bluuebunny/crossref_metadata_2025_split huggingface dataset:
Extended Exposure to Alzheimer's Risk Factors Increases Alzheimer's Diagnosis Risk Amplified in APOε4 Carriers: Implication for Delayed Onset of Alzheimer's Risk Factors
Authors: Merlini Simona , Vitali Francesca , Brinton Roberta Diaz 
Published: January 2025

AbstractBackgroundObesity, diabetes, hypertension, hyperlipidemia, and depression are relevant Alzheimer’s Disease (AD) modifiable risk factors (RFs). However, little is known about how the duration of these conditions, influenced by unmodifiable AD risk factors, such as chromosomal sex and APOE genotype, affects the associated risk. Modeling interactions between patient’s temporal and clinical patterns, integrated with the probability of developing AD remains challenging, particularly when considering the multifactorial progression of AD. To address these challenges, we conducted a retrospective analysis using longitudinal data from the UK Biobank.MethodsInclusion criteria were age older than 55 years, no prior history of neurodegenerative disease, neurosurgery, or cancer, and enrollment with at least 3 years of follow‐up. Propensity score matching was performed based on age at recruitment, educational level, center, and Charlson comorbidity index. Extended Cox proportional hazard models (CPHMs) for time‐to‐event prediction were used to evaluate the impact of the age‐specific effect of multiple AD‐RFs, in combination with sex and APOEε4 carrier status. Age stratification was evaluated when a violation of the hazard ratio (HR) proportionality assumption occurred during aging.ResultPreliminary findings revealed RF‐specific differences in AD on‐set based on the age of RF diagnosis. After age stratification, the risk of developing AD was significantly greater than the APOEε4 effect if hypertension and diabetes were diagnosed before 62yo, while if diagnosed after 72yo, APOEε4 was the major contributor to increased AD risk. Obesity had a 54% increased risk of developing AD if diagnosed before 62yo and was associated with nearly 3 times increased risk if diagnosed between 62‐72yo. Lastly, hyperlipidemia and depression were associated with an age‐strata‐independent increased AD risk of 33% and 69%, respectively.ConclusionsThis study identified critical tipping points indicating a decline in the hazard ratio of modifiable RFs with aging and a stronger association of APOEε4 with late‐onset AD. Age stratification within CPHMs provided valuable insights into age‐specific hazard ratios and identified age‐dependent RFs. Furthermore, these results highlight interactions between age, sex, and APOE genotype which could inform a precision medicine approach for AD prevention.
Metabolic syndrome severity score associates with structural brain features and functional connectivity of Default Mode Network subsystems in the HABS‐HD study
Authors: Green Zachary D. , O'Bryant Sid E. , Johnson Leigh A. , Burns Jeffrey M , Morris Jill K 
Published: January 2025

AbstractBackgroundStates of altered metabolic health such as metabolic syndrome (MetS), obesity, and insulin resistance increase Alzheimer’s Disease (AD) risk. Individuals with these conditions, like those with AD, have demonstrated changes in the structural and functional features of the Default Mode Network (DMN). Here, we characterize associations between systemic metabolic dysfunction, brain structure (Cortical Thickness and Hippocampal Volume) and functional connectivity of DMN subnetworks.MethodWe leveraged data from the Health and Aging Brain Study: Health Disparities (HABS‐HD) dataset, an ongoing longitudinal study that characterizes AD biomarkers across diverse populations. Specifically, we used data from the initial visits of the Hispanic and Non‐Hispanic White (NHW) cohorts. Individuals were categorized as cognitively healthy (n=1192; age=66.1 years, 65% female) or cognitively impaired (n=307; age=67.4 years, 50% female). We used a continuous measure of metabolic risk (Mets‐Z) that is more sensitive and ethnicity‐specific than categorical definitions of MetS. Mets‐Z a weighted composite of systolic blood pressure, triglycerides, HDL cholesterol, glucose, and waist circumference. Structural measures were acquired using FreeSurfer. Functional connectivity was measured via resting‐state fMRI, and pre‐processed using FSL. We utilized both summary metrics (ROI‐based connectivity estimations) and voxel‐wise approaches (FSL’s randomise).ResultMetS‐Z differed between diagnostic groups (t=‐2.387, p=.017) and between Hispanics and NHWs (t=‐11.864, p<.001). Meta‐ROI cortical thickness was negatively associated with both cognitive status (β = ‐.152, p < .001) and MetS‐Z (β = ‐.085, p < .001). Hippocampal volume was found to have a negative relationship with MetS‐Z (left, β = ‐.073, p < .001; right, β = ‐.072, p < .001). Functional connectivity, specifically of the posterior DMN, was significantly associated with MetS‐Z. There was a high degree of overlap between the clusters of voxels in which MetS‐Z and pDMN connectivity associated, and the clusters demonstrating decreased connectivity to due to age and cognitive status.ConclusionWe present evidence of altered DMN connectivity due to a higher load of metabolic risk in an ethnoracially diverse cohort of older adults, with and without cognitive impairment. Future studies should leverage the longitudinal HABS‐HD dataset to examine if higher metabolic dysfunction predicts differences in the trajectory of DMN connectivity.
