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Background: Alzheimer's disease is the most common type of dementia and is responsible for up to 80% of dementia diagnoses and is the sixth leading cause of death in the United States. An estimated 38,000 American Indian/Alaska Native (AI/AN) people aged ≥65 years were living with Alzheimer's disease and related dementias (ADRD) in 2020, a number expected to double by 2030 and quadruple by 2050. Administrative healthcare data from the Indian Health Service (IHS) were used to estimate ADRD among AI/AN populations. Methods: Administrative IHS healthcare data from federal fiscal years 2016 to 2020 from the IHS National Data Warehouse were used to calculate the count and rate per 100,000 AI/AN adults aged ≥45 years with at least one ADRD diagnosis code on their medical record. Results: This study identified 12,877 AI/AN adults aged ≥45 years with an ADRD diagnosis code, with an overall rate of 514 per 100,000. Of those, 1856 people were aged 45–64. Females were 1.2 times (95% confidence interval: 1.1–1.2) more likely than males to have a medical visit with an ADRD diagnosis code. Conclusions: Many AI/AN people with ADRD rely on IHS, tribal, and urban Indian health programs. The high burden of ADRD in AI/AN populations aged 45–64 utilizing IHS health services highlights the need for implementation of ADRD risk reduction strategies and assessment and diagnosis of ADRD in younger AI/AN populations. This study provides a baseline to assess future progress for efforts addressing ADRD in AI/AN communities. [ABSTRACT FROM AUTHOR]

Introduction: Anticipating the diagnosis of Alzheimer's disease (AD) at an early asymptomatic at-risk stage, where therapeutics can more effectively delay conscious cognitive decline, is currently among the biggest challenges in the field. Herein, we aimed to compare the capacity of the Memory Binding Test (MBT) with the official diagnostic tool, the Free and Cued Selective Reminding Test (FCSRT), to anticipate AD diagnosis at an early preclinical stage based on the associative memory component of MBT (binding), suggested as more sensitive to the emergence of subtle episodic memory (EM) deficits (AD hallmark). Methods: We assessed the tests performance longitudinally (over 5 years) in 263 cognitively-normal elderly individuals at risk of AD (>6 months of subjective memory complaints) using linear mixed-effect models controlled for age, sex, and education. We stratified participants in 2 models: amyloid-β (Aβ)/neurodegeneration (N) model, assessing Aβ burden and neurodegeneration effect [3 groups: controls (Aβ-/N-); stable/N- (Aβ+); stable/N+ (Aβ+)]; and the stable/progressors model, assessing progression to prodromal-AD effect [2 groups: stable (Aβ+); progressors (Aβ+)], based on 15 subjects who progressed to AD during follow-up (excluded once diagnosed). Results: Aβ burden was associated with significantly less MBT-intrusions, while Aβ burden and neurodegeneration together, with the most. Progression status had a strong negative effect on both tests performance. When compared with the FCSRT, the MBT seems to anticipate diagnosis based on a worst performance in a higher number of scores (including binding) in at least a year. Discussion: Anticipation of diagnosis to an asymptomatic at-risk stage, while participants remain cognitively-normal according to FCSRT cut-offs and unaware of objective EM deficits, has the potential to delay the onset of AD-linked cognitive decline by applying promising therapeutics before decline becomes too advanced. [ABSTRACT FROM AUTHOR]

Introduction: Emerging evidence suggests a connection between vulnerability to infections and Alzheimer's disease (AD). The nectin cell adhesion molecule 2 (NECTIN2) gene coding for a membrane component of adherens junctions is involved in response to infections, and its single nucleotide polymorphism (SNP) rs6859 was significantly associated with AD risk in several human cohorts. It is unclear, however, how exactly rs6859 influences the development of AD pathology. The aggregation of hyperphosphorylated tau protein (pTau) is a key pathological feature of neurodegeneration in AD, which may be induced by infections, among other factors, and potentially influenced by genes involved in both AD and vulnerability to infections, such as NECTIN2. Materials and methods: We conducted a causal mediation analysis (CMA) on a sample of 708 participants in the Alzheimer's disease Neuroimaging Initiative (ADNI). The relationship between rs6859 and Alzheimer's disease (AD), with AD (yes/no) as the outcome and pTau-181 levels in the cerebrospinal fluid (CSF) acting as a mediator in this association, was assessed. Adjusted estimates from the probit and linear regression models were used in the CMA model, where an additive model considered an increase in dosage of the rs6859 A allele (AD risk factor). Results: The increase in dose of allele A of the SNP rs6859 resulted in about 0.144 increase per standard deviation (SD) of pTau-181 (95% CI: 0.041, 0.248, p < 0.01). When included together in the probit model, the change in A allele dose and each standard deviation change in pTau-181 predicted 6.84% and 9.79% higher probabilities for AD, respectively. In the CMA, the proportion of the average mediated effect was 17.05% and was higher for the risk allele homozygotes (AA), at 19.40% (95% CI: 6.20%, 43.00%, p < 0.01). The sensitivity analysis confirmed the evidence of a robust mediation effect. Conclusion: This study reported a new potential causal relationship between pTau-181 and AD. We found that the association between rs6859 in the NECTIN2 gene and AD is partly mediated by pTau-181 levels in CSF. The rest of this association may be mediated by other factors. Our finding sheds light on the complex interplay between genetic susceptibility, protein aggregation, and neurodegeneration in AD. Further research, using other biomarkers, is needed to uncover the remaining mechanisms of the association between the NECTIN2 gene and AD. [ABSTRACT FROM AUTHOR]

Purpose: Alzheimer's disease (AD) is a common neurodegenerative disease, which can lead to cognitive impairment and dementia. Since AD is tightly associated with aging and cellular senescence, objective of this study was to investigate the association between senescence-related genes and proteins (SRGs and SRPs) and the development of AD. Design: The whole study was based on transcriptomic analysis of control and AD brain tissues and Mendelian randomization (MR) analysis. Methods: For transcriptomic analysis, GSE5281 dataset from GEO database contains the transcriptomic data of human brain tissues (n = 161) from control group and AD patients. The expression of SRGs in control and AD brain tissues were compared by Student's t test. For MR analysis, the instrumental singlenucleotide polymorphisms (SNPs) associated with 110 SRPs were filtered and selected from a large genome-wide association study (GWAS) for plasma proteome. The causality between plasma levels of SRPs and AD was explored using GWAS data of AD from Lambert et al. (17,008 cases and 37,154 controls) and further validated by using data from FinnGen consortium (6,489 patients and 170,489 controls). MR estimate was performed using the inversevariance weighted (IVW) method and the heterogeneity and pleiotropy of results were tested. Results: Transcriptomic analysis identified 36 up-regulated (including PLAUR) and 8 down-regulated SRGs in AD brain tissues. In addition, the MR results at both discovery and validation stages supported the causality between plasma levels of PLAUR (IVW-p = 3.04E-2, odds ratio [OR]= 1.15), CD55 (IVW-p = 1.56E-3, OR= 0.86), and SERPINE2 (IVW-p = 2.74E-2, OR= 0.91) and the risk of AD. Conclusion: Our findings identified that PLAUR, as an SRG, may take part in the development of AD and found that high plasma levels of PLAUR was associated with increased risk of AD, indicating that this gene was a risk factor for this disease and providing the rationale of existing drugs or new preventative and therapeutic strategies. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases, and the most prevalent form of dementia. The main hallmarks for the diagnosis of AD are extracellular amyloid-beta (Aβ) plaque deposition and intracellular accumulation of highly hyperphosphorylated Tau protein as neurofibrillary tangles. The brain consumes more oxygen than any other organs, so it is more easily to be affected by hypoxia. Hypoxia has long been recognized as one of the possible causes of AD and other neurodegenerative diseases, but the exact mechanism has not been clarified. In this review, we will elucidate the connection between hypoxia-inducible factors-1α and AD, including its contribution to AD and its possible protective effects. Additionally, we will discuss the relationship between oxidative stress and AD as evidence show that oxidative stress acts on AD-related pathogenic factors such as mitochondrial dysfunction, Aβ deposition, inflammation, etc. Currently, there is no cure for AD. Given the close association between hypoxia, oxidative stress, and AD, along with current research on the protective effects of antioxidants against AD, we speculate that antioxidants could be a potential therapeutic approach for AD and worth further study. [ABSTRACT FROM AUTHOR]

