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INTRODUCTION: The contribution of neuropsychological assessments to risk assessment for incident dementia is underappreciated. METHODS: We analyzed neuropsychological testing results in dementia‐free participants in the Atherosclerosis Risk in Communities (ARIC) study. We examined associations of index domain–specific neuropsychological test performance with incident dementia using cumulative incidence curves and Cox proportional hazards models. RESULTS: Among 5296 initially dementia‐free participants (mean [standard deviation] age of 75.8 [5.1] years; 60.1% women, 22.2% Black) over a median follow‐up of 7.9 years, the covariate‐adjusted hazard ratio varied substantially depending on the pattern of domain‐specific performance and age, in an orderly manner from single domain language abnormalities (lowest risk) to single domain executive or memory abnormalities, to multidomain abnormalities including memory (highest risk). DISCUSSION: By identifying normatively defined cognitive abnormalities by domains based on neuropsychological test performance, there is a conceptually orderly and age‐sensitive spectrum of risk for incident dementia that provides valuable information about the likelihood of progression. Highlights: Domain‐specific cognitive profiles carry enhanced prognostic value compared to mild cognitive impairment.Single‐domain non‐amnestic cognitive abnormalities have the most favorable prognosis.Multidomain amnestic abnormalities have the greatest risk for incident dementia.Patterns of domain‐specific risks are similar by sex and race. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Many neurocognitive evaluations involve auditory stimuli, yet there are no standard testing guidelines for individuals with hearing loss. The ensuring speech understanding (ESU) test was developed to confirm speech understanding and determine whether hearing accommodations are necessary for neurocognitive testing. METHODS: Hearing was assessed using audiometry. The probability of ESU test failure by hearing status was estimated in 2679 participants (mean age: 81.4 ± 4.6 years) using multivariate logistic regression. RESULTS: Only 2.2% (N = 58) of participants failed the ESU test. The probability of failure increased with hearing loss severity; similar results were observed for those with and without mild cognitive impairment or dementia. DISCUSSION: The ESU test is appropriate for individuals who have variable degrees of hearing loss and cognitive function. This test can be used prior to neurocognitive testing to help reduce the risk of hearing loss and compromised auditory access to speech stimuli causing poorer performance on neurocognitive evaluation. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Non‐Hispanic Black, compared to non‐Hispanic White, older adults are at increased risk for dementia. This may be due partly to greater exposure to psychosocial stressors, such as discrimination; however, few studies have examined this association. METHODS: We examined the association of perceived discrimination (e.g., everyday, lifetime, and discrimination burden) with dementia risk in 1583 Black adults co‐enrolled in the Atherosclerosis Risk in Communities (ARIC) Study and the Jackson Heart Study (JHS). Perceived discrimination (defined continuously and using tertiles) was assessed at JHS Exam 1 (2000–2004; mean age ± SD:66.2 ± 5.5) and related to dementia risk through ARIC visit 6 (2017) using covariate‐adjusted Cox proportional hazards models. RESULTS: Associations of perceived everyday, lifetime, and burden of discrimination with dementia risk were not supported in age‐adjusted models or demographic‐ and cardiovascular health‐adjusted models. Results were similar across sex, income, and education. DISCUSSION: In this sample, associations between perceived discrimination and dementia risk were not supported. Highlights: In Black older adults perceived discrimination not associated with dementia risk.Younger age and greater education linked to greater perceived discrimination.Older age and less education among factors associated with dementia risk.Factors increasing exposure to discrimination (education) are also neuroprotective. [ABSTRACT FROM AUTHOR]