APOE4 moderates the association between cerebral small vessel disease and cortical tau accumulation in midlife
Authors: Espinoza Liliana , Scott Matthew R , Beiser Alexa S , Banh Andy Q , Philip Vinu , Ghosh Saptaparni , Thibault Emma G , Maillard Pauline , Decarli Charles , Fakhri Georges El , Johnson Keith A , Seshadri Sudha , Satizabal Claudia L 
Published: January 2025

AbstractBackgroundRecent research suggests that soluble pathogenic tau accumulates in the brain microvasculature of patients with Alzheimer’s Disease (AD) and primary tauopathies, driving cerebrovascular impairments and further tau accumulation. However, little is known about the interplay of these processes before dementia onset. In the present study, we investigated the association between free water (FW), an early biomarker of cerebral small vessel disease, and tau accumulation in the rhinal, entorhinal, and inferotemporal cortices derived from PET imaging in middle‐aged adults. Additionally, given the known increased risk of AD among APOE‐ɛ4 carriers, we further explored the interaction between FW and APOE‐ɛ4 carriership on tau accumulation.MethodWe included 281 cognitively healthy participants (mean age 55±9 years, 49% male, 23% APOE‐ɛ4 carriers) from the Third Generation Cohort of the Framingham Heart Study who had undergone brain MRI and tau PET imaging. We used linear regression models to relate FW to regional tau, adjusting for potential confounders. Model 1 was adjusted for age, age2, sex, camera, and time interval between MRI and PET scans. Model 2 was additionally adjusted for cardiovascular risk factors (i.e. systolic blood pressure, antihypertensive medication use, type 2 diabetes, body mass index, smoking, and prevalent cardiovascular disease).ResultAlthough we did not find a significant association between FW and regional tau, we observed significant interactions between FW and APOE‐ ɛ4 genotype on tau accumulation in the rhinal (p=0.079) and entorhinal cortices (p=0.071) in fully adjusted models (Table 1). Among APOE‐ɛ4 carriers, we found a significant association between higher FW and increased rhinal tau levels (β=1.49, p=0.031), and a borderline significant association between higher FW and increased entorhinal tau (β=1.25, p=0.061). No significant associations were observed in non‐APOE‐ɛ4 carriers.ConclusionOur findings suggest that the APOE‐ɛ4 genotype is a moderator in the association between cerebrovascular injury and tau accumulation in brain regions typically affected earlier in the pathological spreading of tau in AD. These findings may help further elucidate underlying early processes leading to tau propagation. Replication studies in larger samples are needed to confirm these findings.
