Incident Alzheimer's Disease Research Articles

The association of the triglyceride-glucose index with Alzheimer's disease and its potential mechanisms.

The correlation between Alzheimer's disease (AD) and the glucose-triglyceride (TyG) index remains undetermined. This study aimed to investigate the relationship between the TyG index and AD, as well as the relationship between the TyG index and cerebrospinal fluid (CSF) AD biomarkers and cognition. Six hundred twenty-eight non-dementia participants were included. The TyG index, pathological markers, and cognitive measures were studied using multiple linear regression. Also calculated using a multivariate Cox regression model were the hazard ratio (HR) and its 95% confidence interval (CI). Ten thousand bootstrap iterative causal mediation analyses were performed to investigate the potential mediating effect of AD pathology on cognition. The TyG index was linked to CSF AD biomarkers (βAβ42 = 0.880; βTau = -0.674; βpTau = -0.884; βAβ42/pTau = 1.764; βAβ42/Tau = 1.554; βpTau/Tau = -0.210) and cognitive measurements (βMEM = 0.570; βEF = 0.535; βADAS11 = -0.789). Mediation analysis revealed that the TyG index may influence cognition via CSF AD biomarkers, including Aβ42, tau, and pTau. Furthermore, each 1-unit increase in TyG index was associated with a 29.5% reduction in the risk of incident AD. A delayed rate of cognitive decline and a reduced risk of AD were found to be correlated with higher levels of the TyG index, but this does not mean increasing TyG index levels is beneficial for health. Through AD pathology, the TyG index may influence AD and cognitive changes.

Application of Electrical Stimulation in BCI in Patients with Alzheimer’s Disease

This paper systematically discusses the application prospect of neuromodulation technology in the treatment of Alzheimer’s disease (AD). It focuses on the potential role of various techniques, including transcutaneous electrical nerve stimulation (TENS), deep brain stimulation (DBS), repeated transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), in improving the cognitive function of AD patients. With the aggravation of the global aging problem, the incidence of AD is increasing year by year, and the existing treatment methods are difficult to effectively prevent the progress of the disease. Studies have shown that technologies such as TENS and DBS can improve patients’ memory and cognitive function to some extent. For example, a study by Smith et al. (2020) found that DBS applied to the fornix resulted in a 20% improvement in memory scores over a 6-month period. However, due to the small sample size and inconsistent experimental design, the universality and reliability of the existing research results are still limited. Future studies should aim for larger, more diverse sample sizes and standardized experimental protocols to enhance the robustness of findings. This article reviews the latest research results of these neuromodulation techniques, emphasizing the importance of optimizing treatment parameters and expanding the scale of clinical trials. The paper is structured as follows: first, this paper discusses each neuromodulation technique in detail; then, this paper analyzes their potential benefits and limitations; finally, this paper provides recommendations for future research directions.

Onset of cognitive impairment, diet quality and adherence to dietary guidelines over 12 years: the Personality and Total Health Cohort Study.

Around 55 million people worldwide live with dementia, and more are expected due to population ageing. We aimed to investigate associations between healthy diet and mild cognitive impairment and dementia in 1753 older adults aged 60-64 from the PATH (Personality and Total Health Through Life Cohort) study. Healthy diet was defined by the Mediterranean-DASH diet Intervention for Neurological Delay (MIND) and two dietary guideline quality scores (Dietary Guideline Index (DGI) and Index Diet Quality (IDQ)), which were calculated from baseline FFQ. Higher dietary scores indicated higher diet quality. Incidence of Alzheimer's disease/vascular dementia (National Institute of Neurological Disorders criteria) and mild cognitive impairment (Winbald criteria) was assessed after 12 years of follow-up using validated questionnaires with nominated proxies. Logistic regression explored associations between dietary scores and cognitive function, adjusting for demographics, lifestyle factors and medical preconditions. Adjusted logistic regression comparing the per unit linear increase in diet scores showed MIND (OR = 0·82, 95 % CI = 0·68, 0·99), but not DGI (0·99 (0·97, 1·00)) or IDQ (1·12 (0·95, 1·32)), was significantly associated with lower odds of developing cognitive impairment. In conclusion, a healthier neuroprotective dietary pattern is associated with better cognitive function over time, whereas dietary patterns generated from general dietary guidelines did not show a significant association. Further research and well-designed clinical studies are needed to determine the effects of the MIND diet on cognitive impairment in older adults without a family history of dementia.