Background: Free Water (FW), a Diffusion Tensor Imaging‐based biomarker kit has been demonstrated by the MarkVCID consortium to have excellent instrumental validity1. We sought to determine its clinical relevance by investigating association of FW with clinically meaningful aspects of vascular contributions to cognitive impairment and dementia (VCID) in the MarkVCID consortium cohort as well as 5 independent settings. Method: This study included individuals from the MarkVCID UH3 phase cohort2 (N = 523) and 5 independent legacy cohorts: University of California Davis Alzheimer Disease Research Center3 (ADRC UCD, N = 173), MarkVCID UH2‐ phase data from University of California San Francisco4 (UH2 UCSF, N = 182) and RUSH Alzheimer Disease Center5 (N = 302), Framingham Heart Study6,7 (FHS, N = 2902) and Atherosclerosis Risk in Communities8 (ARIC, N = 1837). Table 1 summarizes participants' characteristics. Our goal was to evaluate whether mean FW (mFW) computed within the white matter tissue as provided by the kit1 is cross‐sectionally associated with a composite measure of executive functions (EFC) derived from item‐response theory (IRT) generated score9,10, which incorporates scores from NACC Uniform Data Set Version 3 neuropsychological tests11. To test this hypothesis, a linear regression was used with EFC score as the dependent variable and mFW as the independent variable, adjusting for age, sex and education. In a second model, this model was additionally adjusted for presence of diabetes, smoking and hypertension to estimate the added contribution of mFW above vascular risk factors. Result: Higher mFW was associated with lower EFC scores (see Figure 1) in all the subject groups studied. In the MarkVCID cohort (ß = ‐3.54, p<0.0001), as well as in the five legacy cohorts (UH2 UCSF: ß = ‐3.54, p<0.0001, RUSH: ß = ‐1.905, p = 0.00597, ADRC: ß = ‐6.18, p<0.0001, FHS: ß = ‐4.06, p<0.0001, ARIC: ß = ‐1.24, p<0.0001). Adjusting for vascular risk factors did not significantly change these associations (p values< 0.01). Conclusion: Findings from this study indicated that mean FW is a sensitive biomarker of cognitive performances, providing strong evidence of the clinical rational of FW as a sensitive biomarker of WM injury in association with cognition for future observational studies and clinical trials in the context of VCID. [ABSTRACT FROM AUTHOR]

Introduction: We evaluated whether better cardiovascular health at midlife and improvement of cardiovascular health within midlife were associated with dementia risk. Methods: Two longitudinal population‐based studies were used: Atherosclerosis Risk in Communities (ARIC) (n = 11,460/visits at ages 54 and 60), and Age, Gene/Environment Susceptibility (AGES)‐Reykjavik (n = 3907/visit at age 51). A cardiovascular health score (range 0–12/0–14, depending on diet availability) including six/seven items was calculated at each visit, with weight assigned to each item as poor (0), intermediate (1), or ideal (2). Cardiovascular health was defined as low (score 0–4/0–5), intermediate (5–7/6–9), or high (8–12/10–14). Incident dementia was ascertained through linkage to health records and with neuropsychological examinations. Results: Midlife high compared to low cardiovascular health (hazard ratios [HRs]: for ARIC: 0.60 [95% confidence interval: 0.52, 0.69]); for AGES‐Reykjavik: 0.83 [0.66, 0.99] and improvement of cardiovascular health score within midlife (HR per one‐point increase: ARIC: 0.94 [0.92, 0.96]) were associated with lower dementia risk. Discussion: Better cardiovascular health at midlife and improvement of cardiovascular health within midlife are associated with lower dementia risk. Highlights: Cardiovascular health and dementia were studied in two large cohort studies.Better cardiovascular health at midlife relates to lower dementia risk.Improvement of cardiovascular health within midlife relates to lower dementia risk.Promotion of cardiovascular health at midlife can help to reduce dementia risk. [ABSTRACT FROM AUTHOR]

Introduction: We studied the replication and generalization of previously identified metabolites potentially associated with global cognitive function in multiple race/ethnicities and assessed the contribution of diet to these associations. Methods: We tested metabolite‐cognitive function associations in U.S.A. Hispanic/Latino adults (n = 2222) from the Community Health Study/ Study of Latinos (HCHS/SOL) and in European (n = 1365) and African (n = 478) Americans from the Atherosclerosis Risk In Communities (ARIC) Study. We applied Mendelian Randomization (MR) analyses to assess causal associations between the metabolites and cognitive function and between Mediterranean diet and cognitive function. Results: Six metabolites were consistently associated with lower global cognitive function across all studies. Of these, four were sugar‐related (e.g., ribitol). MR analyses provided weak evidence for a potential causal effect of ribitol on cognitive function and bi‐directional effects of cognitive performance on diet. Discussion: Several diet‐related metabolites were associated with global cognitive function across studies with different race/ethnicities. Highlights: Metabolites associated with cognitive function in Puerto Rican adults were recently identified.We demonstrate the generalizability of these associations across diverse race/ethnicities.Most identified metabolites are related to sugars.Mendelian Randomization (MR) provides weak evidence for a causal effect of ribitol on cognitive function.Beta‐cryptoxanthin and other metabolites highlight the importance of a healthy diet. [ABSTRACT FROM AUTHOR]