Regional Difference in Dementia Incidence in Older Adults
Authors: Dintica Christina S. , Bahorik Amber L , Xia Feng , Boscardin W John , Yaffe Kristine 
Published: January 2025

AbstractBackgroundStudies in prevalence and incidence in the United States have been limited to clinical populations and single site studies, therefore, there is a notable lack in estimates of regional differences in dementia incidence and the drivers of such disparities.MethodsWe included 1,268,599 US Veterans Health Administration (VHA) dementia‐free patients aged 65 years or older living within the U.S. with a residential zip code from year 2000‐2021. Dementia incidence was estimated according to US geographical areas from residential zip codes, based on the 10 Centers for Disease Control and Prevention (CDC) National Center for Chronic Disease Prevention and Health Promotion (NCCDPHP) regions, labeled from A to J. Incident diagnosis of dementia was ascertained using the 9th and 10th editions of the International Classification of Diseases. Poisson regression models adjusted for age were used to asses differences in dementia incidence based on geographical regions, and the sensitivity of the findings were evaluated by accounting for competing risk of death.ResultsAmong the 1,268,599 study participants (mean age 73.9 [SD, 6.1] years; 25 335 women [2%]; 15.5% received a diagnosis of dementia over a mean follow‐up of 12.6 years. Unadjusted incidence of dementia per 1000 person‐years was the lowest for the Northeast region, B and the highest in in the Southeastern region D (Figure 1). Residence within the Southeastern region D was associated a 27% higher risk of dementia, 19% higher risk in the Southern region F, 17% the midwestern region H and Northwestern region J, 12% for Southeastern region C; the remaining regions had an increased risk <10% compared to region B (Table 1). Additional adjustment for sex and race, and accounting for the competing risk of death produced similar results.ConclusionAmong older adults who received care at VHA medical centers, there were significant geographical differences in dementia incidence across the U.S, suggesting important roles for geographically patterned risk factors. Identifying geographical differences in dementia incidence allows for a more strategic and targeted approach to healthcare planning, public health interventions, and policy development.
Cognition Four Decades After High School: Does School Context Matter for Cognitive Disparities at Midlife?
Authors: Manly Jennifer J. , Hung Koit , Brickman Adam M. , Grodsky Eric , Muller Chandra , Warren John Robert , Culbertson Michael 
Published: January 2025

AbstractBackgroundStructural racism shapes educational quality by perpetuating unequal access to school resources, creating disproportionate exposure to disciplinary actions, and limiting access to advanced courses among racially minoritized children. School quality is linked to later life ADRD risk, but the benefit may vary across groups. We asked 1) whether the same high school social contexts and academic resources predict midlife cognitive functioning across race, ethnicity, and gender, and 2) how much could disparities in midlife cognitive function be narrowed if everyone had equal access to high quality high schools?MethodData was from the nationally representative High School and Beyond cohort, which prospectively followed 12,530 Americans from high school through age ∼60 and administered telephone‐ and web‐based measures of memory, language, and attention in 2021‐22. Extensive information about family, high school social and academic context, and student achievements was gathered directly from students and their schools in 1980‐1982. OLS regression models estimated associations between specific school variables and an IRT‐derived cognitive composite, before and after adjustment for confounders in race, ethnicity, and sex stratified models.ResultHigher average SES of students in each high school predicted better midlife cognitive test scores among White people and Latina women, but not among Latino men or Black participants. This association weakened after adding school academic context variables. A composite measure capturing school‐level academic engagement and rigor (academic press) predicted better cognition among White and Latinx participants but not among Black participants. If everyone had access to high schools of the same quality as the group with the highest test scores (White women), and adjusting for family confounders, disparities between White women and participants from racially minoritized groups would be substantially reduced (by 9% among Black women, 5% among Black men, and 6% among Latino men and Latina women).ConclusionInvestment in high schools that serve Black and Latinx children could meaningfully narrow disparities in cognition four decades later, particularly among Black women. Later life cognitive benefit of specific aspects of school context, such as high SES peers and academic rigor, had differential benefit depending on race, ethnicity, and sex.