SGLT2 Inhibitor Use and Risk of Dementia and Parkinson Disease Among Patients With Type 2 Diabetes.

Despite the mechanistic potential of sodium-glucose cotransporter 2 inhibitor (SGLT2i) to improve neurologic outcomes, the efficacy of SGLT2i in neurodegenerative disorders among patients with type 2 diabetes is not well established. This population-based cohort study aimed to investigate the association of SGLT2i use with risks of incident dementia and Parkinson disease (PD) in patients with type 2 diabetes. This was a retrospective examination of data from a cohort of 1,348,362 participants with type 2 diabetes (≥40 years), who started antidiabetic drugs from 2014 to 2019, evaluated using the Korean National Health Insurance Service Database. Propensity score matching (1:1; SGLT2i to other oral antidiabetic drugs [OADs]) produced a cohort of 358,862 participants. Primary outcomes were the individual incidence of Alzheimer disease (AD), vascular dementia (VaD), and PD. Secondary outcomes were all-cause dementia (AD, VaD, and other dementia) and a composite of all-cause dementia and PD. Cox proportional hazards models were used to investigate the association between SGLT2i use and the risks of dementia and PD. From the 358,862 participants analyzed (mean [SD] age, 57.8 [9.6] years; 58.0% male), 6,837 incident dementia or PD events occurred. Regarding the individual endpoints, SGLT2i use was associated with reduced risks of AD (adjusted hazard ratio [aHR] 0.81, 95% CI 0.76-0.87), VaD (aHR 0.69, 95% CI 0.60-0.78), and PD (aHR 0.80, 95% CI 0.69-0.91) with a 6-month drug use lag period. In addition, use of SGLT2i was associated with a 21% lower risk of all-cause dementia (aHR 0.79, 95% CI 0.69-0.90) and a 22% lower risk of all-cause dementia and PD than use of other OADs (aHR 0.78, 95% CI 0.73-0.83). The association between the use of SGLT2i and the lowered risk of these neurodegenerative disorders was not affected by sex, Charlson Comorbidity Index, diabetic complications, comorbidities, and medications. Sensitivity analysis further adjusting for bioclinical variables from health screening tests, including blood pressure, glucose, lipid profiles, and kidney function, yielded generally consistent results. In this nationwide population-based study, SGLT2i use significantly reduced the risks of neurodegenerative disorders in patients with type 2 diabetes independent of various factors including comorbidities and bioclinical parameters. This study provides Class II evidence that SGLT2 antidiabetic drugs decrease the risk of dementia and PD in people with diabetes.

Ouabain Ameliorates Alzheimer’s Disease-Associated Neuropathology and Cognitive Impairment in FAD4T Mice

Background: Alzheimer’s disease (AD) is a common clinical neurodegenerative disorder, primarily characterized by progressive cognitive decline and behavioral abnormalities. The hallmark pathological changes of AD include widespread neuronal degeneration, plaques formed by the deposition of amyloid β-protein (Aβ), and neurofibrillary tangles (NFTs). With the acceleration of global aging, the incidence of AD is rising year by year, making it a major global public health concern. Due to the complex pathology of AD, finding effective interventions has become a key focus of research. Ouabain (OUA), a cardiac glycoside, is well-known for its efficacy in treating heart disease. Recent studies have also indicated its potential in AD therapy, although its exact mechanism of action remains unclear. Methods: This study integrates bioinformatics, multi-omics technologies, and in vivo and in vitro experiments to investigate the effects of OUA on the pathophysiological changes of AD and its underlying molecular mechanisms. Results: This study analyzed the expression of the triggering receptor expressed on myeloid cells 2 (TREM2) across different stages of AD using bioinformatics. Serum samples from patients were used to validate soluble TREM2 (sTREM2) levels. Using an Aβ1-42-induced microglial cell model, we confirmed that OUA enhances the PI3K/AKT signaling pathway activation by upregulating TREM2, which reduces neuroinflammation and promotes the transition of microglia from an M1 proinflammatory state to an M2 anti-inflammatory state. To evaluate the in vivo effects of OUA, we assessed the learning and memory capacity of FAD4T transgenic mice using the Morris water maze and contextual fear conditioning tests. We used real-time quantitative PCR, immunohistochemistry, and Western blotting to measure the expression of inflammation-associated cytokines and to assess microglia polarization. OUA enhances cognitive function in FAD4T mice and has been confirmed to modulate microglial M1/M2 phenotypes both in vitro and in vivo. Furthermore, through bioinformatics analysis, molecular docking, and experimental validation, TREM2 was identified as a potential target for OUA. It regulates PI3K/Akt signaling pathway activation, playing a crucial role in OUA-mediated M2 microglial polarization and its anti-inflammatory effects in models involving Aβ1-42-stimulated BV-2 cells and FAD4T mice. Conclusions: These findings indicate that OUA exerts anti-neuroinflammatory effects by regulating microglial polarization, reducing the production of inflammatory mediators, and activating the PI3K/Akt signaling pathway. Given its natural origin and dual effects on microglial polarization and neuroinflammation, OUA emerges as a promising therapeutic candidate for neuroinflammatory diseases such as AD.