Background: Women carrying the APOE4 allele are at greater risk of developing Alzheimer's disease (AD) from ages 65-75 years compared to men. To better understand the elevated risk conferred by APOE4 carrier status among midlife women, we investigated the separate and interactive associations of endogenous estrogens, plasma AD biomarkers, and APOE4 carrier status on regional brain volumes in a sample of late midlife postmenopausal women. Methods: Participants were enrolled in MsBrain, a cohort study of postmenopausal women (n = 171, mean age = 59.4 years, mean MoCA score = 26.9; race = 83.2% white, APOE4 carriers = 40). Serum estrone (E1) and estradiol (E2) levels were assessed using liquid chromatography-tandem mass spectrometry. APOE genotype was determined using TaqMan SNP genotyping assays. Plasma AD biomarkers were measured using single molecule array technology. Cortical volume was measured and segmented by FreeSurfer software using individual T1w MPRAGE images. Multiple linear regression models were conducted to determine whether separate and interactive associations between endogenous estrogen levels, plasma AD biomarkers (Aβ42/Aβ40, Aβ42/p-tau181), and APOE4 carrier status predict regional brain volume (21 regions per hemisphere, selected a priori); and, whether significant interactive associations between estrogens and AD biomarkers on brain volume differed by APOE4 carrier status. Results: There was no main effect of APOE4 carrier status on regional brain volumes, endogenous estrogen levels, or plasma AD biomarkers. Estrogens did not associate with regional brain volumes, except for positive associations with left caudal middle frontal gyrus and fusiform volumes. The interactive association of estrogens and APOE4 carrier status on brain volume was not significant for any region. The interactive association of estrogens and plasma AD biomarkers predicted brain volume of several regions. Higher E1 and E2 were more strongly associated with greater regional brain volumes among women with a poorer AD biomarker profile (lower Aβ42/40, lower Aβ42/p-tau181 ratios). In APOE4- stratified analyses, these interactions were driven by non-APOE4 carriers. Conclusion: We demonstrate that the brain volumes of postmenopausal women with poorer AD biomarker profiles benefit most from higher endogenous estrogen levels. These findings are driven by non-APOE4 carriers, suggesting that APOE4 carriers may be insensitive to the favorable effects of estrogens on brain volume in the postmenopause. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common fatal neurodegenerative disease among the elderly worldwide, characterized by memory and cognitive impairment. The identification of biomarkers for AD is crucial and urgent to facilitate the diagnosis and intervention. The aim of this study was to evaluate the diagnostic value of acyl-Coenzyme A thioesterase 7 (ACOT7) as a serum biomarker for the prediction of AD. In our study, we observed a significant increase in ACOT7 expression in patients (n = 366) with AD and animal (n = 8-12) models of AD, compared to the control group. A significant negative correlation was found between ACOT7 levels and Mini-Mental State Examination (MMSE) scores (r = -0.85; p < 0.001). The analysis of the receiver operating characteristic curve (ROC) showed that the area under the curve (AUC) for ACOT7 was 0.83 (95% confidence intervals: 0.80-0.86). The optimal cut-off point of 62.5 pg./mL was selected with the highest sum of sensitivity and specificity. The diagnostic accuracy of serum ACOT7 for AD was 77% (95% confidence intervals: 72-82%), with a sensitivity of 80% (95% confidence intervals: 75-84%) and a specificity of 74% (95% confidence intervals: 69-79%). Moreover, the ROC analysis showed that the AUC of Aβ42/40 ratio is 0.70, and the diagnostic accuracy was 72%, with 69% sensitivity and 76% specificity. Compared with the AD traditional marker Aβ42/40 ratio, ACOT7 shows better superiority as a new serum candidate biomarker of AD. By suppressing the ACOT7 gene, our study provides evidence of the involvement of ACOT7 in the metabolism of amyloid precursor protein (APP), resulting in alterations in the expression levels of Aβ42, BACE1 and βCTF. ACOT7 has the ability to modulate the amyloidogenic pathway of APP metabolism, while it does not have an impact on the non-amyloidogenic pathway. In conclusion, the findings of our study suggest that serum ACOT7 may serve as a promising and non-invasive biomarker for AD. [ABSTRACT FROM AUTHOR]

Introduction: Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Current core cerebrospinal fluid (CSF) AD biomarkers, widely employed for diagnosis, require a lumbar puncture to be performed, making them impractical as screening tools. Considering the role of sleep disturbances in AD, recent research suggests quantitative sleep electroencephalography features as potential non-invasive biomarkers of AD pathology. However, quantitative analysis of comprehensive polysomnography (PSG) signals remains relatively understudied. PSG is a non-invasive test enabling qualitative and quantitative analysis of a wide range of parameters, offering additional insights alongside other biomarkers. Machine Learning (ML) gained interest for its ability to discern intricate patterns within complex datasets, offering promise in AD neuropathology detection. Therefore, this study aims to evaluate the effectiveness of a multimodal ML approach in predicting core AD CSF biomarkers. Methods: Mild-moderate AD patients were prospectively recruited for PSG, followed by testing of CSF and blood samples for biomarkers. PSG signals underwent preprocessing to extract non-linear, time domain and frequency domain statistics quantitative features. Multiple ML algorithms were trained using four subsets of input features: clinical variables (CLINVAR), conventional PSG parameters (SLEEPVAR), quantitative PSG signal features (PSGVAR) and a combination of all subsets (ALL). Cross-validation techniques were employed to evaluate model performance and ensure generalizability. Regression models were developed to determine the most effective variable combinations for explaining variance in the biomarkers. Results: On 49 subjects, Gradient Boosting Regressors achieved the best results in estimating biomarkers levels, using different loss functions for each biomarker: least absolute deviation (LAD) for the Aß42, least squares (LS) for p-tau and Huber for t-tau. The ALL subset demonstrated the lowest training errors for all three biomarkers, albeit with varying test performance. Specifically, the SLEEPVAR subset yielded the best test performance in predicting Aß42, while the ALL subset most accurately predicted p-tau and t-tau due to the lowest test errors. Conclusions: Multimodal ML can help predict the outcome of CSF biomarkers in early AD by utilizing non-invasive and economically feasible variables. The integration of computational models into medical practice offers a promising tool for the screening of patients at risk of AD, potentially guiding clinical decisions. [ABSTRACT FROM AUTHOR]

Background: Themost effective approach tomanaging Alzheimer's disease (AD) lies in identifying reliable biomarkers for AD to forecast the disease in advance, followed by timely early intervention for patients. Methods: Transcriptomic data on peripheral blood mononuclear cells (PBMCs) from patients with AD and the control group were collected, and preliminary data processing was completed using standardized analytical methods. PBMCs were initially segmented into distinct subpopulations, and the divisions were progressively refined until the most significantly altered cell populations were identified. A combination of high-dimensional weighted gene co-expression analysis (hdWGCNA), cellular communication, pseudotime analysis, and single-cell regulatory network inference and clustering (SCENIC) analysis was used to conduct single-cell transcriptomics analysis and identify key gene modules from them. Genes were screened using machine learning (ML) in the key gene modules, and internal and external dataset validations were performed using multiple ML methods to test predictive performance. Finally, bidirectional Mendelian randomization (MR) analysis, regional linkage analysis, and the Steiger test were employed to analyze the key gene. Result: A significant decrease in non-classical monocytes was detected in PMBC of AD patients. Subsequent analyses revealed the inherent connection of non-classical monocytes to AD, and the NAP1L1 gene identified within its gene module appeared to exhibit some association with AD as well. Conclusion: The NAP1L1 gene is a potential predictive biomarker for AD. [ABSTRACT FROM AUTHOR]

