Higher Risk Of Alzheimer's Disease Research Articles

Associated risk and resilience factors of Alzheimer's disease in women with early bilateral oophorectomy: Data from the UK Biobank.

Bilateral oophorectomy (BO) confers immediate estradiol loss. We examined prevalence and predictors of Alzheimer's disease (AD) in women with early BO comparing their odds ratios of AD to those of women with spontaneous menopause (SM). A cohort from UK Biobank (n = 34,603) included women aged 60 + at baseline with and without AD who had early BO or SM. AD was determined based on AD related ICD-10 or ICD-9 code. We used logistic regression to model the association of menopause type with AD. Model predictors included age, education, age at menopause, hormone therapy (HT), APOE4, body mass index (BMI), cancer history, and smoking history. Those with early BO had four times the odds of developing AD (OR = 4.12, 95% CI [2.02, 8.44]) compared to those with SM. APOE4 (OR = 4.29, 95% CI [2.43, 7.56]), and older age (OR = 1.16, 95% CI [1.05, 1.28]) were associated with increased odds of AD in the BO group. Greater years of education were associated with reduced odds of AD for both BO (OR = 0.91, 95% CI [0.85, 0.98]), and SM (OR = 0.95, 95% CI [0.90, 0.99]), while ever use of HT was associated with decreased odds of AD only for the BO group (OR = 0.43, 95% CI [0.23, 0.82]). Women with early BO, particularly with an APOE4 allele, are at high risk of AD. Women with early BO who use HT and those with increased education have lower odds of developing AD.

Enrichment for clinical trials of early AD: Combining genetic risk factors and plasma p-tau as screening instruments.

Identifying low-cost, minimally-invasive screening instruments for Alzheimer's disease (AD) trial enrichment will improve the efficiency of AD trials. A total of 685 cognitively normal (CN) individuals and individuals with mild cognitive impairment (MCI) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were grouped according to cutoffs of genetic risk factor (G) polygenic hazard score (PHS) and tau pathology (T) plasma phosphorylated tau-181 (p-tau181) into four groups: G+T+, G-T-, G+T-, and G-T+. We assessed the associations between group level and longitudinal cognitive decline and AD conversion. Power analyses compared the estimated sample size required to detect differences in cognitive decline. The G+T+ group was associated with faster cognitive decline and higher AD risk. Clinical trials enrolling G+T+ participants would benefit from significantly reduced sample sizes compared with similar trials using only single makers as an inclusion criterion. The combination of two low-cost, minimally-invasive measures-genetics and plasma biomarkers-would be a promising screening procedure for clinical trial enrollment. Participants with unimpaired or mildly impaired cognition were grouped based on cutoffs on genetic risk factors (G: polygenic hazardous score [PHS]) and Alzheimer's pathology (T: baseline plasma phosphorylated tau-181 [p-tau181]). Participants with high PHSs and plasma p-tau181 levels (G+T+) were at risk of faster cognitive decline and AD progression. The combination of PHS and plasma p-tau181 could enhance clinical trial enrichment more effectively than using single biomarkers.

Association between glaucoma and the risk of Alzheimer's disease: A meta-analysis.

The role of glaucoma in predicting Alzheimer's disease (AD) factors is unknown. This current meta-analysis was aimed at evaluating the risk of AD events in individuals suffering from glaucoma based on a meta-analysis. Databases which included Cochrane Library, PubMed, and EMBASE were searched to detect the relevant articles, with language being restricted to English. The risk of AD events in patients with glaucoma was analyzed using the combined hazard ratios. This study included 8 articles with 131,987 subjects published after 2012. We identified glaucoma as the risk factor for disease-free survival (hazard ratio = 1.29; 95% confidence interval = 1.05-1.59; P = .000; I2 = 95.1%) in AD patients. According to subgroup analyses, normal tension glaucoma group was the major risk factor for disease-free survival of AD patients. Although diverse approaches have been used for AD cases of various events, the current meta-analysis indicates that that glaucoma patients have a higher AD risk.

Insulin Glargine Compared with Glucagon-Like Peptide 1 Receptor Agonists (GLP-1 RAs) or SGLT2 Inhibitors Is Associated with Higher Risk of Alzheimer Disease and Alzheimer Disease-Related Dementias (AD/ADRD) in CKD

Insulin Glargine Compared with Glucagon-Like Peptide 1 Receptor Agonists (GLP-1 RAs) or SGLT2 Inhibitors Is Associated with Higher Risk of Alzheimer Disease and Alzheimer Disease-Related Dementias (AD/ADRD) in CKD

Prospective associations of interleukin-6 and APOE allele with cognitive decline in biracial community-dwelling older adults: The Chicago Health and Aging Project (CHAP).