Background: Hearing loss is associated with greater cognitive decline and incident dementia. Whether hearing intervention could reduce cognitive decline in older adults with hearing loss is unknown. Method: The ACHIEVE study is a randomized trial (NCT03243422) of 70‐84 year‐old adults with untreated hearing loss and free from substantial cognitive impairment that took place at four U.S. sites. Participants were recruited from two study populations: 1) a group of adults participating in a longstanding observational study of cardiovascular health (Atherosclerosis Risk in Communities [ARIC] study), and 2) a group of healthy de novo community volunteers. Participants were randomised (1:1) to hearing intervention (HI; audiological counseling and provision of hearing aids) or a successful aging health education control intervention (SA; sessions with a health educator on chronic disease prevention). The primary intention‐to‐treat endpoint was 3‐year change in a global cognition standardized factor score from a comprehensive neurocognitive battery. Result: 977 participants (238 ARIC, 739 de novo) underwent randomisation; 490 were assigned to HI and 487 to SA control. Participants from ARIC were older, had more risk factors for cognitive decline, and had lower baseline cognitive scores than the de novo group. In the primary analysis combining the ARIC and de novo groups, 3‐year cognitive change (in S.D. units) was not significantly different between HI and SA control (HI: ‐0·200 [95% CI: ‐0·256,‐0·144]; SA: ‐0·202 [‐0·258,‐0·145]; Difference 0·002 [‐0·077,0·081],p = 0·96). However, prespecified analyses demonstrated significant differences in the effect of HI on cognitive change between the ARIC and de novo group (p interaction = 0·010). In the ARIC group, HI was associated with a 48% reduction in 3‐year cognitive change compared to SA control (HI: ‐0·211 [‐0·349,‐0·073]; SA: ‐0·402 [‐0·536, ‐0·267]; Difference 0·191 [0·022,0·360,p = 0·027]). In the de novo group, cognitive change was not significantly different between HI and SA control (HI: ‐0·213 [‐0·277,‐0·148]; SA: ‐0·151 [‐0·215,‐0·087]; Difference ‐0·061 [‐0·151,0·028,p = 0·18]). The rate of cognitive change among control participants was observed to be 2.7‐fold faster in the ARIC versus de novo group. Conclusion: Hearing intervention may have a significant effect on reducing cognitive change over 3 years in populations of older adults at increased risk for cognitive decline. [ABSTRACT FROM AUTHOR]

Background: Although amyloid deposition in the brain is often associated with subsequent dementia risk, not everyone with brain amyloid will develop dementia. This discrepancy illustrates the potential importance that risk factors and lived experiences may have in modifying this association. Compared to participants with low social engagement (SE) in mid‐life, we hypothesized that participants with high mid‐life SE will show a weaker association between amyloid burden and incident dementia. Method: We included data from 310 non‐demented participants of the Atherosclerosis Risk in Communities (ARIC)‐PET study. Social support and isolation were assessed via interviewer‐administered questionnaires (Visit 2; 1990 – 1992). Based upon categorization of both factors, participants were classified as having high, intermediate, or low mid‐life SE (Table 1). Brain amyloid was evaluated with florbetapir PET (Visit 5; 2011‐2014). Elevated amyloid burden was defined as standardized uptake value ratio (SUVR) >1.2 in the global cortex. Incident dementia cases were identified from visit 5 through 2019 through ongoing surveillance utilizing in‐person neurocognitive testing, informant interviews, and hospitalization codes. Relative contributions of mid‐life SE and elevated florbetapir SUVR to incident dementia, independently and with multiplicative interaction terms, were evaluated with Cox regression models, adjusted for demographics, APOEε4 and vascular risk factors Result: Among 310 participants, 48 developed dementia (median follow‐up: 4.7 years). Mid‐life SE and elevated SUVR each independently predicted dementia risk but did not interact on a multiplicative scale. Participants with high or intermediate mid‐life SE, relative to low mid‐life SE, were less likely to develop dementia (Table 2). Although the interaction between mid‐life SE and elevated SUVR was not significant, stratified models suggested a stronger association between amyloid burden and dementia in participants with high mid‐life SE (Table 3). Conclusion: Greater mid‐life SE was associated with lower odds of developing dementia, independent of elevated SUVR. Although protective, there was no strong evidence for effect modification of mid‐life SE on the association between amyloid and dementia risk. Future longitudinal studies evaluating the potential influence of social factors measured throughout the life course are needed to inform our understanding as to what factors may preserve cognition in the presence of elevated brain pathology. [ABSTRACT FROM AUTHOR]