Type-2 diabetes (T2D) is a metabolic disorder that is considered a risk factor for Alzheimer's disease (AD). Cognitive impairment can arise due to hypoglycemia associated with T2D, and hyperamylinemia associated with insulin resistance can enhance AD pathology. We explored whether changes occur in the hippocampus in aging (6-12 months old) female V-Lep◦b-/- transgenic (tg) mice, comprising an animal model of T2D. We also investigated whether an increase in vulnerability to Aβ (1-42), a known pathological hallmark of AD, is evident. Using magnetic resonance imaging we detected significant decreases in hippocampal brain volume in female tg-mice compared to wild-type (wt) littermates. Long-term potentiation (LTP) was impaired in tg compared to wt mice. Treatment of the hippocampus with Aβ (1-42) elicited a stronger debilitation of LTP in tg compared to wt mice. Treatment with an amylin antagonist (AC187) significantly enhanced LTP in wt and tg mice, and rescued LTP in Aβ (1-42)-treated tgmice. Taken together our data indicate that a T2D-like state results in an increased vulnerability of the hippocampus to the debilitating effects of Aβ (1-42) and that effects are mediated in part by changes in amylin receptor signaling. [ABSTRACT FROM AUTHOR]

The article examines the effectiveness of aggressive lifestyle interventions, informed by the LIBRA risk score, in mitigating Alzheimer's disease risk and managing early-stage mild cognitive impairment.

BACKGROUND: Increased exposure to ambient air pollution, especially fine particulate matter ≤2.5 μm (PM2.5) is associated with poorer brain health and increased risk for Alzheimer’s disease (AD) and related dementias. The locus coeruleus (LC), located in the brainstem, is one of the earliest regions affected by tau pathology seen in AD. Its diffuse projections throughout the brain include afferents to olfactory areas that are hypothesized conduits of cerebral particle deposition. Additionally, extensive contact of the LC with the cerebrovascular system may present an additional route of exposure to environmental toxicants. OBJECTIVE: Our aim was to investigate if exposure to PM2.5 was associated with LC integrity in a nationwide sample of men in early old age, potentially representing one pathway through which air pollution can contribute to increased risk for AD dementia. METHODS: We examined the relationship between PM2.5 and in vivo magnetic resonance imaging (MRI) estimates of LC structural integrity indexed by contrast to noise ratio (LCCNR) in 381 men [mean age = 67.3; standard deviation (SD)= 2.6] from the Vietnam Era Twin Study of Aging (VETSA). Exposure to PM2.5 was taken as a 3-year average over the most recent period for which data were available (average of 5.6 years prior to the MRI scan). We focused on LCCNR in the rostral-middle portion of LC due to its stronger associations with aging and AD than the caudal LC. Associations between PM2.5 exposures and LC integrity were tested using linear mixed effects models adjusted for age, scanner, education, household income, and interval between exposure and MRI. A co-twin control analysis was also performed to investigate whether associations remained after controlling for genetic confounding and rearing environment. RESULTS: Multiple linear regressions revealed a significant association between PM2.5 and rostral-middle LCCNR (β= -0.16; 푝= 0.02), whereby higher exposure to PM2.5 was associated with lower LCCNR. A co-twin control analysis found that, within monozygotic pairs, individuals with higher PM2.5 exposure showed lower LCCNR (β= -0.11; 푝= 0.02), indicating associations were not driven by genetic or shared environmental confounds. There were no associations between PM2.5 and caudal LCCNR or hippocampal volume, suggesting a degree of specificity to the rostralmiddle portion of the LC. DISCUSSION: Given previous findings that loss of LC integrity is associated with increased accumulation of AD-related amyloid and tau pathology, impacts on LC integrity may represent a potential pathway through which exposure to air pollution increases AD risk. [ABSTRACT FROM AUTHOR]

Objective: To compare how different imputation methods affect the estimates and performance of a prediction model for premature mortality. Study Design and Setting: Sex-specific Weibull accelerated failure time survival models were run on four separate datasets using complete case, mode, single and multiple imputation to impute missing values. Six performance measures were compared to access predictive accuracy (Nagelkerke R2, integrated brier score), discrimination (Harrell's c-index, discrimination slope) and calibration (calibration in the large, calibration slope). Results: The highest proportion of missingness for a single variable was 10.86% for the female model and 8.24% for the male model. Comparing the performance measures for complete case, mode, single and multiple imputation: the Nagelkerke R2 values for the female model was 0.1084, 0.1116, 0.1120 and 0.111–0.1120 with the male model exhibited similar variation of 0.1050, 0.1078, 0.1078 and 0.1078–0.1081. Harrell's c-index also demonstrated small variation with values of 0.8666, 0.8719, 0.8719 and 0.8711–0.8719 for the female model and 0.8549, 0.8548, 0.8550 and 0.8550–0.8553 for the male model. Conclusion: In the scenarios examined in this study, mode imputation performed well when using a population health survey compared to single and multiple imputation when predictive performance measures is the main model goal. To generate unbiased hazard ratios, multiple imputation methods were superior. This study shows the need to consider the best imputation approach for a predictive model development given the conditions of missing data and the goals of the analysis. [ABSTRACT FROM AUTHOR]

Background: Effective prevention is key to addressing the increasing prevalence and mortality of Alzheimer's disease. Assessing the causal relationship between modifiable entertainment activity factors and the risk of Alzheimer's disease is important for developing public health measures, but establishing causal relationships in epidemiological data may be challenging. Methods: This study using the two-sample Mendelian randomization analysis aimed to investigate the causal effect of entertainment activity factors on the risk of Alzheimer's disease. Summary statistics from publicly available genome-wide association studies were used to analyze 14 modifiable entertainment activity. The inverse variance weighted random effects method as the primary analytical method to estimate causal effects was used. Additionally performed MR-Egger, weighted median and weighted model methods to assess the robustness of the results. The reliability of our findings was validated through systematic sensitivity analyses and tests for heterogeneity. Results: We found significant correlation between time spent using computer (odds ratio 0.998; 95% confidence interval 0.996-0.999; p = 0.013) and Alzheimer's disease, compared to other studied entertainment activities that had no significant causal relationship with Alzheimer's disease. Conclusion: Our findings support the hypothesis that increased computer use may reduce the risk of Alzheimer's disease, providing potential strategic directions for the prevention of neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Introduction: Alzheimer's disease (AD) is the most widespread neurodegenerative disease in the world. Previous studies have shown that peripheral immune dysregulation plays a paramount role in AD, but whether there is a protective causal relationship between peripheral immunophenotypes and AD risk remains ambiguous. Methods: Two-sample Mendelian randomization (MR) was performed using large genome-wide association study (GWAS) genetic data to assess causal effects between peripheral immunophenotypes and AD risk. Utilizing the genetic associations of 731 immune cell traits as exposures. We adopted the inverse variance weighted method as the primary approach. The Weighted median and MR-Egger regression methods were employed as supplements. Various sensitivity analyses were performed to assess the robustness of the outcomes. Results: Based on the IVW method, we identified 14 immune cell traits that significantly reduced the risk of AD, of which six demonstrated statistical significance in both IVW and Weighted median methods. Among the seven immune traits, four were related to regulatory T (Treg) cells: (1) CD25++ CD45RA- CD4 not regulatory T cell % T cell (odds ratio (OR) [95% confidence interval (CI)] = 0.96 [0.95, 0.98], adjusted P = 1.17E-02), (2) CD25++ CD45RACD4 not regulatory T cell % CD4+ T cell (OR [95% CI] = 0.97 [0.96, 0.99], adjusted P = 3.77E-02), (3) Secreting CD4 regulatory T cell % CD4 regulatory T cell (OR [95% CI] = 0.98 [0.97, 0.99], adjusted P = 7.10E-03), (4) Activated & secreting CD4 regulatory T cell % CD4 regulatory T cell(OR [95% CI] = 0.98 [0.97, 0.99], adjusted P = 7.10E-03). In addition, HLA DR++ monocyte % monocyte (OR [95% CI] = 0.93 [0.89, 0.98], adjusted P = 4.87E-02) was associated with monocytes, and HLA DR on myeloid Dendritic Cell (OR [95% CI] = 0.93 [0.89, 0.97], adjusted P = 1.17E-02) was related to dendritic cells (DCs). Conclusion: These findings enhance the comprehension of the protective role of peripheral immunity in AD and provide further support for Treg and monocyte as potential targets for immunotherapy in AD. [ABSTRACT FROM AUTHOR]

