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APOE ɛ4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE ɛ4+ (10 352 cases and 9207 controls) and APOE ɛ4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ɛ4 status. Suggestive associations (P

We investigated the genetic overlap between Alzheimer's disease (AD) and Parkinson's disease (PD). Using summary statistics (P-values) from large recent genome-wide association studies (GWAS) (total n=89 904 individuals), we sought to identify single nucleotide polymorphisms (SNPs) associating with both AD and PD. We found and replicated association of both AD and PD with the A allele of rs393152 within the extended MAPT region on chromosome 17 (meta analysis P-value across five independent AD cohorts=1.65 × 10(-7)). In independent datasets, we found a dose-dependent effect of the A allele of rs393152 on intra-cerebral MAPT transcript levels and volume loss within the entorhinal cortex and hippocampus. Our findings identify the tau-associated MAPT locus as a site of genetic overlap between AD and PD, and extending prior work, we show that the MAPT region increases risk of Alzheimer's neurodegeneration.

Leukocyte telomere length (LTL) is associated with a number of common age-related diseases and is a heritable trait. Previous genome-wide association studies (GWASs) identified two loci on chromosomes 3q26.2 (TERC) and 10q24.33 (OBFC1) that are associated

Comorbidites resulting in hospitalization are important to documentin persons developing dementia in order to better understandthe progression and burden of the disease. In this study we investigatedrates and predictors of hospitalizations in 3,602 participants ofthe Cardiovascular Health (CHS) Cognition Study evaluated for dementiaduring 1992-99. Hospitalizations were verified by medical orHCFA records. Unconditional logistic regression was used to estimatethe increased risk of hospitalization by cognitive status and forwardstepwise regression identified predictors. Average age of the cohortwas 75.1 years. Using data collected prospectively in the CHSincluding a cerebral MRI, 577 participants were classified with mildcognitive impairment (MCI), and 480 with incident dementia including245 with AD, 62 with VaD, and 151 with mixed dementia (bothAD and VaD). During 5.4 years of follow-up, more persons with cognitiveproblems were hospitalized: 64% with normal cognition, 75%with MCI, 77% with AD, 84% with mixed dementia and 98% of thosewith VaD (p < .001). Adjusted for age, gender and race, persons withdementia were more than twice as likely to be hospitalized (OR: 2.3,95% CI: 1.7-2.9) compared to those with normal cognition. Thosewith MCI were at a 70% increased risk of hospitalization (OR: 1.7,95% CI: 1.4-2.2). Persons hospitalized at least once were hospitalizedan average of 3.8 times during follow-up if classified with dementia(3.2 with AD, 4.6 with VaD) compared to 3.2 times for those withMCI and 2.7 times for those with normal cognition. The rate of totalhospitalization for those with normal cognition was 297 per 1000 person-years, 432 for persons with MCI and 1049 for incident dementiaincluding 842 for AD, 1690 for VaD, and 1120 for mixed dementia.Adjusted for age and cognition, predictors of hospitalization includedrace, gender, site, presence of cardiovascular disease, low ankle-armindex, difficulty with ADLs, greater carotid intima-media thickness,walking speed, self-perceived health, and weight. Because the num-berand length of hospitalizations increase as cognition declines, care-fulobservation and additional preventive care may help reduce this burden.

Although there is general agreement that the diagnosis of dementia reduces life expectancy, the estimated number of years for survival following the onset of dementia has been reported to vary from 3 to over 9 years. We examined mortality in 3602 participants of the Cardiovascular Health Cognition Study in four U.S. communities evaluated for dementia incidence between 1992 and 1999 and followed an average of 6.5 years. Alzheimer’s disease (AD) was determined using NINCDS–ADRDA criteria and vascular dementia (VaD) used ADDTC criteria. Average age of the cohort was 75.1 years. By June 2000, 33 of 62 (53.2%) participants with VaD had died compared to 79 of 245(32.2%) with AD, 66 of 151 (43.7%) with both AD and VaD, and 429 of 2318 (18.5%) with normal cognition. Using Cox proportional hazards regression with a time-dependent covariate for dementia status adjusted for age, gender and race, individuals with VaD were more than four times as likely to die during follow-up than those with normal cognitive status (HR: 4.4, 95% CI: 3.1–6.3). The hazard ratios were 2.1 (95% CI: 1.6–2.7) for AD and 2.5 (95% CI: 1.9–3.3) for both types. Individuals with VaD were more likely to die of cerebrovascular disease (42.4%) than those with AD (9.2%), both types (9.2%) or with normal cognition (7.5%). Accelerated life models estimated median survival from dementia onset to death as 3.8 years for those with VaD only, 6.8 years for those with AD only, and 5.2 years for those with both types of dementia.

