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Brain aging process is influenced by various lifestyle, environmental and genetic factors, as well as by age-related and often coexisting pathologies. Magnetic resonance imaging and artificial intelligence methods have been instrumental in understanding neuroanatomical changes that occur during aging. Large, diverse population studies enable identifying comprehensive and representative brain change patterns resulting from distinct but overlapping pathological and biological factors, revealing intersections and heterogeneity in affected brain regions and clinical phenotypes. Herein, we leverage a state-of-the-art deep-representation learning method, Surreal-GAN, and present methodological advances and extensive experimental results elucidating brain aging heterogeneity in a cohort of 49,482 individuals from 11 studies. Five dominant patterns of brain atrophy were identified and quantified for each individual by respective measures, R-indices. Their associations with biomedical, lifestyle and genetic factors provide insights into the etiology of observed variances, suggesting their potential as brain endophenotypes for genetic and lifestyle risks. Furthermore, baseline R-indices predict disease progression and mortality, capturing early changes as supplementary prognostic markers. These R-indices establish a dimensional approach to measuring aging trajectories and related brain changes. They hold promise for precise diagnostics, especially at preclinical stages, facilitating personalized patient management and targeted clinical trial recruitment based on specific brain endophenotypic expression and prognosis.
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Background: Examination of Alzheimer's disease (AD) related biomarkers among diverse communities has remained limited. Objective: The aim of this study was to expand on prior work to provide a characterization of ptau181 among a diverse community sample. Consideration was taken regarding the impact of comorbidities on ptau181 levels including medical. Methods: 3,228 (nâ=â770 African American [AA], nâ=â1,231 Hispanic, and nâ=â1,227 non-Hispanic white [NHW]) Health and Aging Brain Study- Health Disparities (HABS-HD) participants were included in this study. ANCOVAs were conducted to examine differences in ptau181 levels across race and ethnic groups. Violin plots were also generated stratified by APOEÉ4 carrier status, Amyloid PET positivity status, medical comorbidity (hypertension, dyslipidemia, chronic kidney disease [CKD], and diabetes) and by cognitive diagnosis. Results: Ptau181 levels were found to differ between Hispanics and NHW after covarying for age, sex, and APOEÉ4 status. Amyloid PET positivity was associated with higher ptau181 levels across all groups. APOEÉ4 positivity status was only significantly associated with ptau181 levels among AAs. Across all race and ethnic groups, those with a diagnosis of CKD had higher levels of ptau181. When stratified by cognitive diagnosis, cognitively unimpaired Hispanics had higher ptau181 if they also had a diagnosis of CKD or diabetes. p-values ≤0.01. Conclusions: Differences in ptau181 levels were shown in a diverse community sample. Medical comorbidities had a differing effect on ptau181 levels particularly among Hispanics even without cognitive impairment. Findings support the need for future work to consider comorbid conditions when examining the utility of ptau181.
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Enfermedad de Alzheimer , Negro o Afroamericano , Hispánicos o Latinos , Proteínas tau , Humanos , Masculino , Femenino , Anciano , Proteínas tau/metabolismo , Enfermedad de Alzheimer/genética , Estudios de Cohortes , Población Blanca , Biomarcadores , Anciano de 80 o más Años , Persona de Mediana Edad , Tomografía de Emisión de Positrones , Apolipoproteína E4/genética , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagenRESUMEN
CONTEXT: Early age at menarche (AAM) is a risk factor for type 2 diabetes later in life, but the pathogenic pathways that confer increased risk remain unknown. OBJECTIVE: We examined the associations between AAM and inflammatory and glucose metabolism biomarkers among U.S. adult women who were free of diabetes. METHODS: Using the National Health and Nutrition Examination Survey (NHANES) 1999-2018, 19,228 women over 20 years old who were free of self-reported cancer and diabetes were included in this cross-sectional analysis. AAM was the self-reported age at first menstruation. CRP, fasting glucose, fasting insulin, and ferritin levels were measured as biomarkers of inflammation and glucose metabolism in adult blood samples using latex-enhanced nephelometry, enzymatic, and immunoassay methods. Multiple linear regression was used to relate AAM to the biomarkers. RESULTS: The median age at the time of blood sample collection was 44 years (IQR, 33-62). After age adjustment, there was an association between a lower AAM and higher CRP (P-trend=0.006); fasting glucose (P-trend<0.0001); fasting insulin (P-trend <0.0001); and ferritin (p-trend<0.0001). These remained significant after additional adjustment for demographic, reproductive, lifestyle, and adiposity variables, except for ferritin. Smoking modified the effect of AAM on CRP (p-interaction = 0.014), fasting insulin (p-interaction <0.001), and fasting glucose (p-interaction<0.001). In stratified analysis, the observed associations became more pronounced in non-smokers, while they were attenuated to non-significance in active smokers. CONCLUSION: Earlier age at menarche is associated with an unfavorable inflammatory and glucose metabolic biomarker profile in a nationally representative sample of adult women free of diabetes, especially among non-smokers.