Background Down syndrome (DS) is the most prevalent chromosomal disorder, being the leading cause of intellectual disability. The increased life expectancy of individuals with DS has led to a shift in the incidence of non-communicable chronic diseases, resulting in new concerns, particularly cardiovascular disease (CVD) and Alzheimer's disease. This study aimed to analyse the blood lipid profile of a large DS cohort to establish a baseline for evaluating health risk parameters. Methods A comprehensive literature search was conducted on PubMed and Virtual Health Library databases to identify original articles published before July 2022. Selected studies were included in the meta-analysis. Results Fifteen studies reporting serum lipid levels in individuals with DS were incorporated into the analysis. The meta-analysis used the means and standard deviations extracted from the selected studies. The analysis encompassed 671 participants in the DS group and 898 euploid controls. The results indicated significant differences in total cholesterol [C] (mean difference [MD]: −3.34; CI: 95%: −4.94 to −1.73; P < 0.0001), HDL-C (MD: −3.39; CI: 95%: −6.72 to −0.06; P = 0.05) and triglycerides (MD: 21.48; CI: 95%: 9.32 to 33.65; P = 0.0005) levels between individuals with DS and their control counterparts. Conclusions Individuals with DS have less favourable blood lipid concentrations than their controls, particularly HDL-C, triglycerides, and total-C, even when grouped by age. These findings underscore the importance of closer monitoring of lipid profiles in people with DS and the necessity for specific cut-offs for this population, considering the risk for ischemic heart and Alzheimer's diseases. [ABSTRACT FROM AUTHOR]

Objectives Generativity, the desire and action to improve the well-being of younger generations, is associated with purpose in life among older adults. However, the neurobehavioral factors supporting the relationship between generativity and purpose in life remain unknown. This study aims to identify the functional neuroanatomy of generativity and mechanisms linking generativity with purpose in life in at-risk older adults. Methods Fifty-eight older adults (mean age = 70.8, SD =  5.03, 45 females) with a family history of Alzheimer's disease (AD) were recruited from the PREVENT-AD cohort. Participants underwent brain imaging and completed questionnaires assessing generativity, social support, and purpose in life. Mediation models examined whether social support mediated the association between generativity and purpose in life. Seed-to-voxel analyses investigated the association between generativity and resting-state functional connectivity (rsFC) to the ventromedial prefrontal cortex (vmPFC) and ventral striatum (VS), and whether this rsFC moderated the relationship between generativity and purpose in life. Results Affectionate social support mediated the association between generative desire and purpose in life. Generative desire was associated with rsFC between VS and precuneus, and, vmPFC and right dorsolateral prefrontal cortex (rdlPFC). The vmPFC–rdlPFC rsFC moderated the association between generative desire and purpose in life. Discussion These findings provide insight into how the brain supports complex social behavior and, separately, purpose in life in at-risk aging. Affectionate social support may be a putative target process to enhance purpose in life in older adults. This knowledge contributes to future developments of personalized interventions that promote healthy aging. [ABSTRACT FROM AUTHOR]

Racially and ethnically diverse populations have recently contributed to the majority of rural and small-town growth. Consequently, the disproportionately high risk and prevalence of Alzheimer's disease and related dementias (ADRD) among rural and minoritized older residents will likely increase. To address this threat, we tested the hypotheses that (1) a faith-based, resident-led approach would increase basic ADRD knowledge and diagnosis, and (2) older age, female gender, lower educational levels, and more years lived rural would predict number of referrals, new dementia diagnoses, and treatment. An adaptation of Schoenberg's Faith Moves Mountains model, previously successful in detection and management of other chronic illnesses in rural settings, guided this community-based participatory research. Local faith community members were trained as research assistants to recruit, administer surveys, conduct brief memory assessments, teach brain health strategies, and follow-up with residents. Outreaches were offered virtually during the pandemic, then in-person monthly at rotating church sites, and repeated ∼1 year later. This rural sample was racially and ethnically diverse (74.5% non-White), with 28% reporting eight or less years of formal education. Findings included that referrals and years lived rural were significant and positive predictors of new ADRD treatments [(b = 3.74, χ2(1, n = 235) = 13.01, p < 0.001); (b = 0.02, χ2(1, n = 235 = 3.93, p = 0.048)], respectively, regardless of participant characteristics. Resident-led action research in rural, diverse, faith communities is a successful approach to increasing ADRD disease knowledge, detection, diagnosis, and treatment. [ABSTRACT FROM AUTHOR]

The targeting of amyloid-beta (Aß) plaques therapeutically as one of the primary causes of Alzheimer's disease (AD) dementia has been an ongoing effort spanning decades. While some antibodies are extremely promising and have been moved out of clinical trials and into the clinic, most of these treatments show similar adverse effects in the form of cerebrovascular damage known as amyloid-related imaging abnormalities (ARIA). The two categories of ARIA are of major concern for patients, families, and prescribing physicians, with ARIA-E presenting as cerebral edema, and ARIA-H as cerebral hemorrhages (microand macro-). From preclinical and clinical trials, it has been observed that the greatest genetic risk factor for AD, APOEε4, is also a major risk factor for anti-Aβ immunotherapy-induced ARIA. APOEe4 carriers represent a large population of AD patients, and, therefore, limits the broad adoption of these therapies across the AD population. In this review we detail three hypothesized mechanisms by which APOEe4 influences ARIA risk: (1) reduced cerebrovascular integrity, (2) increased neuroinflammation and immune dysregulation, and (3) elevated levels of CAA. The effects of APOEε4 on ARIA risk is clear, however, the underlying mechanisms require more research. [ABSTRACT FROM AUTHOR]

Background. Subjective cognitive decline (SCD) in older individuals has been implicated as a possible precursor to Alzheimer's disease. Poor sleep quality and anxiety/depressive symptoms have been linked to the progression of SCD, but these associations and older adults' worries have yet to be fully established in the Chinese older adult population, which is one of the largest in the world. The aim of this study was to explore the relationship between sleep quality, anxiety/depression symptoms, and worries, and SCD prevalence among Chinese community-dwelling older individuals. Methods. A total of 707 adults aged between 60 and 99 from Shanghai, China, completed self-report questionnaires that covered their cognitive and mental well-being, as well as demographic information. Subjective cognitive decline (SCD) was evaluated using the memory/cognition syndromes of the old adult self-report (OASR). Sleep quality, anxiety/depression, and worries were measured from their respective sections of the OASR. Results. The general linear regression models showed that poorer sleep quality was associated with an increased prevalence of anxiety/depression symptoms, worries, and SCD among older adults. As suggested by the mediation analysis, anxiety/depression and worries were significant mediators in the relationship between sleep quality and SCD prevalence, and these two factors also have a serial mediation effect between sleep quality and SCD prevalence. Conclusions. Poorer sleep quality is associated with a higher rate of SCD among older adults, and a higher prevalence of anxiety/depression and worries mediate this relationship, suggesting possible mechanism pathways that lead to SCD. These factors may provide the basis for early, targeted interventions for older adults' mental health preservation and improved quality of life. [ABSTRACT FROM AUTHOR]