The Relationship between Framingham Stroke Risk Profile on Incident Dementia and Alzheimer's Disease: A 40-Year Follow-Up Study Highlighting Female Vulnerability.

Sex differences in the association between cardiovascular risk factors and the incident all-cause dementia and the subtype Alzheimer's disease (AD) risk are unclear. Framingham Heart Study (FHS) participants (n = 4,171, 54% women, aged 55 to 69 years) were included at baseline and followed up to 40 years. The Framingham Stroke Risk Profile (FSRP) was dichotomized into 2 levels (cutoff: 75th percentile of the FSRP z-scores). Cause-specific hazard models, with death as a competing event, and restricted mean survival time (RMST) model were used to analyze the association between FSRP levels and incident all-cause dementia and AD. Interactions between FSRP and sex were estimated, followed by a sex-stratified analysis to examine the sex modification effect. High FSRP was significantly associated with all-cause dementia (hazard ratio [HR] = 1.25, robust 95% confidence interval [CI] = 1.21 to 1.29, p < 0.001) and AD (HR = 1.58, robust 95% CI = 1.57 to 1.59, p < 0.001) in cause-specific hazard models. High FSRP was significantly associated with incident dementia (HR = 2.81, robust 95% CI = 2.75 to 2.87, p < 0.001) and AD (HR = 2.96, robust 95% CI = 2.36 to 3.71, p < 0.001) in women, but not in men. Results were consistent in the RMST models. Current diabetes and high systolic blood pressure as FSRP components were significantly associated with dementia and AD in women but not in men. High FSRP in mid- to early late life is a critical risk factor for all-cause dementia and AD, particularly in women. Sex-specific interventions and further research to elucidate underlying mechanisms are warranted. ANN NEUROL 2024.

A tailored phytosomes based nose-to-brain drug delivery strategy: Silver bullet for Alzheimer's disease

With the aging of the population, the incidence of Alzheimer's disease (AD) has increased dramatically, causing severe medical, care, and economic burdens on society and families. The efficacy of rivastigmine hydrogen tartrate (RHT), the first-line clinical treatment, is severely limited by the complex and multiple pathogenesis of AD and low brain bioavailability caused by the blood-brain barrier (BBB). Confronting such two bottlenecks, the development of multi-target agents encapsulated BBB-bypassing drug delivery systems offer tremendous therapeutics possibilities for AD. In this study, a tailored phytosomes based nose-to-brain drug delivery system with appropriate plume was successfully designed and developed. On the one hand, Ginseng RG3-based phytosomes loaded with RHT was designed for the co-delivery of GRg3 and RHT, achieving the multi-target pharmacology for AD treatment. On the other hand, a tailored nose-to-brain drug delivery system was established for the satisfactory nose-to-brain delivery efficiency, avoiding the obstacle of BBB through bypassing it. In the pharmacodynamic study based on AD rat model, GRg3@RHT exhibited obviously synergic effect, effectively break the vicious cycle of AD progression, ultimately markedly ameliorating learning and memory ability as well as behavioral dysfunctions, and delaying the neurodegenerative process associated with AD. In addition, the strong correlation of viscosity-droplet size-plume geometry-olfactory deposition was also established, and further proved by the in vivo pharmacokinetic study, which is proposed to provide evidence to enhance nose-to-brain delivery efficiency. This study is anticipated to provide novel insights into AD treatment strategies while offering innovative ideas for drug delivery approaches targeting nervous system disorders.