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Objectives: Apraxia is a core feature of Alzheimer's disease, but the pathomechanism of this characteristic symptom is not well understood. Here, we systematically investigated apraxia profiles in a well-defined group of patients with Alzheimer's disease (AD; N=32) who additionally underwent PET imaging with the second-generation tau PET tracer [18F]PI-2620. We hypothesized that specific patterns of tau pathology might be related to apraxic deficits. Methods: Patients (N=32) with a biomarker-confirmed diagnosis of Alzheimer's disease were recruited in addition to a sample cognitively unimpaired controls (CU 1 ; N=41). Both groups underwent in-depth neuropsychological assessment of apraxia (Dementia Apraxia Screening Test; DATE and the Cologne Apraxia Screening; KAS). In addition, static PET imaging with [18F]PI-2620 was performed to assess tau pathology in the AD patients. To specifically investigate the association of apraxia with regional tau-pathology, we compared the PET-data from this group with an independent sample of amyloid-negative cognitively intact participants (CU 2; N=54) by generation of z-score-deviation maps as well as voxel- based multiple regression analyses. Results: We identified significant clusters of tau-aggregation in praxis-related regions (e.g., supramarginal gyrus, angular gyrus, temporal, parietal and occipital regions) that were associated with apraxia. These regions were similar between the two apraxia assessments. No correlations between tau-tracer uptake in primary motor cortical or subcortical brain regions and apraxia were observed. Conclusions: These results suggest that tau deposition in specific cortical brain regions may induce local neuronal dysfunction leading to a dose-dependent functional decline in praxis performance.
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INTRODUCTION: Neighborhood socioeconomic status (NSES) has been linked with overall health, and this study will evaluate whether NSES is cross-sectionally associated with cognition in non-Hispanic whites (NHWs) and Mexican Americans (MAs) from the Health and Aging Brain: Health Disparities Study (HABS-HD). METHODS: The HABS-HD is a longitudinal study conducted at the University of North Texas Health Science Center. The final sample analyzed (n = 1,312) were 50 years or older, with unimpaired cognition, and underwent an interview, neuropsychological examination, imaging, and blood draw. NSES was measured using the national area deprivation index (ADI) percentile ranking, which considered socioeconomic variables. Executive function and processing speed were assessed by the trail making tests (A and B) and the digit-symbol substitution test, respectively. Linear regression was used to assess the association of ADI and cognitive measures. RESULTS: MAs were younger, more likely to be female, less educated, had higher ADI scores, performed worse on trails B (all p < 0.05), and had lower prevalence of APOE4 + when compared to NHWs (p < 0.0001). A higher percentage of MAs lived in the most deprived neighborhoods than NHWs. For NHWs, ADI did not predict trails B or DSS scores, after adjusting for demographic variables and APOE4. For MAs, ADI predicted trails A, trails B, and DSS after adjusting for demographic covariates and APOE4 status. CONCLUSION: Our study revealed that living in an area of higher deprivation was associated with lower cognitive function in MAs but not in NHWs, which is important to consider in future interventions to slow cognitive decline.