Survival following the onset of dementia has been reported to vary from 3 to over 9 years. We examined mortality in 3602 participants of the Cardiovascular Health Cognition Study in four U.S. communities evaluated for dementia incidence between 1992-1999 and followed for 6.5 years. By June 2000, 33 of 62 (53.2%) participants who had developed VaD had died compared to 79 of 245 (32.2%) with AD, 66 of 151 (43.7%) with both AD and VaD, and 429 of 2318 (18.5%) with normal cognition. Using Cox proportional hazards regression with a time-dependent covariate for dementia status adjusted for age, gender and race, individuals with VaD were more than four times as likely to die during follow-up than those with normal cognition (HR: 4.4, 95% CI: 3.1-6.3). The hazard ratios were 2.1. (95% CI: 1.6-2.7) for AD and 2.5 (95% CI: 1.9-3.3) for both types. Adjusted accelerated life models estimated median survival from dementia onset to death as 3.9 years for those with VaD, 7.1 years for AD, and 5.4 years for those with both types of dementia.

Although caffeine can enhance cognitive function acutely, long-term effects of consumption of caffeine-containing beverages such as tea and coffee are uncertain. Data on 4,809 participants aged 65 and older from the Cardiovascular Health Study (CHS) were used to examine the relationship of consumption of tea and coffee, assessed by food frequency questionnaire, on change in cognitive function by gender. Cognitive performance was assessed using serial Modified Mini-Mental State (3MS) examinations, which were administered annually up to 9 times. Linear mixed models were used to estimate rates of change in standard 3MS scores and scores modeled using item response theory (IRT). Models were adjusted for age, education, smoking status, clinic site, diabetes, hypertension, stroke, coronary heart disease, depression score, and APOE genotype. Over the median 7.9 years of follow-up, participants who did not consume tea or coffee declined annually an average of 1.30 points (women) and 1.11 points (men) on standard 3MS scores. In fully adjusted models using either standard or IRT 3MS scores, we found modestly reduced rates of cognitive decline for some, but not all, levels of coffee and tea consumption for women, with no consistent effect for men. Caffeine consumption was also associated with attenuation in cognitive decline in women. Dose-response relationships were not linear. These longitudinal analyses suggest a somewhat attenuated rate of cognitive decline among tea and coffee consumers compared to non-consumers in women but not in men. Whether this association is causal or due to unmeasured confounding requires further study. [ABSTRACT FROM AUTHOR]

The heat shock protein (HSP) 70 family has been implicated in the pathology of Alzheimer's disease (AD). In this study, we examined common genetic variations in the 80 genes encoding HSP70 and its co-chaperones. We conducted a study in a series of 462 patients and 5238 unaffected participants derived from the Rotterdam Study, a population-based study including 7983 persons aged 55 years and older. We genotyped a total of 12,053 Single Nucleotide Polymorphisms (SNPs) using the HumanHap550K Genotyping BeadChip from Illumina. Replication was performed in two independent cohort studies, the Framingham Heart study (FHS; n = 806) and Cardiovascular Health Study (CHS; n = 2150). When adjusting for multiple testing, we found a small but consistent, though not significant effect of rs12118313 located 32 kb from PFDN2, with an OR of 1.19 (p-value from meta-analysis = 0.003). However this SNP was in the intron of another gene, suggesting it is unlikely this SNP reflects the effect of PFDN2. In a formal pathway analysis we found nominally significant evidence for an association of BAG, DNAJA and prefoldin with AD. These findings corroborate with those of a study of 2032 AD patients and 5328 controls, in which several members of the prefoldin family showed evidence for association to AD. Our study did not reveal evidence for a genetic variant if the HSP70 family with a major effect on AD. However, our findings of the single SNP analysis and pathway analysis suggest that multiple genetic variants in prefoldin are associated with AD. [ABSTRACT FROM AUTHOR]