Introduction: Low educational attainment is a potential risk factor for Alzheimer's disease (AD) development. Alpha-secretase ADAM10 plays a central role in AD pathology, attenuating the formation of beta-amyloid peptides and, therefore, their aggregation into senile plaques. This study seeks to investigate ADAM10 as a blood-based biomarker in mild cognitive impairment (MCI) and AD in a diverse group of community-dwelling older adults, focusing on those with limited educational attainment. Methods: Participants were recruited from public health services. Cognition was evaluated using Mini-Mental State Examination (MMSE) and Addenbrooke's Cognitive Examination – Revised (ACE-R) batteries. Blood samples were collected to analyze plasma ADAM10 levels. A logistic regression was conducted to verify the influence of plasma ADAM10 on the AD diagnosis. Results: Significant differences in age, years of education, prescribed medications, and cognitive test scores were found between the MCI and AD groups. Regarding cognitive performance, both ACE-R and MMSE scores displayed significant differences between groups, with post hoc analyses highlighting these distinctions, particularly between AD and cognitively unimpaired individuals. Elevated plasma ADAM10 levels were associated with a 4.5-fold increase in the likelihood of a diagnosis of MCI and a 5.9-fold increase in the likelihood of a diagnosis of AD. These findings suggest ADAM10 levels in plasma as a valuable biomarker for assessing cognitive status in older individuals with low education attainment. Conclusion: This study underscores the potential utility of plasma ADAM10 levels as a blood-based biomarker for cognitive status, especially in individuals with low educational backgrounds, shedding light on their relevance in AD development and diagnosis. [ABSTRACT FROM AUTHOR]

To establish the impact of a 3-minute computerized cognitive training program (START) on cognition in older adults with and without genetic risk of Alzheimer's disease. Two-arm randomized controlled trial of the START program. Remote online trial in adults older than 50 taking part from home. The trial compared the START program with placebo in 6544 people older than 50. Primary outcome was executive function measured through Trailmaking B, with other secondary cognitive measures. Genetic risk profile and ApoE4 status were determined by Illumina Array. START conferred benefit to executive function, attention, memory, and a composite measure, including in people with the ApoE4 genotype. The 3-minute START task offers a means of supporting cognitive health in older adults and could be used at scale and within a precision medicine approach to reduce risk of cognitive decline in a targeted way. [ABSTRACT FROM AUTHOR]

Background and Objectives Dementia-related anxiety (DRA) is the fear of a current or future diagnosis of Alzheimer's disease or another type of dementia. Previous studies suggest diverse factors contribute to DRA, including emotional, social, and cognitive concerns. A mixed-methods investigation was designed to explore DRA's underlying causes; we present a thematic analysis of these causes. Research Design and Methods A semistructured qualitative interview design was used to explore participant's thoughts, feelings, and reactions about dementia. Fifty community-dwelling adults (aged 58–89, M  = 70.80, SD  = 6.02) without dementia diagnoses were interviewed, with a focus on why dementias are anxiety-provoking diagnoses. We engaged in a reflexive inductive thematic approach. Results We identified 7 themes positioned within previously established antecedents of DRA. Anticipated consequences were conveyed in statements identifying dementia as a feared diagnosis and its connection to how one would be treated if diagnosed. Low perceived control was associated with dementia's anticipated effects including the ability of dementia to undermine core aspects of one's personhood, limit independence, and increase reliance on others. Perceived risk was connected to past familial experiences with dementia and the implications of receiving different diagnoses with different trajectories and treatments. Discussion and Implications Findings offer insight into diverse factors contributing to DRA, which can be used to inform public health messaging and develop applicable and clinically relevant interventions to meet the needs of individuals experiencing DRA and their social support systems. [ABSTRACT FROM AUTHOR]

This review provides a comprehensive examination of the role of clathrinmediated endocytosis (CME) in Alzheimer's disease (AD) pathogenesis, emphasizing its impact across various cellular contexts beyond neuronal dysfunction. In neurons, dysregulated CME contributes to synaptic dysfunction, amyloid beta (Aβ) processing, and Tau pathology, highlighting its involvement in early AD pathogenesis. Furthermore, CME alterations extend to non-neuronal cell types, including astrocytes and microglia, which play crucial roles in Aβ clearance and neuroinflammation. Dysregulated CME in these cells underscores its broader implications in AD pathophysiology. Despite significant progress, further research is needed to elucidate the precise mechanisms underlying CME dysregulation in AD and its therapeutic implications. Overall, understanding the complex interplay between CME and AD across diverse cell types holds promise for identifying novel therapeutic targets and interventions. [ABSTRACT FROM AUTHOR]

Introduction: Novelty detection (ND, also known as one-class classification) is a machine learning technique used to identify patterns that are typical of the majority class and can discriminate deviations as novelties. In the context of Alzheimer's disease (AD), ND could be employed to detect abnormal or atypical behavior thatmay indicate early signs of cognitive decline or the presence of the disease. To date, few research studies have used ND to discriminate the risk of developing AD and mild cognitive impairment (MCI) from healthy controls (HC). Methods: In this work, two distinct cohorts with highly heterogeneous data, derived from the Australian Imaging Biomarkers and Lifestyle (AIBL) Flagship Study of Ageing project and the Fujian Medical University Union Hospital (FMUUH) China, were employed. An innovative framework with built-in easily interpretable ND models constructed solely on HC data was introduced along with proposing a strategy of distance to boundary (DtB) to detect MCI and AD. Subsequently, a web-based graphical user interface (GUI) that incorporates the proposed framework was developed for non-technical stakeholders. Results: Our experimental results indicate that the best overall performance of detecting AD individuals in AIBL and FMUUH datasets was obtained by using the Mixture of Gaussian-based ND algorithmapplied to singlemodality, with an AUC of 0.8757 and 0.9443, a sensitivity of 96.79% and 89.09%, and a specificity of 89.63% and 90.92%, respectively. Discussion: The GUI offers an interactive platform to aid stakeholders in making diagnoses of MCI and AD, enabling streamlined decision-making processes. More importantly, the proposed DtB strategy could visually and quantitatively identify individuals at risk of developing AD. [ABSTRACT FROM AUTHOR]

Vitamin D is a lipid soluble steroid hormone, which plays a critical role in the calcium homeostasis, neuronal development, cellular differentiation, and growth by binding to vitamin D receptor (VDR). Associations between VDR gene polymorphism and Alzheimer's disease (AD), Parkinson's disease (PD), and mild cognitive impairment (MCI) risk has been investigated extensively, but the results remain ambiguous. The aim of this study was to comprehensively assess the correlations between four VDR polymorphisms (FokI, BsmI, TaqI, and ApaI) and susceptibility to AD, PD, and MCI. Crude odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to determine the relationship of interest. Pooled analyses suggested that the ApaI polymorphism decreased the overall AD risk, and the TaqI increased the overall PD susceptibility. In addition, the BsmI and ApaI polymorphisms were significantly correlated with the overall MCI risk. Stratified analysis by ethnicity further showed that the TaqI and ApaI genotypes reduced the AD predisposition among Caucasians, while the TaqI polymorphism enhanced the PD risk among Asians. Intriguingly, carriers with the BB genotype significantly decreased the MCI risk in Asian descents, and the ApaI variant elevated the predisposition to MCI in Caucasians and Asians. Further studies are need to identify the role of VDR polymorphisms in AD, PD, and MCI susceptibility. [ABSTRACT FROM AUTHOR]