Background: Genome‐wide association studies (GWAS) of brain volumes have identified common genetic variants with modest effect sizes that lie mainly in non‐coding regions. We sought to identify low frequency and rare variants influencing brain volumes by performing association analyses using whole‐genome sequence data from the Trans‐Omics for Precision Medicine (TOPMed) Program. Method: We analyzed up to 7,607 participants (57% women; 62% European ancestry, 21% African‐Americans, 15% Hispanic/Latino, 2% Chinese‐American), mean age of 60.5 (16.2), from eight TOPMed population‐ or family‐based studies (FHS, GENESTAR, CHS, GENOA, ARIC, CARDIA, MESA, and SAFS). We excluded participants with dementia, stroke, presence of large brain infarcts, tumor or low‐quality scans. We tested the association of hippocampal (HV), total brain (TBV), lateral ventricular (LVV) and intracranial (ICV) volumes to individual genetic variants with minor allele counts ≥ 15 using mixed‐effect linear regression models adjusted for age, age2, sex, study and the first 10 principal components. Models for HV, TBV and log(LVV) were adjusted for ICV. We accounted for relatedness using an empirical kinship matrix and trait variance variability by using a random effect for study. Result: We detected one novel region with low frequency variants associated with HV (13q14, P = 5.8×10−9). The top 13q14 variant for HV (rs115674829) minor allele frequency (MAF) was 2% in our pooled sample but was more common in the pan‐African 1000 Genomes population (MAF = 14%). This variant lies in LINC00598 at 237kb from FOXO1, a member of the forkhead family of transcription factors that has been linked to Alzheimer's Disease. Additionally, we detected new suggestive associations (P≤10−7) for TBV (16p11) and LVV (1q25, 2q22, 3q13, 5q14, and 10q23), including common variants. Finally, we confirmed the association of common variants in GWAS loci for all traits. Conclusion: Our whole genome sequence analyses revealed intriguing new loci of low‐frequency and common variants, and replicated loci previously associated with brain volumes. Future work will include ancestry‐specific and conditional analyses, as well as gene‐based and scan tests. Supported by: AG058589, AG052409, AG054076, NO1‐HC‐25195, HHSN268201500001I and 75N92019D00031, R01HL131136, P30 AG066546, and K99AG066849. [ABSTRACT FROM AUTHOR]

Introduction: Hearing impairment is associated with poor cognitive test performance in older adults. However, hearing's impact on cognitive test completion is poorly described, and missing cognitive data due to hearing impairment could misestimate the association. Methods: We investigated if hearing impairment is associated with missing neurocognitive scores in 3678 adults (72‐94 years). Hearing impairment was defined by the better‐ear pure tone average of speech‐frequency thresholds (0.5‐4 kHz) >25 decibels. Results: Hearing impairment was associated with greater missingness on all auditory‐only tests, including Logical Memory (prevalence ratio [PR] comparing ≥ moderate impairment vs normal hearing:1.68, 95% confidence interval [CI] 1.26, 2.25) and Digits Backwards (PR 1.62; 95% CI 1.21, 2.17); and two non‐auditory tests, Boston Naming (PR 1.61; 95% CI 1.21, 2.17) and Trail Making B (PR 1.55; 95% CI 1.29, 1.86). Models that imputed missing cognitive scores showed the strongest hearing‐cognition associations. Discussion: Older adults with hearing impairment are less likely to complete cognitive testing, thereby underestimating the hearing impairment‐cognition relationship. [ABSTRACT FROM AUTHOR]

Introduction: Head injury is associated with significant morbidity and mortality. Long‐term associations of head injury with dementia in community‐based populations are less clear. Methods: Prospective cohort study of 14,376 participants (mean age 54 years at baseline, 56% female, 27% Black, 24% with head injury) enrolled in the Atherosclerosis Risk in Communities (ARIC) Study. Head injury was defined using self‐report and International Classification of Diseases, Ninth/Tenth Revision (ICD‐9/10) codes. Dementia was defined using cognitive assessments, informant interviews, and ICD‐9/10 and death certificate codes. Results: Head injury was associated with risk of dementia (hazard ratio [HR] = 1.44, 95% confidence interval [CI] = 1.3‐1.57), with evidence of dose‐response (1 head injury: HR = 1.25, 95% CI = 1.13‐1.39, 2+ head injuries: HR = 2.14, 95% CI = 1.86‐2.46). There was evidence for stronger associations among female participants (HR = 1.69, 95% CI = 1.51‐1.90) versus male participants (HR = 1.15, 95% CI = 1.00‐1.32), P‐for‐interaction <.001, and among White participants (HR = 1.55, 95% CI = 1.40‐1.72) versus Black participants (HR = 1.22, 95% CI = 1.02‐1.45), P‐for‐interaction =.008. Discussion: In this community‐based cohort with 25‐year follow‐up, head injury was associated with increased dementia risk in a dose‐dependent manner, with stronger associations among female participants and White participants. [ABSTRACT FROM AUTHOR]