Cardiovascular disease is prevalent in the Korean immigrants. Success of any health interventions depends heavily on our understanding of how health issues are perceived by the recipients. This study describes cardiovascular health perceptions using Photovoice, a qualitative methodology utilizing photography to initiate discussion, in multigenerational Korean immigrants (older adults, teenagers, children). Twenty Korean Americans (7 adults aged >or=50 years, 6 teenagers aged 13 to 19 years, 7 children aged 9 to 12 years) were recruited from the Korean communities in Seattle, Washington. Each subject was given a camera and asked to take 24 pictures of objects, scenes, and environments that represented their perceptions of cardiovascular health and related risk factors. Subjects were asked to pick 2 photos and present their thoughts about them in a tape-recorded group meeting. Key concepts were identified from the discussions. Themes identified promoting cardiovascular health included good diet, exercise, a clean environment, and spirituality. The themes identified as the risk factors for cardiovascular diseases included bad diet, smoking, pollution, and stress. Expression of the risk factors differed by the age group. The shared cultural background also influenced the perception of the risk factors. These observations support the findings that the culture and age-specific interventions may augment intervention effectiveness. [ABSTRACT FROM AUTHOR]

Context: Ginkgo biloba is widely used for its potential effects on memory and cognition. To date, adequately powered clinical trials testing the effect of G. biloba on dementia incidence are lacking.Objective: To determine effectiveness of G. biloba vs placebo in reducing the incidence of all-cause dementia and Alzheimer disease (AD) in elderly individuals with normal cognition and those with mild cognitive impairment (MCI).Design, Setting, and Participants: Randomized, double-blind, placebo-controlled clinical trial conducted in 5 academic medical centers in the United States between 2000 and 2008 with a median follow-up of 6.1 years. Three thousand sixty-nine community volunteers aged 75 years or older with normal cognition (n = 2587) or MCI (n = 482) at study entry were assessed every 6 months for incident dementia.Intervention: Twice-daily dose of 120-mg extract of G. biloba (n = 1545) or placebo (n = 1524).Main Outcome Measures: Incident dementia and AD determined by expert panel consensus.Results: Five hundred twenty-three individuals developed dementia (246 receiving placebo and 277 receiving G. biloba) with 92% of the dementia cases classified as possible or probable AD, or AD with evidence of vascular disease of the brain. Rates of dropout and loss to follow-up were low (6.3%), and the adverse effect profiles were similar for both groups. The overall dementia rate was 3.3 per 100 person-years in participants assigned to G. biloba and 2.9 per 100 person-years in the placebo group. The hazard ratio (HR) for G. biloba compared with placebo for all-cause dementia was 1.12 (95% confidence interval [CI], 0.94-1.33; P = .21) and for AD, 1.16 (95% CI, 0.97-1.39; P = .11). G. biloba also had no effect on the rate of progression to dementia in participants with MCI (HR, 1.13; 95% CI, 0.85-1.50; P = .39).Conclusions: In this study, G. biloba at 120 mg twice a day was not effective in reducing either the overall incidence rate of dementia or AD incidence in elderly individuals with normal cognition or those with MCI. Trial Registration clinicaltrials.gov Identifier: NCT00010803. [ABSTRACT FROM AUTHOR]

Background: Telomere length reflects biological aging and may be influenced by environmental factors, including those that affect inflammatory processes.Objective: With data from 840 white, black, and Hispanic adults from the Multi-Ethnic Study of Atherosclerosis, we studied cross-sectional associations between telomere length and dietary patterns and foods and beverages that were associated with markers of inflammation.Design: Leukocyte telomere length was measured by quantitative polymerase chain reaction. Length was calculated as the amount of telomeric DNA (T) divided by the amount of a single-copy control DNA (S) (T/S ratio). Intake of whole grains, fruit and vegetables, low-fat dairy, nuts or seeds, nonfried fish, coffee, refined grains, fried foods, red meat, processed meat, and sugar-sweetened soda were computed with responses to a 120-item food-frequency questionnaire completed at baseline. Scores on 2 previously defined empirical dietary patterns were also computed for each participant.Results: After adjustment for age, other demographics, lifestyle factors, and intakes of other foods or beverages, only processed meat intake was associated with telomere length. For every 1 serving/d greater intake of processed meat, the T/S ratio was 0.07 smaller ([beta] +/- SE: -0.07 +/- 0.03, P = 0.006). Categorical analysis showed that participants consuming >/=1 serving of processed meat each week had 0.017 smaller T/S ratios than did nonconsumers. Other foods or beverages and the 2 dietary patterns were not associated with telomere length.Conclusions: Processed meat intake showed an expected inverse association with telomere length, but other diet features did not show their expected associations. © American Society for Nutrition [ABSTRACT FROM AUTHOR]