Background: Studies have reported that metabolic disturbance exhibits in patients with Alzheimer's disease (AD). Still, the presence of definitive evidence concerning the genetic effect of metabolites on AD risk remains insufficient. A systematic exploration of the genetic association between blood metabolites and AD would contribute to the identification of new targets for AD screening and prevention. Methods: We conducted an exploratory two-sample Mendelian randomization (MR) study aiming to preliminarily identify the potential metabolites involved in AD development. A genome-wide association study (GWAS) involving 7,824 participants provided information on 486 human blood metabolites. Outcome information was obtained from a large-scale GWAS meta-analysis of AD, encompassing 21,982 cases and 41,944 controls of Europeans. The primary twosample MR analysis utilized the inverse variance weighted (IVW) model while supplementary analyses used Weighted median (WM), MR Egger, Simple mode, and Weighted mode, followed by sensitivity analyses such as the heterogeneity test, horizontal pleiotropy test, and leave-one-out analysis. For the further identification of metabolites, replication and meta-analysis with FinnGen data, steiger test, linkage disequilibrium score regression, confounding analysis, and were conducted for further evaluation. Multivariable MR was performed to assess the direct effect of metabolites on AD. Besides, an extra replication analysis with EADB data was conducted for final evaluation of the most promising findings. Results: After rigorous genetic variant selection, IVW, complementary analysis, sensitivity analysis, replication and meta-analysis with the FinnGen data, five metabolites (epiandrosterone sulfate, X-12680, pyruvate, docosapentaenoate, and 1-stearoylglycerophosphocholine) were identified as being genetically associated with AD. MVMR analysis disclosed that genetically predicted these four known metabolites can directly influence AD independently of other metabolites. Only epiandrosterone sulfate and X-12680 remained suggestive significant associations with AD after replication analysis with the EADB data. Conclusion: By integrating genomics with metabonomics, this study furnishes evidence substantiating the genetic association of epiandrosterone sulfate and X-12680 with AD. These findings hold significance for the screening, prevention, and treatment strategies for AD. [ABSTRACT FROM AUTHOR]

Background: We aimed to examine the association between blood levels of Branched-chain amino acids (BCAAs) - specifically isoleucine, leucine, and valine - and the susceptibility to three neurodegenerative disorders: dementia, Alzheimer's disease (AD), and Parkinson's disease (PD). Methods: Based on data from the UK Biobank, a Cox proportional hazard regression model and a dose-response relationship were used to analyze the association between BCAAs and the risks of dementia, AD, and PD. We also generated a healthy lifestyle score and a polygenic risk score. Besides, we conducted a sensitivity analysis to ensure the robustness of our findings. Results: After adjusting for multiple covariates, blood concentrations of isoleucine, leucine, and valine were significantly associated with a reduced risk of dementia and AD. This association remained robust even in sensitivity analyses. Similarly, higher levels of isoleucine and leucine in the blood were found to be associated with an increased risk of PD, but this positive correlation could potentially be explained by the presence of covariates. Further analysis using a dose-response approach revealed that a blood leucine concentration of 2.14 mmol/L was associated with the lowest risk of dementia. Conclusion: BCAAs have the potential to serve as a biomarker for dementia and AD. However, the specific mechanism through which BCAAs are linked to the development of dementia, AD, and PD remains unclear and necessitates additional investigation. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are short RNA molecules that are not involved in coding for proteins. They have a significant function in regulating gene expression after the process of transcription. Their participation in several biological processes has rendered them appealing subjects for investigating age-related disorders. Increasing data indicates that miRNAs can be influenced by dietary variables, such as macronutrients, micronutrients, trace minerals, and nutraceuticals. This review examines the influence of dietary factors and nutraceuticals on the regulation of miRNA in relation to the process of aging. We examine the present comprehension of miRNA disruption in age-related illnesses and emphasize the possibility of dietary manipulation as a means of prevention or treatment. Consolidating animal and human research is essential to validate the significance of dietary miRNA control in living organisms, despite the abundance of information already provided by several studies. This review elucidates the complex interaction among miRNAs, nutrition, and aging, offering valuable insights into promising areas for further research and potential therapies for age-related disorders. [ABSTRACT FROM AUTHOR]

Background: Chronic infectious diseases are increasingly being considered as potential contributors to dementia risk. Among those infections, Helicobacter pylori, the main cause of chronic gastritis worldwide, has been suggested. As the prevalence of H. pylori infection has decreased, the main objective of this work was to reconsider the association between H. pylori infection and the risk of incident dementia, including Alzheimer's disease. Methods: Prospective cohort of 689 older (≥65 years) agricultural workers from Southwest France. Descriptive and comparative analyses were performed according to H. pylori status determined by serology at baseline. The risk of incident dementia according to H. pylori status over a 7‐year follow‐up was explored by survival analyses: Kaplan–Meier curve and Cox proportional hazards models. Results: Two‐hundred (29.0%) participants were H. pylori‐positive at baseline. Compared to H. pylori‐negative participants, they showed worse cognitive performances at baseline. Eighty‐five incident dementia cases were diagnosed during the follow‐up period. After adjustment for age, sex, education, apolipoprotein ε4, and several cardiovascular risk factors, H. pylori remained associated with an increased risk of dementia (HR 1.70, 95% CI, 1.05–2.74). The risk was stronger for Alzheimer's disease (HR 2.85, 95% CI, 1.58–5.12). Conclusions: Despite an observed decrease in H. pylori infection prevalence, this study provides evidence for the association between H. pylori infection and dementia. These results should encourage further research on the mechanisms underlying the contribution of infectious diseases to pathological brain aging, especially the influence of gut inflammation on the brain. [ABSTRACT FROM AUTHOR]

BACKGROUND: Epidemiological evidence suggests air pollution adversely affects cognition and increases the risk of Alzheimer’s disease (AD), but little is known about the biological effects of fine particulate matter (PM2.5, particulate matter with aerodynamic diameter ≤2.5 μm) on early predictors of future disease risk. OBJECTIVES: We investigated the association between 1-, 3-, and 5-y exposure to ambient and traffic-related PM2.5 and cerebrospinal fluid (CSF) biomarkers of AD. METHODS: We conducted a cross-sectional analysis using data from 1,113 cognitively healthy adults (45-75 y of age) from the Emory Healthy Brain Study in Georgia in the United States. CSF biomarker concentrations of Aβ42, tTau, and pTau, were collected at enrollment (2016-2020) and analyzed with the Roche Elecsys system. Annual ambient and traffic-related residential PM2.5 concentrations were estimated at a 1-km and 250-m resolution, respectively, and computed for each participant's geocoded address, using three exposure time periods based on specimen collection date. Associations between PM2.5 and CSF biomarker concentrations, considering continuous and dichotomous (dichotomized at clinical cutoffs) outcomes, were estimated with multiple linear/logistic regression, respectively, controlling for potential confounders (age, gender, race, ethnicity, body mass index, and neighborhood socioeconomic status). RESULTS: Interquartile range (IQR; IQR=0.845) increases in 1-y [β:-0.101; 95% confidence interval (CI): -0.18, -0.02] and 3-y (β:-0.078; 95% CI: -0.15, -0.00) ambient PM2.5 exposures were negatively associated with Aβ42 CSF concentrations. Associations between ambient PM2.5 and Aβ42 were similar for 5- y estimates (β:-0.076; 95% CI: -0.160, 0.005). Dichotomized CSF variables revealed similar associations between ambient PM2.5 and Aβ42. Associations with traffic-related PM2.5 were similar but not significant. Associations between PM2.5 exposures and tTau, pTau tTau/Aβ42, or pTau/Aβ42 levels were mainly null. CONCLUSION: In our study, consistent trends were found between 1-y PM2.5 exposure and decreased CSF Aβ42, which suggests an accumulation of amyloid plaques in the brain and an increased risk of developing AD. [ABSTRACT FROM AUTHOR]

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Atrial fibrillation (AF) is associated with cognitive impairment, with or without history of stroke. The risk of developing cognitive impairment is increased after clinical stroke. Prospective registries confirm the increased risk of both vascular and Alzheimer's dementia in patients with AF. The purported mechanistic links between AF and cognitive impairment are clinical stroke, subclinical cerebral small-vessel disease, autonomic dysfunction, and systemic and neuroinflammation. Several shared risk factors and genetics also contribute to this interplay. In this review, we explore the evidence bridging cognitive impairment with AF and review the mechanisms and therapeutic targets. [ABSTRACT FROM AUTHOR]