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Envejecimiento , Función Ejecutiva , Americanos Mexicanos , Pruebas Neuropsicológicas , Clase Social , Humanos , Femenino , Masculino , Anciano , Americanos Mexicanos/psicología , Americanos Mexicanos/estadística & datos numéricos , Persona de Mediana Edad , Estudios Longitudinales , Envejecimiento/psicología , Disparidades en el Estado de Salud , Cognición/fisiología , Características del Vecindario , Población Blanca/psicología , Población Blanca/estadística & datos numéricos , Estudios Transversales , Estudios de Cohortes , Anciano de 80 o más Años , Características de la Residencia , Texas/epidemiología , Velocidad de ProcesamientoRESUMEN
INTRODUCTION: People with Down syndrome (DS) have a 75% to 90% lifetime risk of Alzheimer's disease (AD). AD pathology begins a decade or more prior to onset of clinical AD dementia in people with DS. It is not clear if plasma biomarkers of AD pathology are correlated with early cognitive and functional impairments in DS, and if these biomarkers could be used to track the early stages of AD in DS or to inform inclusion criteria for clinical AD treatment trials. METHODS: This large cross-sectional cohort study investigated the associations between plasma biomarkers of amyloid beta (Aß)42/40, total tau, and neurofilament light chain (NfL) and cognitive (episodic memory, visual-motor integration, and visuospatial abilities) and functional (adaptive behavior) impairments in 260 adults with DS without dementia (aged 25-81 years). RESULTS: In general linear models lower plasma Aß42/40 was related to lower visuospatial ability, higher total tau was related to lower episodic memory, and higher NfL was related to lower visuospatial ability and lower episodic memory. DISCUSSION: Plasma biomarkers may have utility in tracking AD pathology associated with early stages of cognitive decline in adults with DS, although associations were modest. Highlights: Plasma Alzheimer's disease (AD) biomarkers correlate with cognition prior to dementia in Down syndrome.Lower plasma amyloid beta 42/40 was related to lower visuospatial abilities.Higher plasma total tau and neurofilament light chain were associated with lower cognitive performance.Plasma biomarkers show potential for tracking early stages of AD symptomology.
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BACKGROUND: In people with genetic forms of Alzheimer's disease, such as in Down syndrome and autosomal-dominant Alzheimer's disease, pathological changes specific to Alzheimer's disease (ie, accumulation of amyloid and tau) occur in the brain at a young age, when comorbidities related to ageing are not present. Studies including these cohorts could, therefore, improve our understanding of the early pathogenesis of Alzheimer's disease and be useful when designing preventive interventions targeted at disease pathology or when planning clinical trials. We compared the magnitude, spatial extent, and temporal ordering of tau spread in people with Down syndrome and autosomal-dominant Alzheimer's disease. METHODS: In this cross-sectional observational study, we included participants (aged ≥25 years) from two cohort studies. First, we collected data from the Dominantly Inherited Alzheimer's Network studies (DIAN-OBS and DIAN-TU), which include carriers of autosomal-dominant Alzheimer's disease genetic mutations and non-carrier familial controls recruited in Australia, Europe, and the USA between 2008 and 2022. Second, we collected data from the Alzheimer Biomarkers Consortium-Down Syndrome study, which includes people with Down syndrome and sibling controls recruited from the UK and USA between 2015 and 2021. Controls from the two studies were combined into a single group of familial controls. All participants had completed structural MRI and tau PET (18F-flortaucipir) imaging. We applied Gaussian mixture modelling to identify regions of high tau PET burden and regions with the earliest changes in tau binding for each cohort separately. We estimated regional tau PET burden as a function of cortical amyloid burden for both cohorts. Finally, we compared the temporal pattern of tau PET burden relative to that of amyloid. FINDINGS: We included 137 people with Down syndrome (mean age 38·5 years [SD 8·2], 74 [54%] male, and 63 [46%] female), 49 individuals with autosomal-dominant Alzheimer's disease (mean age 43·9 years [11·2], 22 [45%] male, and 27 [55%] female), and 85 familial controls, pooled from across both studies (mean age 41·5 years [12·1], 28 [33%] male, and 57 [67%] female), who satisfied the PET quality-control procedure for tau-PET imaging processing. 134 (98%) people with Down syndrome, 44 (90%) with autosomal-dominant Alzheimer's disease, and 77 (91%) controls also completed an amyloid PET scan within 3 years of tau PET imaging. Spatially, tau PET burden was observed most frequently in subcortical and medial temporal regions in people with Down syndrome, and within the medial temporal lobe in people with autosomal-dominant Alzheimer's disease. Across the brain, people with Down syndrome had greater concentrations of tau for a given level of amyloid compared with people with autosomal-dominant Alzheimer's disease. Temporally, increases in tau were more strongly associated with increases in amyloid for people with Down syndrome compared with autosomal-dominant Alzheimer's disease. INTERPRETATION: Although the general progression of amyloid followed by tau is similar for people Down syndrome and people with autosomal-dominant Alzheimer's disease, we found subtle differences in the spatial distribution, timing, and magnitude of the tau burden between these two cohorts. These differences might have important implications; differences in the temporal pattern of tau accumulation might influence the timing of drug administration in clinical trials, whereas differences in the spatial pattern and magnitude of tau burden might affect disease progression. FUNDING: None.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Síndrome de Down , Masculino , Femenino , Humanos , Adulto , Enfermedad de Alzheimer/genética , Estudios Transversales , Péptidos beta-Amiloides/metabolismo , Proteínas tau/metabolismo , Amiloide , Imagen por Resonancia Magnética/métodos , Tomografía de Emisión de Positrones/métodos , Disfunción Cognitiva/patologíaRESUMEN