Background: Dementia is associated with microvascular disease of the retina. In this study, we examine whether cognitive status (normal cognition, mild cognitive impairment, and dementia) is associated with albuminuria, a microvascular disorder of the kidney.Study Design: Cross-sectional analysis.Setting& Participants: 2,316 participants from the Cardiovascular Health Cognition Study who underwent brain magnetic resonance imaging and testing for albuminuria.Predictor: Doubling of albuminuria.Outcome: Dementia defined according to neuropsychological and clinical evaluation.Measurements: Multinomial logistic modeling was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of dementia and mild cognitive impairment with doubling of albuminuria compared with the odds with normal cognition.Results: 283 participants (12.2%) had dementia, 344 (14.9%) had mild cognitive impairment, and 1,689 (72.9%) had normal cognition. Compared with participants with normal cognition, doubling of albuminuria was associated with increased odds of dementia (OR, 1.22; 95% CI, 1.15 to 1.29). Adjustment for prevalent cardiovascular disease and cardiovascular risk factors, lipid levels, C-reactive protein level, estimated glomerular filtration rate, and apolipoprotein E-4 genotype attenuated this association, but it remained statistically significant (OR, 1.12; 95% CI, 1.03 to 1.22). Mild cognitive impairment was associated with albuminuria on unadjusted analysis, but not with adjustment for other factors.Limitations: Results are cross-sectional; causality cannot be imputed.Conclusions: The odds of dementia increased in the presence of albuminuria. These findings suggest a role of shared susceptibility for microvascular disease in the brain and kidney in older adults. [ABSTRACT FROM AUTHOR]

Background: Recent evidence suggests that physical decline and slower gait may be associated with early signs of dementia, but more information on healthy older adults is needed.Methods: We determined associations between cognitive function, gait speed, and self-reported measures of physical function in 3035 healthy mobile participants of the Ginkgo Evaluation of Memory Study evaluated in 2000-2001. Gait speed was measured over a 15-foot course with participants walking at both their usual and rapid pace. Self-reported difficulties with Activities of Daily Living (ADLs) and other physical function tasks were also collected. Results of the Modified Mini-Mental State Examination (3MSE) determined cognitive function.Results: The average age of the cohort was 78.6 years (standard deviation [SD] 3.3), and 53.9% of participants were men. Mean gait speed was 0.95 (SD 0.23) m/s at a usual pace and 1.35 (SD 0.58) m/s at a rapid pace. More than three-fourths of participants had 3MSE scores > 90. In multiple logistic models adjusted for demographics and comorbidities, risk of low cognition (defined as 3MSE score of 80-85) was almost twice as great for participants in the slowest quartile of the rapid-paced walking task than for the fastest walkers (odds ratio: 1.96, 95% confidence interval, 1.25-3.08). Associations between cognition and usual-paced walking were borderline, and no relationships were found with self-reported measures of physical function, including ADLs.Conclusions: In very healthy older adults, performance-based measures better predict early cognitive decline than do subjective measures, and tasks requiring greater functional reserve, such as fast-paced walking, appear to be the most sensitive in assessing these relationships. [ABSTRACT FROM AUTHOR]