Introduction: The risk of developing neurodegenerative disorders (NDDs) such as Alzheimer’s disease and related dementias (ADRD) and Parkinson’s disease and atypical parkinsonism (PDAP), has been alluded to arise predominantly from the interplay between environmental exposures and genetic variability. The contributions of these factors to NDD in Black sub‑Saharan Africans are largely unknown. The broad aim of SERGEND is to investigate the effect of specific environmental exposures and genetic variability on the risk of developing ADRD and PDAP in our population. Methods: The SERGEND, a national, multi‑center, cross‑sectional, descriptive study, will be conducted in Nigeria, within academic hospitals located in all six geopolitical zones of the country. The study population will comprise 3000 consenting adult Nigerians aged 18 years and above, residing within the recruiting geopolitical zone in the preceding 12 months. Cases will be persons with ADRD or PDAP and age‑matched healthy controls. Assessments will include dementia and parkinsonism‑specific case ascertainment, disease severity, functional status, and environmental risk factors assessment. Genotyping for APOE and SNCA REP1 polymorphic variability will be conducted. Future analyses will be performed on biobanked samples. Ethics and Dissemination: The study protocol was approved by the National Health Research Ethics Committee in Nigeria, with institutional HREC concordant approval for all participating sites before enrollment of the study participants. Written informed consent was obtained from all study participants or identified proxies. The study results will be published in peer‑reviewed journals and as conference abstracts. [ABSTRACT FROM AUTHOR]

Introduction: Developing effective treatment for Alzheimer's disease (AD) remains a challenge. This can be partially attributed to the fact that the mouse models used in preclinical research largely replicate familial form of AD, while majority of human cases are sporadic; both forms differ widely in the onset and origin of pathology, therefore requiring specific/targeted treatments. Methods: In this study, we aimed to model sporadic AD in mice by combining two of the many risk factors that are strongly implicated in AD: ApoE4, a major genetic risk factor, together with an inflammatory stimuli. Accordingly, we subjected ApoE4 knock in (KI) mice, expressing humanized ApoE4, to low doses of Lipopolysaccharide (LPS) injections (i.p, weekly, for 4 months). Results: We assessed these animals for behavioral impairments at 6 months of age using Open Field, Y-maze, and Barnes Maze Test. LPS induced hypoactivity was observed in the Open Field and Y-maze test, whereas spatial learning and memory was intact. We then quantified differences in dendritic spine density, which is a strong correlate of AD. ApoE4KI mice showed a significant reduction in the number of spines after treatment with LPS, whereas there were no obvious differences in the total number of microglia and astrocytes. Discussion: To conclude, in the current study the APoEe4 risk gene increases the vulnerability of hippocampal neurons to inflammation induced spine loss, laying a foundation for an early sporadic AD mouse model. [ABSTRACT FROM AUTHOR]

Introduction: Efforts to develop cost-effective approaches for detecting amyloid pathology in Alzheimer's disease (AD) have gained significant momentum with a focus on biomarker classification. Recent research has explored non-invasive and readily accessible biomarkers, including magnetic resonance imaging (MRI) biomarkers and some AD risk factors. Methods: In this comprehensive study, we leveraged a diverse dataset, encompassing participants with varying cognitive statuses frommultiple sources, including cohorts from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and our in-house Dementia Disease Initiation (DDI) cohort. As brain amyloid plaques have been proposed as sufficient for AD diagnosis, our primary aim was to assess the effectiveness of multimodal biomarkers in identifying amyloid plaques, using deep machine learning methodologies. Results: Our findings underscore the robustness of the utilized methods in detecting amyloid beta positivity across multiple cohorts. Additionally, we investigated the potential of demographic data to enhance MRI-based amyloid detection. Notably, the inclusion of demographic risk factors significantly improved our models' ability to detect amyloid-beta positivity, particularly in early-stage cases, exemplified by an average area under the ROC curve of 0.836 in the unimpaired DDI cohort. Discussion: These promising, non-invasive, and cost-effective predictors of MRI biomarkers and demographic variables hold the potential for further refinement through considerations like APOE genotype and plasma markers. [ABSTRACT FROM AUTHOR]

Introduction: Personality traits and neuropsychiatric symptoms such as neuroticism and depression share genetic overlap and have both been identified as risks factors for development of aging-related neurocognitive decline and Alzheimer's disease (AD). This study aimed to examine revised personality factors derived from the Temperament and Character Inventory, previously shown to be associated with psychiatric disorders, as predictors of neuropsychiatric, cognitive, and brain trajectories of participants from a population-based aging study. Methods: Mixed-effect linear regression analyses were conducted on data for the full sample (Nmax = 1,286), and a healthy subsample not converting to ADdementia during 25-year follow-up (Nmax = 1,145), complemented with Cox proportional regression models to determine risk factors for conversion to clinical AD. Results: Two personality factors, Closeness to Experience (CE: avoidance of new stimuli, high anxiety, pessimistic anticipation, low reward seeking) and Tendence to Liabilities (TL: inability to change, low autonomy, unaware of the value of their existence) were associated with higher levels of depressive symptoms, stress (CE), sleep disturbance (TL), as well as greater decline in memory, vocabulary and verbal fluency in the full sample. Higher CE was additionally associated with greater memory decline across 25 years in the healthy subsample, and faster right hippocampal volume reduction across 8 years in a neuroimaging subsample (N = 216). Most, but not all, personality-cognition associations persisted after controlling for diabetes, hypertension and cardiovascular disease. Concerning risks for conversion to AD, higher age, and APOE-ε4, but none of the personality measures, were significant predictors. Conclusion: The results indicate that personality traits associated with psychiatric symptoms predict accelerated age-related neurocognitive declines even in the absence of neurodegenerative disease. The attenuation of some personality effects on cognition after adjustment for health indicators suggests that those effects may be partly mediated by somatic health. Taken together, the results further emphasize the importance of personality traits in neurocognitive aging and underscore the need for an integrative (biopsychosocial) perspective of normal and pathological age-related cognitive decline. [ABSTRACT FROM AUTHOR]

Introduction: As individuals age, their sleep patterns change, and sleep disturbances can increase the risk of dementia. Poor sleep quality can be a risk factor for mild cognitive impairment (MCI) and dementia. Epidemiological studies show a connection between sleep quality and cognitive changes, with brain imaging revealing grey matter volume reduction and amyloid beta accumulation in Alzheimer's disease. However, most research has focused on Europeans, with little attention to other ethnic groups. Methods: This is a cross sectional study comparing effects across countries and ethnicities. Group 1 (n = 193) will be Indians residing in India (new participant recruitment), Group 2 will be South Asians residing in UK and group 3 will be Europeans residing in the UK. For group 2 and 3 (n = 193), data already collected by UK-based Southall and Brent REvisited (SABRE) tri-ethnic study will be used. For group 1, Pittsburgh Sleep Quality Index questionnaire (PSQI) will be used for assessment of sleep quality, Indian Council of Medical Research (Neurocognitive ToolBox) (ICMR-NCTB) for cognition testing and a 3 T MRI cerebral scan for brain morphometry. The data will be compared to sleep, cognitive function and brain MRI parameters from SABRE. Discussion: Racial and ethnic differences can impact the relationships of cognitive function, sleep quality and brain structure in older adults. Earlier studies have highlighted higher prevalence of poor sleep among black individuals compared to white individuals. Genetic or epigenetic mechanisms may contribute to these variations. Socio-cultural and environmental factors, such as neighbourhood, migration, lifestyle, stress and perceived discrimination may influence sleep patterns. The aim of the study is to examine the ethnogeographic variations in sleep quality, cognitive performance and brain morphometry among Indians living in India, and South Asians and Europeans residing in the UK. [ABSTRACT FROM AUTHOR]