INTRODUCTION: Virtually all people with Down syndrome (DS) develop neuropathology associated with Alzheimer's disease (AD). Atrophy of the hippocampus and entorhinal cortex (EC), as well as elevated plasma concentrations of neurofilament light chain (NfL) protein, are markers of neurodegeneration associated with late-onset AD. We hypothesized that hippocampus and EC gray matter loss and increased plasma NfL concentrations are associated with memory in adults with DS. METHODS: T1-weighted structural magnetic resonance imaging (MRI) data were collected from 101 participants with DS. Hippocampus and EC volume, as well as EC subregional cortical thickness, were derived. In a subset of participants, plasma NfL concentrations and modified Cued Recall Test scores were obtained. Partial correlation and mediation were used to test relationships between medial temporal lobe (MTL) atrophy, plasma NfL, and episodic memory. RESULTS: Hippocampus volume, left anterolateral EC (alEC) thickness, and plasma NfL were correlated with each other and were associated with memory. Plasma NfL mediated the relationship between left alEC thickness and memory as well as hippocampus volume and memory. DISCUSSION: The relationship between MTL gray matter and memory is mediated by plasma NfL levels, suggesting a link between neurodegenerative processes underlying axonal injury and frank gray matter loss in key structures supporting episodic memory in people with DS.
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INTRODUCTION: Identification of psychosocial-behavioral phenotypes to understand within-group heterogeneity in risk and resiliency to Alzheimer's disease (AD) within Black/African American and Hispanic/Latino older adults is essential for the implementation of precision health approaches. METHODS: A cluster analysis was performed on baseline measures of socioeconomic resources (annual income, social support, occupational complexity) and psychiatric distress (chronic stress, depression, anxiety) for 1220 racially/ethnically minoritized adults enrolled in the Health and Aging Brain Study-Health Disparities (HABS-HD). Analyses of covariance adjusting for sociodemographic factors examined phenotype differences in cognition and plasma AD biomarkers. RESULTS: The cluster analysis identified (1) Low Resource/High Distress (n = 256); (2) High Resource/Low Distress (n = 485); and (3) Low Resource/Low Distress (n = 479) phenotypes. The Low Resource/High Distress phenotype displayed poorer cognition and higher plasma neurofilament light chain; differences between the High Resource/Low Distress and Low Resource/Low Distress phenotypes were minimal. DISCUSSION: The identification of psychosocial-behavioral phenotypes within racially/ethnically minoritized older adults is crucial to the development of targeted AD prevention and intervention efforts.
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Enfermedad de Alzheimer , Negro o Afroamericano , Hispánicos o Latinos , Anciano , Humanos , Biomarcadores , Cognición , FenotipoRESUMEN
Importance: By age 40 years over 90% of adults with Down syndrome (DS) have Alzheimer's disease (AD) pathology and most progress to dementia. Despite having few systemic vascular risk factors, individuals with DS have elevated cerebrovascular disease (CVD) markers that track with the clinical progression of AD, suggesting a role for CVD that is hypothesized to be mediated by inflammatory factors. Objective: To examine the pathways through which small vessel CVD contributes to AD-related pathophysiology and neurodegeneration in adults with DS. Design: Cross sectional analysis of neuroimaging, plasma, and clinical data. Setting: Participants were enrolled in Alzheimer's Biomarker Consortium - Down Syndrome (ABC-DS), a multisite study of AD in adults with DS. Participants: One hundred eighty-five participants (mean [SD] age=45.2 [9.3] years) with available MRI and plasma biomarker data were included. White matter hyperintensity (WMH) volumes were derived from T2-weighted FLAIR MRI scans and plasma biomarker concentrations of amyloid beta (Aß42/Aß40), phosphorylated tau (p-tau217), astrocytosis (glial fibrillary acidic protein, GFAP), and neurodegeneration (neurofilament light chain, NfL) were measured with ultrasensitive immunoassays. Main Outcomes and Measures: We examined the bivariate relationships of WMH, Aß42/Aß40, p-tau217, and GFAP with age-residualized NfL across AD diagnostic groups. A series of mediation and path analyses examined causal pathways linking WMH and AD pathophysiology to promote neurodegeneration in the total sample and groups stratified by clinical diagnosis. Results: There was a direct and indirect bidirectional effect through GFAP of WMH on p-tau217 concentration, which was associated with NfL concentration in the entire sample. Among cognitively stable participants, WMH was directly and indirectly, through GFAP, associated with p-tau217 concentration, and in those with MCI, there was a direct effect of WMH on p-tau217 and NfL concentrations. There were no associations of WMH with biomarker concentrations among those diagnosed with dementia. Conclusions and Relevance: The findings suggest that among individuals with DS, CVD promotes neurodegeneration by increasing astrocytosis and tau pathophysiology in the presymptomatic phases of AD. This work joins an emerging literature that implicates CVD and its interface with neuroinflammation as a core pathological feature of AD in adults with DS.