It is unclear whether inflammation, that is, high interleukin-6 (IL-6) levels, and genetic risk, that is, apolipoprotein E (APOE) ε4 allele, have a compounding effect on cognitive decline (CD). We analyzed a subset of participants from the longitudinal cohort study, Chicago Health and Aging Project, comprising 1120 biracial community-dwelling older adults (60% Black and 62% women), and mean follow-up=6.4 years. We ran adjusted mixed-effects models on2 longitudinal CD. In APOE ε4 carriers, higher serum IL-6 was not associated with the rate of CD (β=-0.0091 [standard deviation (SD)=0.0165, p=0.5800]). Conversely, in non-ε4 carriers, compared to the lower tertile, those with the upper tertile of serum IL-6 levels experienced significantly accelerated CD (β=-0.0257 [SD=0.0084, p=0.0023]). Even without the largest genetic risk factor for late-onset Alzheimer's disease/Alzheimer's disease and related dementias (AD/ADRD), elevated serum IL-6 still accelerate the rate of CD in non-APOE ε4 carriers. Hence, interventions ameliorating inflammation may prevent AD/ADRD. Interleukin-6 (IL-6) and the apolipoprotein E (APOE) ε4 allele have been separately associated with an increased risk for cognitive decline, but their interaction remains unclear.In ε4 carriers, IL-6 was not associated with cognitive decline. However, even without the biggest genetic risk factor for Alzheimer's disease (AD), that is, APOE ε4, elevated serum IL-6 still could confer accelerated rate of cognitive decline, with a detrimental effect half of that imposed by APOE ε4 alone.We found no racial differences in these associations.These findings contribute complementary evidence on non-APOE ε4-dependent and non-AD biological pathways through which cognitive decline can still be accelerated in non-APOE ε4 carriers and highlight a specific subgroup of older adults who are at a higher risk of AD and thus may benefit from anti-inflammatory interventions.

Lipid Trajectories Improve Risk Models for Alzheimer's Disease and Mild Cognitive Impairment.

To assess the relationship between lipids and cognitive dysfunction, we retrospectively analyzed blood-lipid levels in clinically well-characterized individuals with stable mild cognitive impairment (MCI) or Alzheimer's disease (AD) over the decade prior to first cognitive symptoms. In this case/control cohort study, AD and MCI cases were diagnosed using DSM-IV criteria; MCI cases had not progressed to dementia for ≥5 years; and controls were propensity matched to cases at age of symptom onset (MCI: 116 cases, 435 controls; AD: 215 cases, 483 controls). Participants were grouped based on longitudinal trajectories and quintile of variability independent of the mean (VIM) for total cholesterol, HDL-C, LDL-C, non-HDL-C and ln(triglycerides). Models for the risk of cognitive dysfunction evaluated trajectory and VIM groups, APOE genotype, polygenic risk scores (PRS) for AD and lipid levels, age, comorbidities, and longitudinal correlates of blood-lipid concentrations. Lower HDL-C trajectories (OR = 3.8, 95% CI = 1.3-11.3) and the lowest VIM quintile of non-HDL-C (OR = 2.2, 95% CI = 1.3-3.0) were associated with higher MCI risk. Lower HDL-C trajectories (OR = 3.0, 95% CI = 1.6-5.7) and the lowest VIM quintile of total cholesterol (OR = 2.4, 95% CI = 1.5-3.9) were associated with higher AD risk. The inclusion of lipid-trajectory and VIM groups improved risk-model predictive performance independent of APOE genotype or PRS for AD and lipid levels. These results provide an important real-world perspective on the influence of lipid metabolism and blood-lipid levels on the development of stable MCI and AD.

Causal Associations of Sleep Apnea With Alzheimer Disease and Cardiovascular Disease: A Bidirectional Mendelian Randomization Analysis.

Sleep apnea (SA) has been linked to an increased risk of dementia in numerous observational studies; whether this is driven by neurodegenerative, vascular, or other mechanisms is not clear. We sought to examine the bidirectional causal relationships between SA, Alzheimer disease (AD), coronary artery disease (CAD), and ischemic stroke using Mendelian randomization. Using summary statistics from 4 recent, large genome-wide association studies of SA (n=523 366), AD (n=94 437), CAD (n=1 165 690), and stroke (n=1 308 460), we conducted bidirectional 2-sample Mendelian randomization analyses. Our primary analytic method was fixed-effects inverse variance-weighted (IVW) Mendelian randomization; diagnostics tests and sensitivity analyses were conducted to verify the robustness of the results. We identified a significant causal effect of SA on the risk of CAD (odds ratio [ORIVW]=1.35 per log-odds increase in SA liability [95% CI=1.25-1.47]) and stroke (ORIVW=1.13 [95% CI=1.01-1.25]). These associations were somewhat attenuated after excluding single-nucleotide polymorphisms associated with body mass index (ORIVW=1.26 [95% CI=1.15-1.39] for CAD risk; ORIVW=1.08 [95% CI=0.96-1.22] for stroke risk). SA was not causally associated with a higher risk of AD (ORIVW=1.14 [95% CI=0.91-1.43]). We did not find causal effects of AD, CAD, or stroke on risk of SA. These results suggest that SA increased the risk of CAD, and the identified causal association with stroke risk may be confounded by body mass index. Moreover, no causal effect of SA on AD risk was found. Future studies are warranted to investigate cardiovascular pathways between sleep disorders, including SA, and dementia.