Introduction: Clinic‐based study samples, including the Alzheimer's Disease Neuroimaging Initiative (ADNI), offer rich data, but findings may not generalize to community‐based settings. We compared associations in ADNI to those in the Atherosclerosis Risk in Communities (ARIC) study to assess generalizability across the two settings. Methods: We estimated cohort‐specific associations among risk factors, cognitive test scores, and neuroimaging outcomes to identify and quantify the extent of significant and substantively meaningful differences in associations between cohorts. We explored whether using more homogenous samples improved comparability in effect estimates. Results: The proportion of associations that differed significantly between cohorts ranged from 27% to 34% across sample subsets. Many differences were substantively meaningful (e.g., odds ratios [OR] for apolipoprotein E ε4 on amyloid positivity in ARIC: OR = 2.8, in ADNI: OR = 8.6). Discussion: A higher proportion of associations differed significantly and substantively than would be expected by chance. Findings in clinical samples should be confirmed in more representative samples. [ABSTRACT FROM AUTHOR]

Background: Hearing loss is associated with cognitive decline and dementia. The ongoing ACHIEVE Study was the first randomized trial to test the effects of hearing treatment on three‐year cognitive change. The ACHIEVE – Brain Health Follow‐Up Study will extend follow‐up to six years post‐randomization to determine the long‐term and potentially nonlinear effects of hearing treatment vs. health education control with delayed treatment on dementia and cognitive decline. Methods: Participants will be recruited from the 977 participants enrolled in the ACHIEVE Study. After Year 3, hearing intervention participants will continue to receive hearing care and the control group will be offered the hearing intervention. Co‐primary study outcomes will be cognitive decline and a composite of incident mild cognitive impairment (MCI)/probable dementia. Secondary outcomes include domain‐specific cognitive decline, brain structural changes on magnetic resonance imaging (MRI), and other functional outcomes (e.g., physical activity, social isolation). Power analyses for the co‐primary outcomes assumed an annual attrition rate of 10% and an immediate, lagged, or cumulative treatment effect. Results: When comparing multi‐year cognitive decline (Table 1), in the scenario of a constant treatment effect that assumes a strong and immediate treatment effect, the benefit of extended follow‐up is not greater power, but additional information on the long‐term effects of hearing intervention. In a scenario of a lagged treatment effect, a two‐year lag in the treatment effect causes the Year 3 assessment to be severely underpowered (28%) but provides sufficient power (80%) at Year 6 despite attrition. In a scenario of a cumulative treatment effect that increases with time, analyses are similarly underpowered at Year 3 (65%) but not at Year 6 (82%). The same pattern is evident when estimating the power at Year 3 (57%) and Year 6 (80%) to detect incident MCI/probable dementia in a Cox regression model that assumes a protective hazard ratio of 0.70 (Figure 1). Conclusion: Across all non‐constant scenarios of potential treatment effect, six years of follow‐up increases precision and provides valuable information to better delineate long‐term cognitive trajectories. The ACHIEVE ‐ Brain Health Follow‐Up Study will be completed in 2025. [ABSTRACT FROM AUTHOR]

Background: Early life factors, such as birth weight (BW), may have long‐term health consequences, but the importance of these factors in dementia risk is poorly understood. Our objective was to prospectively examine the association of BW with dementia incidence over mid‐ to late‐adulthood in the ARIC study. We hypothesized that participants who report lower BW experience more incident dementia than participants who report normal BW, and this association may differ by race. Method: 10,789 participants who were dementia‐free at ARIC baseline (Visit 1: 1987‐1989; ages 45‐64) and followed through 2019 were included. Participants were asked their BW through standard interviews at Visit 4 (1996‐1998), but if unable to recall, they selected their BW category: low (<5.5 lbs.), medium (normal) (5.5‐9.0 lbs.), or high (>9.0 lbs.), and to identify if they were premature (yes/no). Adjudicated dementia cases from baseline through 2019 were classified using in‐person cognitive evaluations, informant interviews, and phone assessments as well as hospitalization codes and death certificate codes. The associations between having high or low (vs medium) BW and dementia, or premature birth status and dementia were investigated using Cox proportional hazards models, with testing for interaction by race. Result: Our overall population was 54 yo at baseline, 56% female, and 20% Black; 2,255 dementia cases were identified over a median of 28.2 years. Participants who reported a low BW had 1.2 times (95% CI 1.02, 1.41) increased risk of incident dementia compared to those with medium BW in demographic‐ and APOE‐adjusted models (Table 1). This association was no longer significant when the model additionally adjusted for vascular risk factors. The risk for dementia was not increased among participants who reported having been born premature (vs not premature). When stratified by race, the risk of incident dementia was elevated in Black participants reporting high (vs medium) BW, but not in White participants reporting high BW (p‐interaction = 0.006) (Table 2). Conclusion: In this cohort, low BW was associated with risk of dementia in minimally adjusted models. The association was attenuated after accounting for vascular risk factors. High BW was associated with risk of dementia in Black participants only. [ABSTRACT FROM AUTHOR]