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INTRODUCTION: The effects of bilingualism on neuropsychological test performance in bilinguals with and without cognitive impairment are not well-understood and are relatively limited by small sample sizes of Latinos. METHODS: Using analysis of covariance (ANCOVA), we explored patterns of cognitive performance and impairment across a large sample of community-dwelling bilingual and monolingual Latino older adults with (n = 180) and without (n = 643) mild cognitive impairment (MCI) enrolled in HABS-HD. RESULTS: Bilinguals demonstrated cognitive resiliency in the form of significantly better performance on the Trail Making Test and Digit Symbol Substitution Test, observed across the cognitively unimpaired and MCI groups. In contrast, bilinguals demonstrated cognitive vulnerability in the form of significantly poorer performance and higher impairment rates on phonemic fluency in the MCI phase, only. Follow-up analyses revealed less balanced bilinguals demonstrated poorer performance and higher impairment rates on this measure, supported by lower levels of plasma Aß 42/40. DISCUSSION: Patterns of cognitive performance and impairment differ as a function of bilingualism. Bilingualism must be considered when evaluating cognitive and biomarker outcomes in Latino older adults. Highlights: Latino bilinguals perform better on measures of processing speed and coding.Latino bilinguals with MCI demonstrate cognitive vulnerability in verbal fluency.Less balanced bilinguals demonstrate greatest vulnerability anchored by Aß 42/40.
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INTRODUCTION: Here we evaluate frequencies of the top 10 Alzheimer's disease (AD) risk alleles for late-onset AD in Mexican American (MA) and non-Hispanic White (NHW) American participants enrolled in the Health and Aging Brain Study-Health Disparities Study cohort. METHODS: Using DNA extracted from this community-based diverse population, we calculated the genotype frequencies in each population to determine whether a significant difference is detected between the different ethnicities. DNA genotyping was performed per manufacturers' protocols. RESULTS: Allele and genotype frequencies for 9 of the 11 single nucleotide polymorphisms (two apolipoprotein E variants, CR1, BIN1, DRB1, NYAP1, PTK2B, FERMT2, and ABCA7) differed significantly between MAs and NHWs. DISCUSSION: The significant differences in frequencies of top AD risk alleles observed here across MAs and NHWs suggest that ethnicity-specific genetic risks for AD exist. Given our results, we are advancing additional projects to further elucidate ethnicity-specific differences in AD.