The telomere length of replicating somatic cells is inversely correlated with age and has been reported to be associated cross-sectionally with cardiovascular disease (CVD). Leukocyte telomere length, as expressed by mean terminal restriction fragment (TRF) length, was measured in 419 randomly selected participants from the Cardiovascular Health Study, comprising a community-dwelling cohort recruited in four US communities. The authors investigated associations between TRF length and selected measures of subclinical CVD/risk factors for CVD (data were collected at the 1992/1993 clinic visit) and incident CVD (ascertained through June 2002). In these participants (average age = 74.2 years (standard deviation, 5.2)), mean TRF length was 6.3 kilobase pairs (standard deviation, 0.62). Significant or borderline inverse associations were found between TRF length and diabetes, glucose, insulin, diastolic blood pressure, carotid intima-media thickness, and interleukin-6. Associations with body size and C-reactive protein were modified by gender and age, occurring only in men and in participants aged 73 years or younger. In younger (but not older) participants, each shortened kilobase pair of TRF corresponded with a threefold increased risk of myocardial infarction (hazard ratio = 3.08, 95% confidence interval: 1.22, 7.73) and stroke (hazard ratio = 3.22, 95% confidence interval: 1.29, 8.02). These results support the hypotheses that telomere attrition may be related to diseases of aging through mechanisms involving oxidative stress, inflammation, and progression to CVD. [ABSTRACT FROM AUTHOR]

Background: Observational studies link high midlife systolic blood pressure to increased dementia risk. However, synthesis of evidence from randomized controlled trials has not definitively demonstrated that antihypertensive medication use reduces dementia risk. Here, we emulate target trials of antihypertensive medication initiation on incident dementia using three cohort studies, with attention to potential violations of necessary assumptions., Methods: We emulated trials of antihypertensive medication initiation on incident dementia using data from the Atherosclerosis Risk in Communities (ARIC) study, Cardiovascular Health Study (CHS), and Health and Retirement Study (HRS). We used data-driven methods to restrict participants to initiators and non-initiators with overlap in propensity scores and positive control outcomes to look for violations of positivity and exchangeability assumptions., Results: Analyses were limited by the small number of cohort participants who met eligibility criteria. Associations between antihypertensive medication initiation and incident dementia were inconsistent and imprecise (ARIC: HR = 0.30 [0.05, 1.93]; CHS: HR = 0.66 [0.27, 1.64]; HRS: HR = 1.09 [0.75, 1.59]). More stringent propensity score restriction had little effect on findings. Sensitivity analyses using a positive control outcome unexpectedly suggested antihypertensive medication initiation increased risk of coronary heart disease in all three samples., Conclusions: Positive control outcome analyses suggested substantial residual confounding in effect estimates from our target trials, precluding conclusions about the impact of antihypertensive medication initiation on dementia risk through target trial emulation. Formalized processes for identifying violations of necessary assumptions will strengthen confidence in target trial emulation and avoid inappropriate confidence in emulated trial results., Competing Interests: Conflicts of Interest:, (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

We rigorously assessed a comprehensive association testing framework for heteroplasmy, employing both simulated and real-world data. This framework employed a variant allele fraction (VAF) threshold and harnessed multiple gene-based tests for robust identification and association testing of heteroplasmy. Our simulation studies demonstrated that gene-based tests maintained an appropriate type I error rate at α = 0.001. Notably, when 5 % or more heteroplasmic variants within a target region were linked to an outcome, burden-extension tests (including the adaptive burden test, variable threshold burden test, and z-score weighting burden test) outperformed the sequence kernel association test (SKAT) and the original burden test. Applying this framework, we conducted association analyses on whole-blood derived heteroplasmy in 17,507 individuals of African and European ancestries (31 % of African Ancestry, mean age of 62, with 58 % women) with whole genome sequencing data. We performed both cohort- and ancestry-specific association analyses, followed by meta-analysis on both pooled samples and within each ancestry group. Our results suggest that mtDNA-encoded genes/regions are likely to exhibit varying rates in somatic aging, with the notably strong associations observed between heteroplasmy in the RNR1 and RNR2 genes (p < 0.001) and advance aging by the Original Burden test. In contrast, SKAT identified significant associations (p < 0.001) between diabetes and the aggregated effects of heteroplasmy in several protein-coding genes. Further research is warranted to validate these findings. In summary, our proposed statistical framework represents a valuable tool for facilitating association testing of heteroplasmy with disease traits in large human populations., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors have nothing to disclose, except for the disclosure from following authors. Dr. Abecasis reports grants from National Heart Lung and Blood Institute (NIH), during the conduct of the study; personal fees and other from Regeneron Pharmaceuticals, outside the submitted work; Dr. Psaty serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson; outside the submitted work., (Copyright © 2024 Elsevier B.V. and Mitochondria Research Society. All rights reserved.)