Urine dicarboxylic acid as a potential AD biomarker associated with fusiform gyrus volume in older cognitively healthy adults
Authors: Fonteh Alfred N , Maldonado Salvador , Butler Ryan , Kang Jimmy , Macias Thomas , Nolty Anne , Yu J , Mack Wendy J , Chui Helena C , Minazad Yafa , Kloner Robert A , Arakaki Xianghong 
Published: January 2025

AbstractBackgroundOur study aims to determine if urine dicarboxylic acids (DCA) concentrations might be associated with specific brain region volumes in older cognitively healthy (CH) adults.MethodWe recruited CH study participants (> 65 years) and acquired MRI data analyzed using NeuroQuant. Urine DCAs were quantified using GC‐MS. For n=62 participants, DCA variables of interest—C4+C5 and C7+C8+C9 (% of the sum of C4 to C10), and their ratio—were assessed for association with each of six intracranial volume (icv)‐normalized brain region volumes; C4+C5 with 61 additional regions. We modeled volume as a function of a discretized DCA variable (sample tertiles), age, and sex, for each pair. Pairs with a statistically significant estimated association were assessed by fitting natural cubic spline models with a range of spline degrees of freedom in a second stage of analysis. The Benjamini–Hochberg procedure was used to control the false discovery rate below q1 = 0.2 in the first stage and q2 = 0.05 in the second stage.ResultThere was a significant estimated inverse association of categorical C7+C8+C9 with the fusiform gyrus (FG) volume (Table 1). Similarly, there was a significant estimated positive association between categorical (C4+C5)/(C7+C8+C9) and FG volume (Table 1). The FG was estimated to decrease by 0.004 for every one‐unit increase in C7+C8+C9, and this estimated association remained significant after adjusting P values for all tests (95% CI ‐0.007 to 0.002; adjusted P = .035, Table 2). The observed Cohen’s f2 for the DCA variable was 0.18. For the (C4+C5)/(C7+C8+C9)–FG couple, it was the 2‐df natural cubic spline model that had the lowest Bayesian information criterion values among the spline models considered, with a significant estimated association of the DCA variable with the FG (spline adjusted P = 0.035). Figure 1 depicts the estimated spline. The observed Cohen’s f2 for the spline was 0.29.ConclusionOur analysis suggests that DCA metabolism may be associated with FG volume differences between individuals. Since the FG participates in visual processing, memory, and multisensory integration, urinary DCA levels may be biomarkers to monitor AD pathophysiology associated with differences in these functions.
Longitudinal Plasma pTau217 Measurements in Preclinical Alzheimer’s Disease
Authors: Wilson Rachael E , Reyes Ramiro Eduardo Rea , Langhough Rebecca E. , Jonaitis Erin M. , Du Lianlian , Legois Emily , Keske Elysse , Fredricks Aaron , Marshall Martie , Jensen Cindy , VandenLangenberg Monica , Jeffers Beckie , Wheelock Bailey , Mershon Max , Kaseno Jo , Betthauser Tobey J. , Christian Bradley T. , Okonkwo Ozioma C , Bendlin Barbara B. , Engelman Corinne D. , Gleason Carey E. , Hogan Kirk J. , Chin Nathaniel A. , Carlsson Cynthia M. , Asthana Sanjay , Johnson Sterling C. , Zetterberg Henrik 
Published: January 2025

AbstractBackgroundPlasma pTau217 (tau phosphorylated at threonine 217) assays will expand access to screening for Alzheimer’s disease (AD). However, clinical interpretation is not well‐established, particularly during the preclinical window when interventions may be most effective. Using plasma samples from primarily late‐midlife, cognitively unimpaired Wisconsin Registry for Alzheimer’s Prevention (WRAP) and Wisconsin Alzheimer’s Disease Center (WADRC) participants, we investigated pTau217 agreement with amyloid and tau PET then compared trajectories between participants grouped by baseline pTau217.MethodsEDTA plasma samples from 428 participants were analyzed using the ALZpath pTau217 Simoa assay on a Quanterix HD‐X (Table 1). Amyloid and tau positivity were defined as global [11C]‐PiB DVR>1.19 (21.6 centiloids) and [18F]‐MK6240 temporal meta‐ROI SUVR>1.3, respectively. In separate receiver operating characteristic (ROC) analyses using pTau217 to classify amyloid and tau PET, the