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BACKGROUND: Blood biomarkers have the potential to transform Alzheimer's disease (AD) diagnosis and monitoring, yet their integration with common medical comorbidities remains insufficiently explored. OBJECTIVE: This study aims to enhance blood biomarkers' sensitivity, specificity, and predictive performance by incorporating comorbidities. We assess this integration's efficacy in diagnostic classification using machine learning, hypothesizing that it can identify a confident set of predictive features. METHODS: We analyzed data from 1,705 participants in the Health and Aging Brain Study-Health Disparities, including 116 AD patients, 261 with mild cognitive impairment, and 1,328 cognitively normal controls. Blood samples were assayed using electrochemiluminescence and single molecule array technology, alongside comorbidity data gathered through clinical interviews and medical records. We visually explored blood biomarker and comorbidity characteristics, developed a Feature Importance and SVM-based Leave-One-Out Recursive Feature Elimination (FI-SVM-RFE-LOO) method to optimize feature selection, and compared four models: Biomarker Only, Comorbidity Only, Biomarker and Comorbidity, and Feature-Selected Biomarker and Comorbidity. RESULTS: The combination model incorporating 17 blood biomarkers and 12 comorbidity variables outperformed single-modal models, with NPV12 at 92.78%, AUC at 67.59%, and Sensitivity at 65.70%. Feature selection led to 22 chosen features, resulting in the highest performance, with NPV12 at 93.76%, AUC at 69.22%, and Sensitivity at 70.69%. Additionally, interpretative machine learning highlighted factors contributing to improved prediction performance. CONCLUSIONS: In conclusion, combining feature-selected biomarkers and comorbidities enhances prediction performance, while feature selection optimizes their integration. These findings hold promise for understanding AD pathophysiology and advancing preventive treatments.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/epidemiología , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/epidemiología , Biomarcadores , Encéfalo , ComorbilidadRESUMEN
BACKGROUND AND OBJECTIVES: Elevations in circulating glial fibrillary acidic protein (GFAP), a putative marker of reactive astrocytosis, have been found to associate with cognitive decline and dementia status. Further validation in diverse cohorts and evaluation of potential health disparities are necessary for broader generalization. The goal of this study was to examine the associations between demographics, cardiovascular risk factors, and APOE ε4 status with serum GFAP levels among Mexican American and non-Hispanic White older adults across the continuum from cognitively unimpaired to Alzheimer disease dementia. METHODS: Serum GFAP levels were assayed using a Simoa HD-1 analyzer in older adults enrolled in the observational Texas Alzheimer Research and Care Consortium. Associations between demographic and clinical characteristics with serum GFAP levels were evaluated using linear regression. The diagnostic accuracy of serum GFAP was further examined using area under the receiver operating characteristic curves (AUROC) in univariate and adjusted models, and optimal cut points were derived using the maximum Kolmogorov-Smirnov metric. All models were also stratified by ethnicity and disease stage. RESULTS: A total of 1,156 Mexican American and 587 non-Hispanic White participants were included (mean age = 68 years, standard deviation = 10; 65% female). Older age (ß = 0.562 (95% CI 0.515-0.609), p < 0.001), apolipoprotein ε4 status (ß = 0.139 (95% CI 0.092-0.186), p < 0.001), and cognitive impairment (ß = 0.150 (95% CI 0.103-0.197), p < 0.001) were positively associated with serum GFAP. By contrast, higher body mass index (ß = -0.181 (95% CI -0.228 to -0.134), p < 0.001), diabetes (ß = -0.065 (95% CI -0.112 to -0.018), p < 0.001), and tobacco use (ß = -0.059 (95% CI -0.106 to -0.012), p < 0.001) were inversely associated with serum GFAP. AUROC values were generally comparable across ethnicities and model fit improved with inclusion of additional covariates. However, optimal cut-off values were consistently lower in Mexican Americans relative to non-Hispanic White participants. DISCUSSION: The study results highlight the importance of understanding the role of broader demographic and clinical factors on circulating GFAP levels within diverse cohorts to enhance precision across clinical, research, and community settings.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Diabetes Mellitus , Humanos , Femenino , Anciano , Masculino , Proteína Ácida Fibrilar de la Glía , Enfermedad de Alzheimer/diagnóstico , Demografía , BiomarcadoresRESUMEN
BACKGROUND: The Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT) was the first-ever large-scale anti-inflammatory prevention trial targeting Alzheimer's disease. OBJECTIVE: The overall goal of this study was to evaluate predictive blood biomarker profiles that identified individuals most likely to be responders on NSAID treatment or placebo at 12 and 24 months. METHODS: Baseline (nâ=â193) and 12-month (nâ=â562) plasma samples were assayed. The predictive biomarker profile was generated using SVM analyses with response on treatment (yes/no) as the outcome variable. RESULTS: Baseline (AUCâ=â0.99) and 12-month (AUCâ=â0.99) predictive biomarker profiles were highly accurate in predicting response on Celecoxib arm at 12 and 24 months. The baseline (AUCâ=â0.95) and 12-month (AUCâ=â0.9) predictive biomarker profile predicting response on Naproxen were also highly accurate at 12 and 24 months. The baseline (AUCâ=â0.93) and 12-month (AUCâ=â0.99) predictive biomarker profile was also highly accurate in predicting response on placebo. As with our prior work, the profiles varied by treatment arm. CONCLUSIONS: The current results provide additional support for a precision medicine model for treating and preventing Alzheimer's disease.