Novel plasma protein biomarkers: A time-dependent predictive model for Alzheimer's disease

BackgroundThe accurate prediction of Alzheimer's disease (AD) is crucial for the efficient management of its progression. The objective of this research was to construct a new risk predictive model utilizing novel plasma protein biomarkers for predicting AD incidence in the future and analyze their potential biological correlation with AD incidence. MethodsA cohort of 440 participants aged 60 years and older from the Alzheimer's Disease Neuroimaging Initiative (ADNI) longitudinal cohort was utilized. The baseline plasma proteomics data was employed to conduct Cox regression, LASSO regression, and cross-validation to identify plasma protein signatures predictive of AD risk. Subsequently, a multivariable Cox proportional hazards model based on these signatures was constructed. The performance of the risk prediction model was evaluated using time-dependent receiver operating characteristic (t-ROC) curves and Kaplan-Meier curves. Additionally, we analyzed the correlations between protein signature expression in plasma and predicted AD risk, the time of AD onset, the expression of protein signatures in cerebrospinal fluid (CSF), the expression of CSF and plasma biomarkers, and APOE ε4 genotypes. Colocalization and Mendelian randomization analyses was conducted to investigate the association between protein features and AD risk. GEO database was utilized to analyze the differential expression of protein features in the blood and brain of AD patients. ResultsWe identified seven protein signatures (APOE, CGA, CRP, CCL26, CCL20, NRCAM, and PYY) that independently predicted AD incidence in the future. The risk prediction model demonstrated area under the ROC curve (AUC) values of 0.77, 0.76, and 0.77 for predicting AD incidence at 4, 6, and 8 years, respectively. Furthermore, the model remained stable in the range of the 3rd to the 12th year (ROC ≥ 0.74). The low-risk group, as defined by the model, exhibited a significantly later AD onset compared to the high-risk group (P < 0.0001). Moreover, all protein signatures exhibited significant correlations with AD risk (P < 0.001) and the time of AD onset (P < 0.01). There was no strong correlation between the protein expression levels in plasma and CSF, as well as AD CSF biomarkers. APOE, CGA, and CRP exhibited significantly lower expression levels in APOE ε4 positive individuals (P < 0.05). Additionally, colocalization analysis reveals a significant association between AD and SNP loci in APOE. Mendelian randomization analysis shows a negative correlation between NRCAM and AD risk. Transcriptomic analysis indicates a significant downregulation of NRCAM and PYY in the peripheral blood of AD patients (P < 0.01), while APOE, CGA, and NRCAM are significantly downregulated in the brains of AD patients (P < 0.0001). ConclusionOur research has successfully identified protein signatures in plasma as potential risk biomarkers that can independently predict AD onset in the future. Notably, this risk prediction model has demonstrated commendable predictive performance and stability over time. These findings underscore the promising utility of plasma protein signatures in dynamically predicting the risk of AD, thereby facilitating early screening and intervention strategies.

Identifying Comorbidity Patterns in People with and without Alzheimer's Disease Using Latent Dirichlet Allocation.

Multimorbidity is common in older adults and complicates diagnosing and care for this population. We investigated co-occurrence patterns (clustering) of medical conditions in persons with Alzheimer's disease (AD) and their matched controls. The register-based Medication use and Alzheimer's disease study (MEDALZ) includes 70,718 community-dwelling persons with incident AD diagnosed during 2005-2011 in Finland and a matched comparison cohort. Latent Dirichlet Allocation was used to cluster the comorbidities (ICD-10 diagnosis codes). Modeling was performed separately for AD and control cohorts. We experimented with different numbers of clusters (also known as topics in the field of Natural Language Processing) ranging from five to 20. In both cohorts, 17 of the 20 most frequent diagnoses were the same. Based on a qualitative assessment by medical experts, the cluster patterns were not affected by the number of clusters, but the best interpretability was observed in the 10-cluster model. Quantitative assessment of the optimal number of clusters by log-likelihood estimate did not imply a specific optimal number of clusters. Multidimensional scaling visualized the variability in cluster size and (dis)similarity between the clusters with more overlapping of clusters and variation in group size seen in the AD cohort. Early signs and symptoms of AD were more commonly clustered together in the AD cohort than in the comparison cohort. This study experimented with using natural language processing techniques for clustering patterns from an epidemiological study. From the computed clusters, it was possible to qualitatively identify multimorbidity that differentiates AD cases and controls.