Introduction: Whether circulating levels of sphingolipids are prospectively associated with cognitive decline and dementia risk is uncertain., Methods: We measured 14 sphingolipid species in plasma samples from 4488 participants (mean age 76.2 years; 40% male; and 25% apolipoprotein E ( APOE) ε4 allele carriers). Cognitive decline was assessed annually across 6 years using modified Mini-Mental State Examination (3MSE) and Digital Symbol Substitution Test (DSST). Additionally, a subset of 3050 participants were followed for clinically adjudicated dementia., Results: Higher plasma levels of sphingomyelin-d18:1/16:0 (SM-16) were associated with a faster cognitive decline measured with 3MSE, in contrast, higher levels of sphingomyelin-d18:1/22:0 (SM-22) were associated with slower decline in cognition measured with DSST. In Cox regression, higher levels of SM-16 (hazard ration [HR] = 1.24 [95% confidence interval [CI]: 1.08-1.44]) and ceramide-d18:1/16:0 (Cer-16) (HR = 1.26 [95% CI: 1.10-1.45]) were associated with higher risk of incident dementia., Discussion: Several sphingolipid species appear to be involved in cognitive decline and dementia risk., Highlights: Plasma levels of sphingolipids were associated with cognitive decline and dementia risk.Ceramides and sphingomyelins with palmitic acid were associated with faster annual cognitive decline and increased risk of dementia.The direction of association depended on the covalently bound saturated fatty acid chain length in analysis of cognitive decline., Competing Interests: Manja Koch is currently employed by Biogen and was previously employed by Harvard School of Public Health during the period when the research was conducted. Héléne T. Cronjé is currently employed by Lane Clark & Peacock LLP. Manja Koch and Héléne T. Cronjé have no financial or non‐financial conflicts of interest to declare regarding the research or manuscript presented herein. None of the other authors have competing interests to disclose. Author disclosures are available in the supporting information., (© 2024 The Author(s). Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Sphingolipids are implicated in neurodegeneration and neuroinflammation. We assessed the potential role of circulating ceramides and sphingomyelins in subclinical brain pathology by investigating their association with brain magnetic resonance imaging (MRI) measures and circulating biomarkers of brain injury, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in the Cardiovascular Health Study (CHS), a large and intensively phenotyped cohort of older adults., Methods: Brain MRI was offered twice to CHS participants with a mean of 5 years between scans, and results were available from both time points in 2,116 participants (mean age 76 years; 40% male; and 25% APOE ε4 allele carriers). We measured 8 ceramide and sphingomyelin species in plasma samples and examined the associations with several MRI, including worsening grades of white matter hyperintensities and ventricular size, number of brain infarcts, and measures of brain atrophy in a subset with quantitative measures. We also investigated the sphingolipid associations with serum NfL and GFAP., Results: In the fully adjusted model, higher plasma levels of ceramides and sphingomyelins with a long (16-carbon) saturated fatty acid were associated with higher blood levels of NfL [β = 0.05, false-discovery rate corrected P ( P FDR ) = 0.004 and β = 0.06, P FDR  = < 0.001, respectively]. In contrast, sphingomyelins with very long (20- and 22-carbon) saturated fatty acids tended to have an inverse association with levels of circulating NfL. In secondary analyses, we found an interaction between ceramide d18:1/20:0 and sex ( P for interaction = <0.001), such that ceramide d18:1/20:0 associated with higher odds for infarcts in women [OR = 1.26 (95%CI: 1.07, 1.49), P FDR  = 0.03]. We did not observe any associations with GFAP blood levels, white matter grade, ventricular grade, mean bilateral hippocampal volume, or total brain volume., Conclusion: Overall, our comprehensive investigation supports the evidence that ceramides and sphingomyelins are associated with increased aging brain pathology and that the direction of association depends on the fatty acid attached to the sphingosine backbone., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Moseholm, Horn, Fitzpatrick, Djoussé, Longstreth, Lopez, Hoofnagle, Jensen, Lemaitre and Mukamal.)