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Importance: Understanding how socioeconomic factors are associated with cognitive aging is important for addressing health disparities in Alzheimer disease. Objective: To examine the association of neighborhood disadvantage with cognition among a multiethnic cohort of older adults. Design, Setting, and Participants: In this cross-sectional study, data were collected between September 1, 2017, and May 31, 2022. Participants were from the Health and Aging Brain Study-Health Disparities, which is a community-based single-center study in the Dallas/Fort Worth area of Texas. A total of 1614 Mexican American and non-Hispanic White adults 50 years and older were included. Exposure: Neighborhood disadvantage for participants' current residence was measured by the validated Area Deprivation Index (ADI); ADI Texas state deciles were converted to quintiles, with quintile 1 representing the least disadvantaged area and quintile 5 the most disadvantaged area. Covariates included age, sex, and educational level. Main Outcomes and Measures: Performance on cognitive tests assessing memory, language, attention, processing speed, and executive functioning; measures included the Spanish-English Verbal Learning Test (SEVLT) Learning and Delayed Recall subscales; Wechsler Memory Scale, third edition (WMS-III) Digit Span Forward, Digit Span Backward, and Logical Memory 1 and 2 subscales; Trail Making Test (TMT) parts A and B; Digit Symbol Substitution Test (DSST); Letter Fluency; and Animal Naming. Raw scores were used for analyses. Associations between neighborhood disadvantage and neuropsychological performance were examined via demographically adjusted linear regression models stratified by ethnic group. Results: Among 1614 older adults (mean [SD] age, 66.3 [8.7] years; 980 women [60.7%]), 853 were Mexican American (mean [SD] age, 63.9 [7.9] years; 566 women [66.4%]), and 761 were non-Hispanic White (mean [SD] age, 69.1 [8.7] years; 414 women [54.4%]). Older Mexican American adults were more likely to reside in the most disadvantaged areas (ADI quintiles 3-5), with 280 individuals (32.8%) living in ADI quintile 5, whereas a large proportion of older non-Hispanic White adults resided in ADI quintile 1 (296 individuals [38.9%]). Mexican American individuals living in more disadvantaged areas had worse performance than those living in ADI quintile 1 on 7 of 11 cognitive tests, including SEVLT Learning (ADI quintile 5: ß = -2.50; 95% CI, -4.46 to -0.54), SEVLT Delayed Recall (eg, ADI quintile 3: ß = -1.11; 95% CI, -1.97 to -0.24), WMS-III Digit Span Forward (eg, ADI quintile 4: ß = -1.14; 95% CI, -1.60 to -0.67), TMT part A (ADI quintile 5: ß = 7.85; 95% CI, 1.28-14.42), TMT part B (eg, ADI quintile 5: ß = 31.5; 95% CI, 12.16-51.35), Letter Fluency (ADI quintile 4: ß = -2.91; 95% CI, -5.39 to -0.43), and DSST (eg, ADI quintile 5: ß = -4.45; 95% CI, -6.77 to -2.14). In contrast, only non-Hispanic White individuals living in ADI quintile 4 had worse performance than those living in ADI quintile 1 on 4 of 11 cognitive tests, including SEVLT Learning (ß = -2.35; 95% CI, -4.40 to -0.30), SEVLT Delayed Recall (ß = -0.95; 95% CI, -1.73 to -0.17), TMT part B (ß = 15.95; 95% CI, 2.47-29.44), and DSST (ß = -3.96; 95% CI, -6.49 to -1.43). Conclusions and Relevance: In this cross-sectional study, aging in a disadvantaged area was associated with worse cognitive functioning, particularly for older Mexican American adults. Future studies examining the implications of exposure to neighborhood disadvantage across the life span will be important for improving cognitive outcomes in diverse populations.