Associations among dietary 1-carbon metabolism nutrients, genetic risk, and Alzheimer disease: a prospective cohort study

BackgroundThe associations between 1-carbon metabolism (OCM) nutrients (methionine, folate, vitamin B-6, and vitamin B-12) and Alzheimer disease (AD) remains inconclusive. ObjectivesThis study aimed to investigate the association of dietary OCM nutrients with subsequent risk of AD and further assess whether participants with high genetic risk for AD might benefit from dietary OCM nutrients. MethodsWe analyzed data from 192,214 participants who completed at least one 24-h dietary questionnaire and had no previous history of AD based on the UK Biobank. Nutrients intake was calculated using McCance and Widdowson’s The Composition of Food and USDA’s Food and Nutrient Database for Dietary Studies. Cox proportional models with restricted cubic splines were applied to explore the associations. ResultsOver a median follow-up of 13.35 y, 959 cases of AD (41 early-onset cases and 918 late-onset cases) were identified. Compared with those in the low-intake OCM group (quartile 1), participants in the high-intake OCM group (quartile 4) had reduced risk of developing AD. The corresponding hazard ratios (HRs) and 95% confidence intervals (CIs) for methionine, folate, vitamin B-6, and vitamin B-12 intake were 0.66 (0.54, 0.80), 0.71 (0.58, 0.87), 0.71 (0.59, 0.87), and 0.77 (0.64, 0.93), respectively. Similar associations were observed in late-onset AD. In early-onset AD, high methionine and vitamin B-12 intake were associated with 70% (HR: 0.30; 95% CI: 0.10, 0.86) and 71% (HR: 0.29; 95% CI: 0.09, 0.96) reduction in risk, respectively. Participants with low genetic risk and high OCM nutrients intake had >75% reduced AD risk compared with high-risk, low-intake participants. ConclusionsIn this prospective cohort study, we found that higher intake of OCM nutrients is associated with reduced risk of AD. Participants with high genetic risk of AD are more likely to benefit from dietary OCM nutrients intake.

Moving Beyond Depression: Mood Symptoms Across the Spectrum Relate to Tau Pathology in Older Women at Risk for Alzheimer's Disease.

We examined how symptoms across the mood spectrum relate to Alzheimer's disease (AD) biomarkers in older women at high risk for AD. Participants included 25 women aged 65+ with mild cognitive deficits and elevated AD genetic risk. The Profile of Mood States Questionnaire measured mood symptoms and a total mood disturbance (TMD) score. Tau burden in the meta-temporal region of interest was measured using MK-6240 Tau positron emission tomography (PET) imaging. A subset (n = 12) also had p-Tau181, and Aß40/42 levels measured in plasma. Higher TMD scores related to higher tau PET standardized uptake value ratio (SUVR). Greater negative mood symptoms correlated with higher tau PET SUVR, while greater vigor correlated with lower SUVR. Similar results were seen with plasma p-Tau181 levels, but not with Aβ40/42 levels. In conclusion, positive and negative mood symptoms related to tau pathology in older women at high risk for AD, highlighting a role of mental well-being in AD risk.

TOMM40 and APOC1 variants differentiate the impacts of the APOE ε4 allele on Alzheimer's disease risk across sexes, ages, and ancestries.

The variability in apolipoprotein E (APOE) ε4-attributed susceptibility to Alzheimer's disease (AD) across ancestries, sexes, and ages may stem from the modulating effects of other genetic variants. We examined associations of compound genotypes (CompGs) comprising the ε4-encoding rs429358, TOMM40 rs2075650, and APOC1 rs12721046 polymorphisms with AD in White (7181/16,356 AD-affected/unaffected), Hispanic/Latino (2305/2921), and Black American (547/1753) participants across sexes and ages. The absence and presence of the rs2075650 and/or rs12721046 minor alleles in the ε4-bearing CompGs define lower- and higher-AD-risk profiles, respectively, in White participants. They differentially impact AD risks in men and women of different ancestries, exhibiting an increasing, decreasing, flat, and nonlinear-with lower risks at ages younger than 65/70 years and older than 85 years compared to the ages in between-patterns across ages. The ε4-bearing CompGs have a potential to differentiate biological mechanisms of sex-, age-, and ancestry-specific AD risks and serve as AD biomarkers. Younger White women carrying the lower-risk (LR) CompG are at small risk of AD.Black carriers of the LR CompG are at negligible risk of AD at 85 years and older.The higher-risk (HR) CompGs confer high AD risk in Whites and Blacks at 70 to 85 years.AD risk decreases with age for Hispanic/Lation women carrying the HR CompGs.Hispanic/Lation carriers of the LR CompG but not HR CompGs have higher AD risk than Blacks.