Background: It is unclear how post-stroke cognitive trajectories differ by stroke type and ischemic stroke subtype. We studied associations between stroke types (ischemic, hemorrhagic), ischemic stroke subtypes (cardioembolic, large artery atherosclerotic, lacunar/small vessel, cryptogenic/other determined etiology), and post-stroke cognitive decline., Methods: This pooled cohort analysis from four US cohort studies (1971-2019) identified 1,143 dementia-free individuals with acute stroke during follow-up: 1,061 (92.8%) ischemic, 82 (7.2%) hemorrhagic, 49.9% female, 30.8% Black. Median age at stroke was 74.1 (IQR, 68.6, 79.3) years. Outcomes were change in global cognition (primary) and changes in executive function and memory (secondary). Outcomes were standardized as T-scores (mean [SD], 50 [10]); a 1-point difference represents a 0.1-SD difference in cognition. Median follow-up for the primary outcome was 6.0 (IQR, 3.2, 9.2) years. Linear mixed-effects models estimated changes in cognition after stroke., Results: On average, the initial post-stroke global cognition score was 50.78 points (95% CI, 49.52, 52.03) in ischemic stroke survivors and did not differ in hemorrhagic stroke survivors (difference, -0.17 points [95% CI, -1.64, 1.30]; P =0.82) after adjusting for demographics and pre-stroke cognition. On average, ischemic stroke survivors showed declines in global cognition, executive function, and memory. Post-stroke declines in global cognition, executive function, and memory did not differ between hemorrhagic and ischemic stroke survivors. 955 ischemic strokes had subtypes: 200 (20.9%) cardioembolic, 77 (8.1%) large artery atherosclerotic, 207 (21.7%) lacunar/small vessel, 471 (49.3%) cryptogenic/other determined etiology. On average, small vessel stroke survivors showed declines in global cognition and memory, but not executive function. Initial post-stroke cognitive scores and cognitive declines did not differ between small vessel survivors and survivors of other ischemic stroke subtypes. Post-stroke vascular risk factor levels did not attenuate associations., Conclusion: Stroke survivors had cognitive decline in multiple domains. Declines did not differ by stroke type or ischemic stroke subtype.

Background and Aims: Subclinical cardiovascular disease (CVD) measures may reflect biological pathways that contribute to increased risk for coronary heart disease (CHD) events, stroke, and dementia beyond conventional risk scores., Methods: The Multi-Ethnic Study of Atherosclerosis (MESA) followed 6814 participants (45-84 years of age) from baseline in 2000-2002 to 2018 over 6 clinical examinations and annual follow-up interviews. MESA baseline subclinical CVD procedures included: seated and supineblood pressure, coronary calcium scan, radial artery tonometry, and carotid ultrasound. Baseline subclinical CVD measures were transformed into z-scores before factor analysis to derive composite factor scores. Time to clinical event for all-cause CVD, CHD, stroke and ICD code-based dementia events were modeled using Cox proportional hazards models reported as area under the curve (AUC) with 95% Confidence Intervals (95%CI) at 10 and 15 years of follow-up. All models included all factor scores together, and adjustment for conventional risk scores for global CVD, stroke, and dementia., Results: After factor selection, 24 subclinical measures aggregated into four distinct factors representing: blood pressure, atherosclerosis, arteriosclerosis, and cardiac factors. Each factor significantly predicted time to CVD events and dementia at 10 and 15 years independent of each other and conventional risk scores. Subclinical vascular composites of atherosclerosis and arteriosclerosis best predicted time to clinical events of CVD, CHD, stroke, and dementia. These results were consistent across sex and racial and ethnic groups., Conclusions: Subclinical vascular composites of atherosclerosis and arteriosclerosis may be useful biomarkers to inform the vascular pathways contributing to events of CVD, CHD, stroke, and dementia., Competing Interests: Declaration of competing interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Growing evidence links air pollution exposure to the risk of dementia. We hypothesized that hypertension may partially mediate this effect., Methods: We previously documented an association between air pollution and dementia in the Ginkgo Evaluation of Memory Study, a randomized, placebo-controlled trial of 3069 adults ≥75 years across four US sites who were evaluated for dementia every 6 months from 2000-2008. We utilized a two-stage regression approach for causal mediation analysis to decompose the total effect of air pollution on dementia into its natural direct and indirect effect through prevalent hypertension. Exposure to air pollution in the 10 or 20 years before enrollment was assigned using estimates from fine-scale spatial-temporal models for PM 2.5 , PM 10 , and NO 2 . We used Poisson regression models for hypertension and Cox proportional hazard models for time-to-incident all-cause dementia, adjusting for a priori confounders., Results: Participants were free of mild cognitive impairment at baseline (n = 2564 included in analyses); 69% had prevalent hypertension at baseline. During follow-up, 12% developed all-cause dementia (Alzheimer's disease [AD] = 212; vascular dementia with or without AD [VaD/AD mixed] = 97). We did not find an adverse effect of any air pollutant on hypertension. Hypertension was associated with VaD/AD mixed (HR, 1.92 [95% CI = 1.14, 3.24]) but not AD. We did not observe mediation through hypertension for the effect of any pollutant on dementia outcomes., Conclusions: The lack of mediated effect may be due to other mechanistic pathways and the minimal effect of air pollution on hypertension in this cohort of older adults., Competing Interests: The authors declare that they have no conflicts of interest with regard to the content of this report., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The Environmental Epidemiology. All rights reserved.)