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Cognición , Americanos Mexicanos , Características del Vecindario , Blanco , Femenino , Humanos , Estudios Transversales , Función Ejecutiva , Masculino , Persona de Mediana Edad , Anciano , Estados UnidosRESUMEN
INTRODUCTION: People with Down syndrome (DS) often develop Alzheimer's disease (AD). Here, we asked whether ultrasensitive plasma immunoassays for a tau N-terminal fragment (NT1-tau) and Aß isoforms predict cognitive impairment. METHODS: Plasma NT1-tau, Aß37 , Aß40 , and Aß42 levels were measured in a longitudinal discovery cohort (N = 85 participants, 220 samples) and a cross-sectional validation cohort (N = 239). We developed linear models and predicted values in the validation cohort. RESULTS: Discovery cohort linear mixed models for NT1-tau, Aß42 , and Aß37:42 were significant for age; there was no main effect of time. In cross-sectional models, NT1-tau increased and Aß42 decreased with age. NT1-tau predicted cognitive and functional scores. The discovery cohort linear model for NT1-tau predicted levels in the validation cohort. DISCUSSION: NT1-tau correlates with age and worse cognition in DS. Further validation of NT1-tau and other plasma biomarkers of AD neuropathology in DS cohorts is important for clinical utility.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Síndrome de Down , Humanos , Proteínas tau , Estudios Transversales , Cognición , Biomarcadores , Péptidos beta-Amiloides , Fragmentos de PéptidosRESUMEN
Timely detection of the pathophysiological changes and cognitive impairment caused by Alzheimer's disease (AD) is increasingly pressing because of the advent of biomarker-guided targeted therapies that may be most effective when provided early in the disease. Currently, diagnosis and management of early AD are largely guided by clinical symptoms. FDA-approved neuroimaging and cerebrospinal fluid biomarkers can aid detection and diagnosis, but the clinical implementation of these testing modalities is limited because of availability, cost, and perceived invasiveness. Blood-based biomarkers (BBBMs) may enable earlier and faster diagnoses as well as aid in risk assessment, early detection, prognosis, and management. Herein, we review data on BBBMs that are closest to clinical implementation, particularly those based on measures of amyloid-ß peptides and phosphorylated tau species. We discuss key parameters and considerations for the development and potential deployment of these BBBMs under different contexts of use and highlight challenges at the methodological, clinical, and regulatory levels.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/líquido cefalorraquídeo , Péptidos beta-Amiloides , Disfunción Cognitiva/diagnóstico , Biomarcadores/líquido cefalorraquídeo , Atención a la Salud , Proteínas tau/líquido cefalorraquídeo , Fragmentos de PéptidosRESUMEN
Objective: This study aims to investigate the association between neighborhood deprivation and the prevalence of major cardiovascular disease (CVD) risk factors (hypertension, diabetes, dyslipidemia, and obesity) in a Mexican American (MA) population compared to NonHispanic Whites (NHW). Method: A cross-sectional analysis was conducted to include 1,867 subjects (971 MA and 896 NHW). Participants underwent a clinical interview, neuropsychological exam battery, functional examination, MRI of the head, amyloid PET scan, and blood draw for clinical and biomarker analysis. We use the Area Deprivation Index (ADI) Model to assign an ADI score to participants based on their neighborhoods. Descriptive, Cochran-Armitage test for trend, and odds ratio statistical analysis were applied. Results: Our results suggest that NHW had higher odds of having HTN, DM, and obesity in the most deprived neighborhoods, while MA showed no increased odds. The study also found that neighborhood deprivation contributed to diabetes in both MA and NHW and was associated with obesity in NHW. Conclusions: These findings highlighted the importance of addressing both individual and societal factors in efforts to reduce cardiovascular risk. Future research should explore the relationship between socio-economic status and cardiovascular risk in more detail to inform the development of targeted interventions.
RESUMEN
INTRODUCTION: The influence of apolipoprotein E (APOE) genotype on mild cognitive impairment (MCI) and Alzheimer's disease (AD) is well studied in the non-Hispanic white (NHW) population but not in the Hispanic population. Additionally, health risk factors such as hypertension, stroke, and depression may also differ between the two populations. METHODS: We combined three data sets (National Alzheimer's Coordinating Center [NACC], Alzheimer's Disease Neuroimaging Initiative [ADNI], Health and Aging Brain Study: Health Disparities [HABS-HD]) and compared risk factors for MCI and AD between Hispanic and NHW participants, with a total of 24,268 participants (11.1% Hispanic). RESULTS: APOEε4 was associated with fewer all-cause MCI cases in Hispanic participants (Hispanic odds ratio [OR]: 1.114; NHW OR: 1.453), and APOEε2 (Hispanic OR: 1.224; NHW OR: 0.592) and depression (Hispanic OR: 2.817; NHW OR: 1.847) were associated with more AD cases in Hispanic participants. DISCUSSION: APOEε2 may not be protective for AD in Hispanic participants and Hispanic participants with depression may face a higher risk for AD. HIGHLIGHTS: GAAIN allows for discovery of data sets to use in secondary analyses. APOEε2 was not protective for AD in Hispanic participants. APOEε4 was associated with fewer MCI cases in Hispanic participants. Depression was associated with more AD cases in Hispanic participants.