Systolic blood pressure variability in late-life predicts cognitive trajectory and risk of Alzheimer's disease.

The relationship of systolic blood pressure variability (SBPV) with Alzheimer's disease (AD) remains controversial. We aimed to explore the roles of SBPV in predicting AD incidence and to test the pathways that mediated the relationship of SBPV with cognitive functions. Longitudinal data across 96 months (T0 to T4) were derived from the Alzheimer's disease Neuroimaging Initiative cohort. SBPV for each participant was calculated based on the four measurements of SBP across 24 months (T0 to T3). At T3, logistic regression models were used to test the SBPV difference between 86 new-onset AD and 743 controls. Linear regression models were used to test the associations of SBPV with cognition and AD imaging endophenotypes for 743 non-demented participants (median age = 77.0, female = 42%). Causal mediation analyses were conducted to explore the effects of imaging endophenotypes in mediating the relationships of SBPV with cognitive function. Finally, Cox proportional hazard model was utilized to explore the association of SBPV with incident risk of AD (T3 to T4, mean follow-up = 3.5 years). Participants with new-onset AD at T3 had significantly higher SBPV compared to their controls (p = 0.018). Higher SBPV was associated with lower scores of cognitive function (p = 0.005 for general cognition, p = 0.029 for memory, and p = 0.016 for executive function), higher cerebral burden of amyloid deposition by AV45 PET (p = 0.044), lower brain metabolism by FDG PET (p = 0.052), and higher burden of white matter hyperintensities (WMH) (p = 0.012). Amyloid pathology, brain metabolism, and WMH partially (ranging from 17.44% to 36.10%) mediated the associations of SBPV with cognition. Higher SBPV was significantly associated with elevated risk of developing AD (hazard ratio = 1.29, 95% confidence interval = 1.07 to 1.57, p = 0.008). These findings supported that maintaining stable SBP in late life helped lower the risk of AD, partially by modulating amyloid pathology, cerebral metabolism, and cerebrovascular health.

Causal association of circulating inflammatory proteins on neurodegenerative diseases: Insights from a mendelian randomization study.

Neuroinflammation is increasingly recognized as a pivotal factor in the development and progression of neurodegenerative disorders. While correlations between inflammatory cytokines and these diseases are documented, the definitive causal dynamics remain to be elucidated. We explored the causal association between 91 circulating inflammatory cytokines and Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS) and Parkinson's disease (PD) through Mendelian randomization analysis. Leveraging genetic variants from the most comprehensive genome-wide association studies (GWAS) available for these cytokines, AD, ALS, MS and PD, we sought to uncover the causality. Our study validated a causal influence of genetically determined cytokine levels on the susceptibility to AD, with notable cytokines including C-X-C motif chemokine 1 (OR = 0.9993, p = 0.0424), Interleukin-18 (OR = 0.9994, p = 0.0186), Leukaemia inhibitory factor receptor (OR = 0.9993, p = 0.0122) and Monocyte chemoattractant protein-1 (OR = 0.9992, p = 0.0026) in risk attenuation. Additionally, a positive causal relationship was identified between two cytokines-C-C motif chemokine 19 (OR = 1.0005, p = 0.0478) and Fms-related tyrosine kinase 3 ligand (OR = 1.0005, p = 0.0210)-and AD incidence. Conversely, transforming growth factor-alpha (OR = 0.8630, p = 0.0298), CD40L receptor (OR = 0.7737, p = 1.1265E-09) and Interleukin-12 subunit beta (OR = 0.8987, p = 0.0333) showed inverse associations with ALS, MS and PD, respectively. The consistency observed in various MR analyses, alongside sensitivity analysis, underscored the absence of horizontal pleiotropy, thus supporting our causal findings. This study reveals, for the first time, a genetically anchored causal nexus between levels of circulating inflammatory cytokines and the risk of neurodegenerative diseases.