This article explores how the meanings and values of diagnosis are being reconfigured at the interface between technological innovation and imaginaries of precision medicine. From genome sequencing to biological and digital 'markers' of disease, technological innovation occupies an increasingly central space in the way we imagine future health and illness. These imaginaries are usually centred on the promise of faster, more precise and personalised diagnosis, and the associated hope that if detected early enough disease can be effectively treated and prevented. Underpinning and reproduced through these narratives of the future is a re‐conceptualisation of diagnostic processes and categories around the anticipation of future risk, as noted by recent theoretical developments in the sociology of diagnosis and related disciplines. Adding to this literature, in this article we explore what makes these emerging diagnostic arrangements valuable, to whom and how. Drawing on interviews with experts involved in the development of digital biomarkers for Alzheimer's disease, we trace how multiple and at times conflicting applications of the tools, and the value(s) attached to them, are coproduced. We thus ask what possibilities are pursued, or foreclosed, through the work of imagining the future of diagnosis. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the accuracy of longitudinal trajectories of blood biomarkers for predicting future onset of AD among MCI participants as well as to demonstrate dynamic prediction of the individual conversion risk applying joint modeling. Methods: A total of 446 participants with MCI at baseline from the Alzheimer's Disease Neuroimaging Initiative database were included. We introduced joint modeling to analyze the effects of the longitudinal blood biomarkers on the conversion risk to AD, and further to build individual‐specific prediction risk model. Results: During the follow‐up, 345 participants remained with MCI and 101 progressed to AD, and were categorized as non‐progression and progression group, respectively. Longitudinally, the positive association of the concentration dynamics of plasma p‐tau181 and NfL with the conversion risk to AD from MCI was also demonstrated, with Hazard Ratio (HR) = 5.83 and HR = 4.18, respectively. When incorporating plasma p‐tau181 and NfL together to predict AD progression, we observed improved performance (AUC = 0.701, Brier Score = 0.119). Two participants were chosen to exemplify the individual‐specific risk prediction at different follow‐up time for comparative analysis. Conclusions: Plasma p‐tau181 and NfL could serve as biomarkers for the prediction of AD onset, and the individualized prediction opens up the possibility to provide clinical information at a personal level. Key points: Dynamic risk prediction of AD from MCI applying joint modeling using blood biomarkers and easily accessible participant characteristics.Plasma p‐tau181 and NfL could serve as biomarkers for the prediction of AD onset in the primary care settings and yield significant public health benefit. [ABSTRACT FROM AUTHOR]

Background: The ApoE genotype and neuropsychiatric symptoms (NPS) are known risk factors for cognitive decline in older adults. However, the interaction between these variables is still unclear. The aim of this study was to determine the association between the presence of the ApoE ε4 allele and the occurrence of NPS in older adults without dementia. Methods: In this cross‐sectional investigation we determined the apolipoprotein E (ApoE) genotype of 74 older adults who were either cognitively normal (20.3% / Clinician Dementia Rating Scale (CDR): 0) or had mild cognitive impairment (MCI: 79.7% / CDR: 0.5). We used a comprehensive cognitive assessment protocol, and NPS were estimated by the Neuropsychiatric Inventory‐Clinician Rating Scale (NPI‐C), Mild Behavioural Impairment‐Checklist (MBI‐C), Hamilton Rating Scale for Depression (HAM‐D), and Apathy Inventory. Results: ApoE ε4 carriers had higher MBI‐C total scores than ApoE ε4 noncarriers. Correlations between NPS and ApoE genotype were observed for two NPI‐C domains, although in opposite directions: the ApoE ε4 allele was associated with a 1.8 unit decrease in the estimated aberrant motor disturbance score and with a 1.3 unit increase in the estimated appetite/eating disorders score. All fitted models were significant, except for the one fitted for the domain delusions from the NPI‐C. Among individuals with amnestic MCI, ε4 carriers presented higher depression score (HAM‐D) than noncarriers; in turn, ε4 noncarriers exhibited higher aggression score (NPI‐C) than ε4 carriers. Conclusions: Our analyses showed associations between NPS and the presence of the ApoE ε4 allele in two NPI‐C domains, despite the sample size. Furthermore, compared to noncarriers, the presence of the ApoE ε4 correlated positively with appetite/eating disorders and negatively with aberrant motor disturbance domain. Examination of the amnestic MCI group displayed significant, although weak, associations. Therefore, ε4 carriers exhibited higher depression scores according to the HAM‐D scale compared to ε4 noncarriers. Conversely, ε4 noncarriers had higher scores in the aggression domain of the NPI‐C than ε4 carriers. [ABSTRACT FROM AUTHOR]

Aim: To investigate the possible role of systemic inflammatory markers (interleukin; IL-6, C-reactive protein; CRP, and albumin levels) in the development of Alzheimer's dementia (AD) and also find their association with the severity of disease. Material and Methods: It was a cross-sectional study. Patients with Alzheimer's dementia (AD) and vascular dementia (VaD) from outpatient settings in tertiary care hospitals and non-demented controls (NDC) were recruited from the community. Individuals aged 50 years and older (n = 110) were included. Serum levels of IL-6, CRP, and albumin levels in patients with AD, VaD, and NDC were measured. The clinical Dementia Rating Scale was used for staging the severity of dementia. Serum levels of IL-6, CRP, and serum albumin were compared in study subjects and also analyzed with the severity of dementia in dementia subgroups. Results: Our main finding was that serum levels of IL-6 were significantly elevated in patients with AD and VaD (7.79 and 6.60) as compared to NDC (2.98) (P < 0.001). No significant difference in CRP or albumin levels was observed between the three groups. Serum IL-6 and CRP showed a positive correlation with the severity of AD, though the correlation was significant only for IL-6 (r = 0.777). The serum albumin levels showed a statistically significant negative correlation with the severity of AD (r > 0.3 but <0.5). Conclusion: The study demonstrates a notable association between systemic inflammatory markers, particularly IL-6, and the severity of AD, indicating their potential role in its pathogenesis. These findings suggest that targeting these markers could offer new insights into therapeutic strategies for AD. [ABSTRACT FROM AUTHOR]

Copyright of Health & Society is the property of Instituto de Ensino e Pesquisa Periodicojs and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Objectives: Cognitive aging is a lifelong process with implications for Alzheimer's disease and dementia. This study aims to fill major gaps in research on the natural history of and social disparities in aging-related cognitive decline over the life span. Methods: We conducted integrative data analysis of four large U.S. population-based longitudinal studies of individuals aged 12 to 105 followed over two decades and modeled age trajectories of cognitive function in multiple domains. Results: We found evidence for the onset of cognitive decline in the 4th decade of life, varying gender differences with age, and persistent disadvantage among non-Hispanic Blacks, Hispanics, and those without college education. We further found improvement in cognitive function across 20th century birth cohorts but widening social inequalities in more recent cohorts. Discussion: These findings advance an understanding of early life origins of dementia risk and invite future research on strategies for promoting cognitive health for all Americans. [ABSTRACT FROM AUTHOR]

Background: The 'Australian National University Alzheimer's Disease Risk Index' (ANU‐ADRI) assesses the risk of developing Alzheimer's disease (AD) and is a potential tool for its prevention. Objectives: The aim of this study is to adapt the ANU‐ADRI‐SF (the short version of ANU‐ADRI) into the Turkish language and Turkish cultural context. Methods: The study was methodological and involved the translation and intercultural adaptation of the ANU‐ADRI‐SF into the Turkish language. The study included 384 community‐based participants from a province in the Western Black Sea Region of Türkiye. Data was collected via an online form prepared using Google Forms. Results: The index was translated from its original language, English, into Turkish and then retranslated to English by bilingual translators. It was then reviewed and evaluated for possible issues related to translation and degrees of equivalence. When TR‐ANU‐ADRI‐SF levels were compared according to sex, the mean risk scores were found to be 11.25 ± 7.02 for males and 11.69 ± 7.99 for females. After cross‐cultural adaptation, the TR‐ANU‐ADRI‐SF was conceptually intelligible to Turkish adults. Conclusions: The TR‐ANU‐ADRI‐SF is a valid and reliable AD risk assessment tool. Implications for practice: Given the increase in AD and its impact on people's health, there is a great need for strategies to be implemented by health professionals to improve the lifestyle of the adult population. For use in conjunction with these strategies, a localised AD risk assessment tool that can be applied by clinicians or by individual patients has been adapted and introduced to the Turkish literature. [ABSTRACT FROM AUTHOR]