area under the curve (95% CI) and optimal (Youden) cutoffs were, respectively: 0.91 (0.87‐0.94), 0.37 pg/mL; and 0.89 (0.83‐0.94), 0.53 pg/mL. To characterize pTau217 rates of change based on baseline measurements, participants were clustered into low (≤0.37 pg/mL), intermediate (0.37 < pTau217 < 0.53 pg/mL), and high (≥0.53 pg/mL) groups according to the ROC thresholds. Linear mixed models were then run with group and age as fixed effects and including random person‐level intercept and age slopes.ResultsMean pTau217 concentration was 2.5 times higher for amyloid positive participants compared to amyloid negative (Figure 1A; p < 0.001). Significant differences were also observed between CU, MCI, and dementia groups (Figure 1B; CU‐MCI: p < 0.001, CU‐MCI: p<0.001, Dementia‐MCI: p<0.001). Mixed effects models indicated that pTau217 increased at a higher rate in the high group compared to other groups (Figure 2; simple slopes low‐high: t(361)=‐7.010, p<0.001, intermediate‐high: t(318)=‐5.712, p < 0.001). No differences were observed between simple slopes for low and intermediate groups (t(235)=‐0.314, p=0.9470).ConclusionThese results suggest that plasma ALZpath pTau217 is a very good proxy for molecular PET for detecting AD pathology prior to symptoms. Strategies such as assigning an indeterminate zone for secondary confirmation (Brum, W., et al, 2023) would improve accuracy and lessen the burden on existing resources while expanding access to the broader community.
Multi‐Component and Cognitive Skills Training in Mild Cognitive Impairment: Outcomes from a South American Study
Authors: Martin Maria Eugenia , Martinez Carlos , Worff Iris , Belucci Maria Agustina , Keller Greta , Arruabarrena Micaela Maria , Corvalan Nicolas , Clarens Maria Florencia , Allegri Ricardo , Crivelli Lucia 
Published: January 2025

AbstractBackgroundDementia represents a significant health challenge, with evidence suggesting that it can be potentially delayed or prevented through non‐pharmacological interventions. There are different types of non‐pharmacological interventions for Mild Cognitive Impairment (MCI). The Aging Well through Interaction and Scientific Education (AgeWISE) Program is a notable cognitive intervention designed to educate both individuals experiencing normal aging and those with age‐related diseases. It offers strategies for managing age‐related cognitive changes and provides skill training.GoalsThis study aims to evaluate the effects of a multi‐component psychoeducation intervention (AgeWise) in patients with MCI, focusing on the aging brain, lifestyle factors associated with successful brain aging, and strategies to compensate for age‐related cognitive decline.MethodA group of 25 amnesic and amnestic‐multidomain MCI patients (mean age: 75.26±5.5, 65.38% female, education level: 14.46±2.8, MOCA: 22.96±2.91) were recruited from a Memory Clinic in Buenos Aires. Patients underwent 10 treatment sessions based on the AgeWISE program. Pre‐treatment (week 0) and post‐treatment (week 10) assessments included the Multifactor Memory Questionnaire (MMQ) for various memory dimensions and the Depression, Anxiety, and Stress Scale (DASS‐21) to assess mood. The Wilcoxon‐Mann‐Whitney model was used to analyze the impact of treatment on each outcome.ResultThe pre and post‐treatment measures were compared, revealing an improvement in the total DASS‐21 (P = 0.05), with a significant reduction in depression (DASS‐21‐Depression P = 0.02). While changes in the MMQ scale did not reach significance, there was a trend towards improved satisfaction with memory performance (P = 0.083).ConclusionIn regions with limited access to clinical and pharmacological trials, non‐pharmacological interventions emerge as a viable option for MCI patients. The AgeWISE intervention specifically demonstrated improvements in mood among MCI patients, with significant changes were observed in specific items (DASS‐21‐Total and Depression) related to initiative, tolerance for interruptions, and enthusiasm, suggesting positive outcomes for individuals undergoing this intervention. These findings highlight the potential benefits of non‐pharmacological interventions for individuals with MCI.