Background: Genome‐wide association studies (GWAS) conducted primarily in populations of European ancestry have revealed the polygenic nature of cognitive abilities [1, 2] but genetic discoveries in other populations, including Hispanics/Latinos, are lagging. Genetically, US Hispanics/Latinos have uniquely admixed genomes, encompassing African, Amerindian, and European ancestries.[3] Admixture patterns in genomic regions (local ancestry) can be leveraged in gene mapping when frequencies of trait‐associated genetic variants located within these regions differ between ancestries. Method: We conducted genome‐wide admixture mapping analyses followed by fine mapping to identify genetic variants associated with cognitive function in 7,140 Hispanic and Latino adults (mean age 55 years; 60.5% women) from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). Five measures of cognitive function were investigated: Six‐Item Screener (SIS), Brief Spanish English Verbal Learning Test (SEVLT), Word Fluency Test (WFT), Digit Symbol Substitution Test (DSST), and a measure of general cognitive function (PC1). We tested the identified variants for replication in independent samples with similar neurocognitive measures. Result: We identified 9 significant local ancestry‐associated regions for the 5 cognitive tests. Counts of African ancestry on at 13q12.11, 4q14, 10p12.2 and 9p22.1 were associated with DSST, PC1, SIS, and WFT, respectively. Counts of Amerindian ancestry at 1q25.2 were associated with DSST; and at 12q14.2 and 12q15 with SIS. Counts of European ancestry at 8p22 were associated with SEVLT; and at 13q12.13 with, both, DSST and PC1. Fine mapping via SNP association testing in each region identified genetic variants that partially or totally explained the admixture signal. While statistical evidence of independent replication of the prioritized variants was generally weak, with only two replicated associations at chr8p22 and chr13q12.13, there was strong biological support for the observed associations to cognitive function. For example, the prioritized variant at 8q22 is an eQTL for CNOT7, which regulates synaptic plasticity and is essential for hippocampal‐dependent learning and memory [4]. Conclusion: Our admixture mapping analyses identified multiple novel loci associated with measures of cognitive function. This demonstrates the effectiveness of admixture mapping in complementing GWAS [5] and provides an opportunity to identify genetic loci that may be particularly relevant in underrepresented populations. [ABSTRACT FROM AUTHOR]

Background: A recent instrumental validation analysis positioned peak‐width of skeletonized mean diffusivity (PSMD) as a biomarker for vascular contributions to cognitive impairment and dementia (VCID) with excellent reliability, repeatability, and reproducibility. As the next step of biomarker development, the current study aimed to (1) perform a clinical validation of PSMD and cognitive function in MarkVCID and three independent replication samples, and (2) assess whether PSMD explains cognitive function above and beyond white matter hyperintensities (WMH). Method: The clinical validation of PSMD included n = 395 participants from the multi‐site MarkVCID consortium, n = 6172 from population‐based CHARGE cohorts, n = 287 from RUSH, and n = 435 from the UC Davis ADRC cohort spanning diverse ages and racial/ethnic backgrounds. PSMD was derived from DTI using an automated algorithm and further log‐transformed to normalize its distribution. A composite measure of general cognitive function was calculated from neuropsychological tests assessing at least three different cognitive domains. Linear regression models were run to determine the association between PSMD and cognitive function, adjusting for age, sex, and education. A secondary model was adjusted for vascular risk factors: hypertension, diabetes, and smoking. Lastly, both models included WMH volume to evaluate PSMD beyond WMH. Result: Higher PSMD values were associated with lower general cognitive function in the MarkVCID (Beta (95% CI), ‐0.82 (‐1.03, ‐0.61), p<0.001) in primary models, and remained unchanged after additional adjustment for vascular risk factors in secondary model (‐0.87 (‐1.09, ‐0.65), p<0.001). These findings were replicated across the CHARGE, RUSH, and UC Davis ADRC cohorts (Table 1). We further observed that PSMD explained an additional 0.2% of the variance in cognitive function beyond WMH in the youngest cohort (48.1 ±8.9 years), whereas the variance explained rose to 2.51% for the oldest cohort (76.4 ±5.2 years). Conclusion: This comprehensive clinical validation study suggests that PSMD is related to general cognition across diverse samples, potentially explaining more variation in cognitive function than a classic cerebrovascular marker such as WMH. Together, our instrumental and clinical validation studies support using PSMD as a robust biomarker with potential for risk stratification and disease monitoring in multi‐site clinical trials of VCID. Additional longitudinal validation studies are underway. [ABSTRACT FROM AUTHOR]