The Canine Behavioral Assessment and Research Questionnaire (C-BARQ) is a 100-item owner-completed survey instrument used for assessing behavior and temperament of companion dogs. The shortened version of the C-BARQ (C-BARQ(S)) consists of 42 items of the long C-BARQ. We aimed to validate the shortened C-BARQ(S) by comparing it with the long questionnaire in the same human-dog pair. We examined data from a nationwide cohort of companion dogs enrolled in the large-scale longitudinal Dog Aging Project (DAP) study. Among 435 participating owners who completed both the long and shortened versions of the C-BARQ within 60 days of each other, agreement between individual questions of the long and shortened C-BARQ using an unweighted kappa statistic and percent agreement was examined. Associations between the two questionnaires for mean behavior and temperament domain scores and mean miscellaneous category scores were assessed using Pearson correlation coefficients. Of 435 dogs in the study, the mean (SD) age was 7.3 (4.3) years and 216 (50%) were female. Kappa values between the long and shortened C-BARQ for individual questions within the 14 behavior and temperament domains and a miscellaneous category ranged from fair to moderate (0.23 to 0.40 for 21 items and 0.41 to 0.58 for 26 items, respectively). Pearson correlation coefficients above 0.60 between both questionnaires for 12 of the 14 mean behavior and temperament domain scores and a category of miscellaneous items were observed. Kappa values for individual questions between the long and shortened C-BARQ ranged from fair to moderate and correlations between mean domain scores ranged from moderate to strong., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Wilkins et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

This study aimed to estimate the incidence rates of post-COVID-19 fatigue and chronic fatigue and to quantify the additional incident fatigue caused by COVID-19. We analyzed electronic health records data of 4,589 patients with confirmed COVID-19 during February 2020-February 2021 who were followed for a median of 11.4 (interquartile range 7.8-15.5) months and compared them to data from 9,022 propensity score-matched non-COVID-19 controls. Among COVID-19 patients (15% hospitalized for acute COVID-19), the incidence rate of fatigue was 10.2/100 person-years and the rate of chronic fatigue was 1.8/100 person-years. Compared with non-COVID-19 controls, the hazard ratios were 1.68 (95% CI 1.48-1.92) for fatigue and 4.32 (95% CI 2.90-6.43) for chronic fatigue. The observed association between COVID-19 and the significant increase in the incidence of fatigue and chronic fatigue reinforces the need for public health actions to prevent SARS-CoV-2 infections.

Introduction: Retinal vascular network changes may reflect the integrity of the cerebral microcirculation, and may be associated with cognitive impairment., Methods: Associations of retinal vascular measures with cognitive function and MRI biomarkers were examined amongst Multi-Ethnic Study of Atherosclerosis (MESA) participants in North Carolina who had gradable retinal photographs at Exams 2 (2002 to 2004, n = 313) and 5 (2010 to 2012, n = 306), and detailed cognitive testing and MRI at Exam 6 (2016 to 2018)., Results: After adjustment for covariates and multiple comparisons, greater arteriolar fractal dimension (FD) at Exam 2 was associated with less isotropic free water of gray matter regions (β = -0.0005, SE = 0.0024, p = 0.01) at Exam 6, while greater arteriolar FD at Exam 5 was associated with greater gray matter cortical volume (in mm 3 , β = 5458, SE = 20.17, p = 0.04) at Exam 6., Conclusion: Greater arteriolar FD, reflecting greater complexity of the branching pattern of the retinal arteries, is associated with MRI biomarkers indicative of less neuroinflammation and neurodegeneration., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)