Global, regional, and national burdens of Alzheimer's disease and other forms of dementia in the elderly population from 1999 to 2019: A trend analysis based on the Global Burden of Disease Study 2019

AbstractDementia represents a significant health issue, afflicting both patients and their families. To assess the global trends in the incidence, prevalence, mortality, and disability‐adjusted life years (DALYs) of Alzheimer's disease (AD) and other dementias in the elderly population, the Global Burden of Disease Study (1999−2019) was used. The average annual percentage change (AAPC) was estimated using linear regression. Stratified analysis of the global trends by age, sex, region, national level, and social development index (SDI) were also performed. The global incidence of AD and other dementias increased from 507.96 per 100,000 in 1990 to 569.39 per 100,000 in 2019, showing a significant increase in this period. In males, the incidence increased from 387.56 per 100,000 population in 1990 to 462.40 per 100,000 in 2019 (AAPC = 0.61), whereas females experienced a slower rise (AAPC = 0.31) and had a higher incidence in 2019 (662.93 per 100,000 population). The most significant increase was observed in individuals aged 60−64 and those in the middle‐SDI quintile. Regionally, the high‐income Asia Pacific had the highest incidence (890.01 per 100,000 population) and DALYs (3043.86 per 100,000) in AD and other dementias in 2019. As for national trends, Japan had the most pronounced increase in the incidence and DALYs of AD and other dementias during the 1990−2019 period. These findings highlight the growing burden of dementias on life expectancy at a population level, which is significant for healthcare professionals and decision‐makers to conduct the ongoing debate on the policy of AD and other dementias.

Apolipoprotein E and Alzheimer's Disease in Italian Population: Systematic Review and Meta-Analysis.

Objective: This meta-analysis with a systematic review was undertaken to assess the association between APOE allelic genotypes and the risk of Alzheimer's disease (AD) in the Italian population. Methods: The Web of Science, PubMed, and Scopus databases were searched until 15 November 2023. The odds ratio (OR) with a 95% confidence interval (CI) was calculated using fixed and random effect models, depending on the I2 statistic value. The systematic review and meta-analysis were conducted in agreement with the PRISMA guideline and registered with PROSPERO (CRD42023492580). Results: Our meta-analysis based on 15 studies revealed a higher risk of AD among Italian individuals carrying the APOE ε4 allele (OR = 3.60, 95% CI [2.90-4.47], p < 0.0001). The association of AD genotype APOE ε2ε4 (OR = 1.36, 95% CI [0.76-2.41], p = 0.29) was not statistically significant, while APOE ε3ε4 (OR = 3.43, 95% CI [2.95-3.99], p < 0.0001) has a high risk of AD development; the risk is more notably in the APOE ε4ε4 genotype (OR = 7.08, 95% CI [4.22-11.86], p < 0.0001). The APOE ε2 allele has a protective effect (APOE ε2 (OR = 0.47, 95% CI [0.29-0.74], p = 0.0013)), and similar results were achieved by APOE ε3 (OR = 0.49, 95% CI [0.37-0.65], p < 0.0001). Subgroup analysis of three areas of Italy (southern, northern, and center) revealed that that APOE ε4 allele was a risk factor with a higher OR in northern Italy (OR 4.22; 95% CI [3.46-5.16], p < 0.0001) compared to southern and center Italy (OR 3.02; 95% CI [2.28-4.01], p < 0.0001 and OR 3.97; 95% CI [1.37-11.56], p < 0.0001, respectively). As well, APOE ε4ε4 genotype carriers had a significantly higher OR in northern Italy (OR 9.69; 95% CI [4.94-18.99], p < 0.0001) compared to in southern and center Italy (OR 4.38; 95% CI [1.54-12.47], p < 0.0001 and OR 3.59; 95% CI [0.87-14.86], p < 0.0001, respectively). Conclusions: This systematic review with a meta-analysis of the Italian population on APOE alleles, genotyping, and AD incidence, highlights that individuals harboring APOE ε4 have a higher risk of developing AD compared to those with other alleles. It also supports the protective effect of the APOE ε2 allele against the progress of AD. The qualitative analysis on the complex genetic interactions influencing Alzheimer risk emphasizes the need for further research on genetic and environmental factors for effective prevention strategies.

Metabolic-associated steatotic liver disease and risk of Alzheimer's disease: a real-world retrospective cohort study.