Background: Neurofilament light chain (NfL) levels in circulation have been established as a sensitive biomarker of neuro‐axonal damage across a range of neurodegenerative disorders. Elucidation of the genetic architecture of blood NfL levels and its genetic correlation with neurological traits could therefore provide new insights into shared molecular mechanisms underlying neurodegenerative disorders. Method: To identify the genetic variations underlying blood NfL levels, we conducted an ancestry‐specific meta‐analyses of genome‐wide association studies (GWAS) based on 18,532 participants from 11 cohorts of European and 1142 participants (3 cohorts) of African‐American ancestry. In the post‐GWAS analyses, we performed expression quantitative trait loci (eQTL) analysis, LD‐regression, and genetic risk score (GRS) association analysis with neurological traits. Result: In the European ancestry GWAS meta‐analysis, we identified two genome‐wide significant (P< 5×10−8) loci at 16p12 (UMOD), and 17q24 (SLC39A11). In the African‐American ancestry GWAS meta‐analysis, we identified three novel loci at 1q43 (FMN2), 12q14, and 12q21. Genetic correlation based on the European ancestry meta‐analysis with neurological traits showed a strong genetic correlation of NfL with Alzheimer's disease (AD) (rg = 0.32, P = 1.74×10−6), total‐tau (rg = 2.01, P = 1.03×10−6), amyloid‐beta (Aβ)‐40 (rg = 0.80, P = 6.92×10−6),and Aβ‐42 (rg = 1.03, P = 4.39×10−5). A higher genetic risk score based on NfL‐associated genetic variants was also related to increased plasma levels of total‐tau (P = 1.97×10−4), Aβ‐ 40 (P = 2.24×10−5), Aβ‐42 (P = 2.92×10−4) in the Rotterdam Study. Conclusion: This large‐scale GWAS meta‐analysis revealed multiple novel genetic loci of NfL levels in blood in participants from European and African‐American ancestry. Significant genetic correlation of genes underlying NfL with AD, Aβ‐42, and total‐tau may indicate a common underlying pathway of neurodegeneration. [ABSTRACT FROM AUTHOR]

Background: While plasma levels of several etiologically relevant molecules have been associated with Alzheimer's disease and dementia more broadly, information about the full range of changes in the plasma proteome that precede dementia is lacking. Accordingly, this study used modified aptamer technology (SOMAscan) to examine the relationship between the plasma levels of 4,877 proteins and risk for incident dementia in a large community‐based sample. Methods: Plasma levels of 4,877 proteins were measured in non‐demented participants who attended visit 5 of the Atherosclerosis Risk in Communities (ARIC) study (2011‐2013; Figure 1A). We examined the association of log2 protein levels with incident dementia risk over 5 years using Cox proportional hazard models adjusted for demographic and cardiovascular risk factors. Dementia‐associated proteins were then measured from plasma samples collected 18 years earlier (visit 3; 1993‐1995) and related to dementia risk between visits 3 and 5 (Figure 1B). Candidate proteins were related to measures of brain structure (by MRI) and amyloid burden (by PET). Ingenuity Pathway Analyses and Mendelian randomization were used to inform biological pathways and causal relationships. Results: Among 4,144 participants seen at visit 5 (age: 75 (SD 5)), there were 444 incident dementia cases over the next 5 years. In a proteome‐wide analysis, 50 proteins were significantly associated with incident dementia at a Bonferroni‐corrected threshold (P<1.03e‐05; Figure 2A). When these dementia‐associated proteins were measured in plasma collected almost 20 years earlier (n=11,069; 1,131 dementia cases), 21 of the 50 proteins continued to show a significant association with incident dementia (P<0.001; Figure 2B). We found causal associations with Alzheimer's disease for two of the top five dementia‐associated proteins using Mendelian randomization, and we demonstrated a relationship between protein levels and neuroimaging measures of atrophy, white matter disease, and cerebral amyloid. A systems‐level analysis of dementia‐associated proteins implicated biological mechanisms involved in metabolic and inflammatory signaling, coagulation and prothrombin activation, and innate immune function, among others (Figure 3). Conclusions: These findings provide insight into the plasma proteomic patterns that precede the onset of dementia in old age and middle age and highlight novel molecules and mechanistic pathways for further study. [ABSTRACT FROM AUTHOR]

Introduction: As hearing loss has been identified as an important risk factor for dementia, we aimed to assess the association between hearing loss and microstructural integrity of the brain. Methods: A total of 1086 dementia‐free participants (mean age = 75.2 [standard deviation: 4.9], 61.4% female) of the population‐based Atherosclerosis Risk in Communities (ARIC) study underwent hearing assessment (2016–2017) and magnetic resonance imaging of the brain (2011–2013). Microstructural integrity was determined with diffusion tensor imaging. Multivariable linear regression was used to investigate associations between hearing loss and microstructural integrity of different brain regions and white matter (WM) tracts. Results: Hearing loss was associated with lower WM microstructural integrity in the temporal lobe, lower gray matter integrity of the hippocampus, and with lower WM microstructural integrity of the limbic tracts and the uncinate fasciculus. Conclusion: Our results demonstrate that hearing loss is indepedently associated with lower microstructural integrity in brain regions that are important for different cognitive processes. [ABSTRACT FROM AUTHOR]

