PGS was also associated with the AD risk in many other populations of diverse ancestries. A cross-ancestry polygenic risk score improved the association with the AD risk in most of the multiancestry populations tested when the APOE region was included. Finally, we found that the PGS/polygenic risk score captured AD-specific information because the association weakened as the diagnosis was broadened. In conclusion, a simple PGS captures the AD-specific genetic information that is common to populations of different ancestries, although studies of more diverse populations are still needed to better characterize the genetics of AD.

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.

Alzheimer's Disease (AD) and traumatic brain injuries (TBI) are frequently associated in medical literature, with a significant prevalence of TBI history observed among individuals diagnosed with AD. Our investigation focuses on this intersection, explicitly examining the risk of AD in individuals with a history of TBI. While current targets in cerebrospinal fluid and plasma can effectively detect acute TBI, the challenge lies in identifying biosignatures associated with TBI long after injury. Neuron-derived small extracellular vesicles (NEVs) from plasma offer potential biomarkers linked to neuronal dysfunction. Prior research has demonstrated that the AD-associated protein amyloid-beta (Aβ) is sequestered in NEVs, making them more sensitive biomarkers than free proteins in native plasma. To evaluate the effectiveness of NEV cargo proteins in predicting TBI exposure, we used plasma samples from the third wave of the Vietnam Era Twin Study of Aging (VETSA3). We hypothesized that previous exposure to TBI is associated with abnormalities in AD-related proteins in circulating NEVs. Participants in the VETSA3 study, comprising a community-based sample of male twins aged 61-73 (average 68), self-reported a 40% history of mild to moderate TBI. We precipitated NEVs from biobanked VETSA3 plasma samples and enriched them for the neuronal-specific protein L1CAM using magnetic immunocapture and fluorescence-activated cell sorting. Following the International Society of Extracellular Vesicles’ guidelines, we characterized NEVs for size, integrity, and homogeneity using NanoSight and ELISA. We quantified AD neuropathogenic proteins Aβ40–42, tau, p-tau, and Nf-L in NEVs using SIMOA assays. Our analyses explored the influence of TBI characteristics (number, age at occurrence, severity) on NEV cargo compared to non-TBI individuals, assessing their utility as potential biomarkers. NEVs derived from VETSA3 plasma demonstrated similar size distributions and shape characteristics required for cargo analysis. The outcomes of the ELISA validated the presence of the NEV marker protein Flotillin-1. A significant variation was observed in several neuropathogenic proteins, demonstrating the relationship between TBI exposure and AD. Our findings give insight into TBI as a risk factor for AD and the role of NEV cargo proteins as potential clinical biomarkers of neurodegeneration.

The locus coeruleus (LC) is one of the earliest sites of tau accumulation and integrity of the rostral-middle LC may be a particularly early marker of AD-related changes. LC dysfunction may also promote further pathological accumulation. We examined relationships between LC integrity and plasma phospho-tau (pTau) and the astrocytic marker glial fibrillary acidic protein (GFAP), and whether baseline LC integrity moderates subsequent change in biomarker levels. Participants were 669 men from waves 3 and 4 of the Vietnam Era Twin Study of Aging (VETSA) (wave 3 age=67.423 [SD=2.59], follow-up interval=5.52 years [SD=0.39]). All were cognitively unimpaired at wave 3. Linear mixed effects models tested concurrent and longitudinal relationships between baseline MRI-assessed LC rostral-middle integrity and pTau231 and GFAP across level of genetic risk for AD (APOE-ε4+ versus APOE-ε4-). Covariates included storage time, testing site, and age. Age was positively associated with pTau231 (β=0.11, p=0.024) and GFAP levels (β=0.26, p<0.001). APOE-ε4+ carriers showed higher levels of GFAP compared non-carriers (β=0.23, p=0.011); APOE-ε4 groups did not differ in levels of pTau231 or LC integrity. Baseline LC integrity was not associated with concurrent biomarker levels in either APOE-ε4 group. In longitudinal analyses, pTau231 and GFAP increased from waves 3 to 4 (β=0.94, p=0.006, β=1.23, p<0.001, respectively). However, baseline LC integrity moderated the rate of increases, such that higher LC integrity at wave 3 was associated with less pTau231 accumulation (interaction β=-0.19, p=0.027) for both APOE-ε4 groups. Additionally, baseline LC integrity moderated change in GFAP from waves 3-4, and this effect significantly differed by APOE-ε4 status (3-way interaction β=-0.38, p=0.004). Effects of baseline LC integrity on biomarker change were specific to rostral-middle but not caudal regions. Wave 3 biomarker levels did not moderate longitudinal change in LC integrity. Results support the idea that higher baseline rostral-middle LC integrity is protective against factors that cause accumulation of pTau231 and GFAP. However, the nature of the moderating effect of LC integrity on change in GFAP may be dependent on APOE-ε4 status. Baseline biomarker levels did not moderate change in LC integrity over time, suggesting changes in LC may be an upstream event.

Low educational attainment is recognized as a modifiable risk factor for dementia. Despite the commonly accepted notion that greater educational attainment confers lower dementia risk, few family-based studies have investigated the causal bases for the association. Using data from seven twin samples from Sweden, Denmark, Australia, and the US participating in the IGEMS (Interplay of Genes and Environment in Multiple Studies) consortium ( N = 60,027, 10.92% with dementia), we tested whether twins who achieve higher education than their co-twins have lower risk of dementia. The primary analysis applied a multilevel between-within regression framework, supported by descriptive statistics of within-pair differences. Results confirmed an overall association between educational attainment and dementia risk, such that individuals with higher educational attainment had less likelihood of developing dementia (phenotypic regression coefficient = -0.68, p <.0001). Within twin pairs, however, twins who achieved greater education than their co-twins did not uniformly show lower dementia risk (within-family regression coefficient = -0.07, p =.0983, while between-family regression coefficient = -0.98, p <.0001). Taken together, the pattern of results shows that the effect of educational attainment on dementia risk is largely attributable to genetic influences in common to educational attainment and dementia, although there are also contributions from environmental influences shared between members of the same family. Results were similar in men and women. These findings add to the literature by using a co-twin control design to address possible reasons that low educational attainment is associated with greater dementia risk.

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.