Alzheimer's Disease (AD) is increasingly recognized as being associated with metabolic disorders, including Metabolic Associated Steatotic Liver Disease (MASLD). This study aimed to assess the relative risk of AD in individuals with MASLD. In this retrospective cohort study, we analyzed data from individuals aged over 65 who underwent health check-ups between January 2018 and June 2023. MASLD was diagnosed based on ultrasound findings and cardiometabolic criteria. AD incidence was identified using ICD-10 codes and self-reports. Poisson regression models estimated the relative risk of AD in relation to MASLD, adjusting for age, BMI, sex, SBP, HbA1c, HDL-c, triglycerides, hs-CRP, GGT, and estimated GFR. The study included 4,582 MASLD patients and 6,318 controls. MASLD patients showed a higher incidence of AD (127 cases) compared to controls (61 cases). The fully adjusted Poisson regression model indicated an increased AD risk in MASLD patients [RR: 2.80 (95% CI: 1.79-4.38)]. Our findings suggested MASLD as an independent risk factor for AD, underlining the role of metabolic dysfunctions in AD pathogenesis. The study emphasized the need for comprehensive metabolic health management in AD prevention strategies, particularly among high-risk groups.

Inhibition of colorectal cancer in Alzheimer’s disease is mediated by gut microbiota via induction of inflammatory tolerance

Epidemiological studies have revealed an inverse relationship between the incidence of Alzheimer's disease (AD) and various cancers, including colorectal cancer (CRC). We aimed to determine whether the incidence of CRC is reduced in AD-like mice and whether gut microbiota confers resistance to tumorigenesis through inducing inflammatory tolerance using 16S ribosomal RNA gene sequencing and fecal microbiota transplantation (FMT). AD-like mice experienced a significantly decreased incidence of CRC tumorigenesis induced by azoxymethane-dextran sodium sulfate as evidenced by suppressed intestinal inflammation compared with control mice. However, FMT from age-matched control mice reversed the inhibitory effects on the tumorigenesis of CRC and inflammatory response in AD-like mice. The key bacterial genera in gut microbiota, including Prevotella, were increased in both the AD-like mice and in patients with amnestic mild cognitive impairment (aMCI) but were decreased in patients with CRC. Pretreatment with low-dose Prevotella-derived lipopolysaccharides (LPS) induced inflammatory tolerance both in vivo and in vitro and inhibited CRC tumorigenesis in mice. Imbalanced gut microbiota increased intestinal barrier permeability, which facilitated LPS absorption from the gut into the blood, causing cognitive decline in AD-like mice and patients with aMCI. These data reveal that intestinal Prevotella-derived LPS exerts a resistant effect to CRC tumorigenesis via inducing inflammatory tolerance in the presence of AD. These findings provide biological evidence demonstrating the inverse relationship between the incidence of AD and CRC.

Investigating Alzheimer’s Disease Resistance in Okinawan Centenarians’ Offspring: A Population Study in a Blue Zone

Alzheimer’s disease (AD) is a neurodegenerative condition characterized by cognitive decline and the accumulation of amyloid-β plaques and neurofibrillary tangles in the brain. Although developing the disease becomes increasingly common as people age, centenarians — individuals who reach the age of 100 — have shown an unexpected resilience to AD, and these individuals are more prevalent in regions known as blue zones, where people experience exceptional longevity and health. This study focuses on the offspring of centenarians in one of these blue zones, Okinawa, Japan, to investigate what potential protective factors they may possess against AD. By screening this unique population using a questionnaire and the Mini-Mental State Examination (MMSE) and tracking AD pathology through advanced biomarker assays following the A/T/N criteria, A: Aβ40/42 ratio, T: phosphorylated tau (pT217-tau), and N: neurofilament light chain (NfL) levels, we aim to uncover genetic, environmental, or lifestyle-related factors that contribute to the decreased incidence of AD in these populations. This study seeks to identify key factors contributing to their resilience by comparing the results of centenarian offspring with age-matched non-centenarians. The spouses of these offspring of centenarians will also be included in the study, acting as a control group of individuals who are likely to share many of the lifestyle and environmental factors with the centenarian offspring but with different genetics. These findings could provide valuable insights for the future development of public health strategies and approaches to mitigate AD risk in the broader population.

Incidence and Prevalence of Early-Onset Dementia in Finland.