Background: Machine learning and artificial intelligence methods have been applied to brain images to estimate measures of brain aging. However, only rarely have these measures been examined in the context of biologic age. Here, we investigated associations of an MRI‐based measure of dementia risk the Alzheimer's disease pattern similarity (AD‐PS) scores with measures of longevity and biological age. Method: Participants were those from visit 5 of the Atherosclerosis Risk in Community Study with cognitive status adjudication and MRI available. The AD‐PS score was estimated based on previously reported machine learning methods. We evaluated associations of the AD‐PS score with all‐cause mortality. Participants were stratified by AD‐PS tertiles and the analyses were adjusted for age, race, sex, hypertension and smoking. AD‐PS score was examined in association with 32 proteins reported to be associated with age. In these analyses, we used Bonferroni correction (α = 0.05,p<0.0016). Finally, associations with a deficit accumulation index(DAI) based on 38 health items was investigated. In both cases, linear regression models were adjusted for age, race and sex. Sensitivity analyses using only cognitively normal (CN) individuals were performed. Result: Mortality – A total of 356 participants died within 8 years of follow‐up. The AD‐PS score was significantly associated(p<0.001) with time to all‐cause mortality. Participants in the lowest tertile had lower all‐cause mortality rate compared to those in the highest tertile (HR: 0.43;95% CI:0.31,0.60). The association remained significant when restricting the sample to only CN subjects (HR for lowest tertile:0.53; 95% CI:0.35,0.81, p = 0.0028). Age related proteins ‐ The AD‐PS scores were significantly associated (p<0.05, uncorrected) with 10 of the 32 proteins. Growth/differentiation factor 15(GDF‐15) and pleiotrophin remained significant after correction for multiple‐testing. Analysis of CN participants showed a subset of the same proteins to be significant (p<0.05,uncorrected) but only the GDF‐15 remained significant after correction for multiple‐testing. DAI ‐ A linear regression model showed a significant association between DAI and AD‐PS scores overall (coeff = 0.52; 95% CI:0.37‐0.67) and in the CN subset (coeff = 0.3,95% CI:0.13‐0.48). Conclusion: While the AD‐PS scores were created as a measure of dementia risk, our analyses suggest that they could also be capturing brain aging. [ABSTRACT FROM AUTHOR]

Background: A number of studies show an association between long‐term exposure to ambient particulate matter ≤ 2.5 um (PM2.5) and late‐life cognitive impairment. Mechanistic models suggest that PM2.5 may influence cognitive health through promotion of Alzheimer's disease, which is characterized by brain amyloid accumulation. However, the association between long‐term PM2.5 exposure and brain amyloid deposition remains poorly characterized in epidemiological studies. Method: We used data from the Atherosclerosis Risk in Communities (ARIC) study cohort. We used a chemical transport model with data fusion to estimate mean PM2.5 concentrations (ug/m3) in 36‐, 12‐, 4‐, and 1‐km grid cells in ARIC study areas. We linked the concentrations to geocoded participant addresses and calculated mean PM2.5 concentrations from 2000 to 2007. We estimated amyloid deposition using florbetapir amyloid positron emission tomography (PET) scans in 346 ARIC‐PET participants with normal cognition or mild cognitive impairment in 2011‐2014. We defined amyloid positivity as a global cortical standardized uptake value ratio (SUVR) ≥ the sample median of 1.2. We used logistic regression models to quantify the association between amyloid positivity and mean 2000‐2007 PM2.5 concentration after adjusting for potential confounders. We additionally explored effect measure modification by APOE e4 allele status and tested whether effect estimates were consistent using alternate PM2.5 exposure methods. Result: After restricting to participants with non‐missing exposure and confounder data and excluding one participant with dementia, the analytic sample included 279 participants. At the time of amyloid‐PET scans, their mean age was 78 years, 56% were female, 42% were Black, and 26% had mild cognitive impairment. After adjusting for age, sex, education, and race‐study center, we found no significant association between brain amyloid positivity and long‐term mean PM2.5 exposure. We also found no evidence of effect measure modification by APOE e4 allele status. Results were consistent when we used alternate PM2.5 estimation methods. Conclusion: Our findings suggest that ambient PM2.5 may induce neurotoxic effects through non‐amyloid, potentially vascular pathways, though we note the small sample size may have made us underpowered to detect a significant association. [ABSTRACT FROM AUTHOR]