Current epidemiologic data of early-onset dementia (EOD), characterized by the onset of the disease before the age of 65, are notably scarce. We evaluated the incidence (from January 2010 to December 2021) and prevalence (on December 31, 2021) of EOD and its subtypes in 2 defined areas in Finland. All visits at the dementia outpatient clinics were manually retrospectively reviewed and reassessed (N = 12,490). In the population aged ≤65 years, crude incidence of EOD was 12.3/100,000 persons at risk/year based on 794 new cases from January 1, 2010, to December 31, 2021. Incidence rates for EOD were 20.5 and 33.7 per 100,000 person years in the age group of 30-64 and 45-64 years, respectively. The prevalence of EOD was 110.4 in the age group of 30-64 years and 190.3 in the age group 45-64. Alzheimer disease (AD) (48.2%) and behavioral variant frontotemporal dementia (12.7%) were the most frequent subtypes. The incidence of AD increased during the follow-up, whereas incidence of other forms of EOD remained stable. We found higher incidence rates of EOD than previously reported. Unlike other forms of EOD, the incidence of early-onset AD seems to be increasing.

The Associations of Sensory Impairment With 10-Year Risk of Dementia and Alzheimer's Disease: The Health and Retirement Study, 2010-2020.

Studies have examined the association between dual sensory impairment and late-life cognitive outcomes in the U.S with inconsistent findings. To examine the associations between sensory impairment and 10-year risk of dementia or Alzheimer's disease among U.S. adults aged ≥ 50. A prospective cohort study based on the Health and Retirement Study from 2010 to 2020. Individuals aged ≥ 50 years without self-reported dementia and Alzheimer's disease in 2010 were included in the analysis. Self-reported visual and hearing impairments were measures in 2010. Main failure events included self-reported incident dementia and Alzheimer's disease over a 10-year follow-up period. Participants were categorized as having no visual or hearing impairment, visual impairment only, hearing impairment only, and dual sensory impairment. Fine-Gray competing risk regression model was applied to estimate the associations of sensory impairment with incident dementia and Alzheimer's disease, adjusted for demographic characteristics, health behaviors, and health conditions at baseline. Of 20,248 identified individuals, 14.6% had visual impairment only, 11.2% had hearing impairment only, and 9.1% had dual impairment at baseline. After adjusting for all covariates, dual sensory impairment was associated with higher risk of dementia (HR = 1.46, 95% CI: 1.23-1.73) and Alzheimer's disease (HR = 1.35, 95% CI: 1.03-1.76). Visual impairment only was also associated with incident dementia and Alzheimer's disease among individuals <65 years. Older adults in the U.S. with visual and hearing impairments simultaneously had a particularly greater risk of dementia and Alzheimer's disease, indicating the needs of targeted screening for timely treatment and further prevention of dementia and Alzheimer's disease.

Brain resident microglia in Alzheimer's disease: foe or friends.

The neurobiology of Alzheimer's disease (AD) is unclear due to its multifactorial nature. Although a wide range of studies revealed several pathomechanisms of AD, dementia is yet unmanageable with current pharmacotherapies. The recent growing literature illustrates the role of microglia-mediated neuroinflammation in the pathogenesis of AD. Indeed, microglia serve as predominant sentinels of the brain, which diligently monitor the neuroimmune axis by phagocytosis and releasing soluble factors. In the case of AD, microglial cells are involved in synaptic pruning and remodeling by producing inflammatory mediators. The conditional inter-transformation of classical activation (proinflammatory) or alternative activation (anti-inflammatory) microglia is responsible for most brain disorders. In this review, we discussed the role of microglia in neuroinflammatory processes in AD following the accumulation of amyloid-β and tau proteins. We also described the prominent phenotypes of microglia, such as disease-associated microglia (DAM), dark microglia, interferon-responsive microglia (IRMs), human AD microglia (HAMs), and microglial neurodegenerative phenotype (MGnD), which are closely associated with AD incidence. Considering the key role of microglia in AD progression, microglial-based therapeutics may hold promise in mitigating cognitive deficits by addressing the neuroinflammatory responses.

Lead Exposure and Incidence of Alzheimer's Disease and Related Dementias in the United States

Lead Exposure and Incidence of Alzheimer's Disease and Related Dementias in the United States