Polygenic risk associated with Alzheimer's disease and other traits influences genes involved in T cell signaling and activation.

T cells, known for their ability to respond to an enormous variety of pathogens and other insults, are increasingly recognized as important mediators of pathology in neurodegeneration and other diseases. T cell gene expression phenotypes can be regulated by disease-associated genetic variants. Many complex diseases are better represented by polygenic risk than by individual variants. We first compute a polygenic risk score (PRS) for Alzheimer's disease (AD) using genomic sequencing data from a cohort of Alzheimer's disease (AD) patients and age-matched controls, and validate the AD PRS against clinical metrics in our cohort. We then calculate the PRS for several autoimmune disease, neurological disorder, and immune function traits, and correlate these PRSs with T cell gene expression data from our cohort. We compare PRS-associated genes across traits and four T cell subtypes. Several genes and biological pathways associated with the PRS for these traits relate to key T cell functions. The PRS-associated gene signature generally correlates positively for traits within a particular category (autoimmune disease, neurological disease, immune function) with the exception of stroke. The trait-associated gene expression signature for autoimmune disease traits was polarized towards CD4+ T cell subtypes. Our findings show that polygenic risk for complex disease and immune function traits can have varying effects on T cell gene expression trends. Several PRS-associated genes are potential candidates for therapeutic modulation in T cells, and could be tested in in vitro applications using cells from patients bearing high or low polygenic risk for AD or other conditions.

Impact of sleep duration and sleep disturbances on the incidence of dementia and Alzheimer's disease: A 10-year follow-up study

The nature of the relationship between sleep problems and dementia remains unclear. This study investigated the relationship between sleep measures and dementia in older adults (≥ 65) using data from the English Longitudinal Study of Ageing (ELSA) and further investigated the causal association in Mendelian randomization (MR) analysis. In total of 7,223 individuals, 5.7 % developed dementia (1.7 % Alzheimer's disease (AD)) within an average of 8 (± 2.9) years. Cox regression models and MR were employed. Long sleep duration (>8 h) was associated with 64 % increased risk of incident dementia and 2-fold high risk of AD compared to ideal sleep duration (7–8 h). This association was particularly evident in older-older adults (≥70 years) and those who consumed alcohol. Short sleep duration (<7 h) was associated with lower risk of incident dementia among older-older but higher risk among younger-older adults. Sleep disturbances and perceived sleep quality were not associated with dementia or AD. The MR study did not reveal causal associations between sleep duration and dementia. These findings suggest that self-reported short sleep in younger-older and long sleep in older-older adults and those with frequent alcohol consumption are associated with dementia. Early detection of these sleep patterns may help identify individuals at higher dementia risk.

Identification of diagnostic molecules and potential traditional Chinese medicine components for Alzheimer's disease by single cell RNA sequencing combined with a systematic framework for network pharmacology.

Single-cell RNA sequencing (scRNA-Seq) provides new perspectives and ideas to investigate the interactions between different cell types and organisms. By integrating scRNA-seq with new computational frameworks or specific technologies, better Alzheimer's disease (AD) treatments may be developed. The single-cell sequencing dataset GSE158234 was obtained from the GEO database. Preprocessing, quality control, dimensionality-reducing clustering, and annotation to identify cell types were performed on it. RNA-seq profiling dataset GSE238013 was used to determine the components of specific cell subpopulations in diverse samples. A set of genes included in the OMIM, Genecards, CTD, and DisGeNET databases were selected as highly plausible AD-related genes. Then, ROC curves were created to predict the diagnostic value using the significantly expressed genes in the KO group as hub genes. The genes mentioned above were mapped to the Coremine Medical database to forecast prospective therapeutic Chinese medicines, and a "Chinese medicine-ingredient-target" network was constructed to screen for potential therapeutic targets. The last step was to undertake Mendelian randomization research to determine the causal link between the critical gene IL1B and AD in the genome-wide association study. Using the scRNA-seq dataset, five unique cell clusters were discovered. These clusters were further subdivided into four distinct cell types using marker genes. The KO group showed a more substantial differential subgroup of macrophages than the WT group. By using the available datasets and PPI network analysis, 54 common genes were discovered. Four clusters were identified using the MCODE approach, and correlation analysis showed that seven genes in those four clusters had a significantly negative correlation with macrophages. Six genes in four sets had a significantly positive correlation. Five genes had different levels of expression in the WT and KO groups. The String database was used to identify the regulatory relationships between the four genes (IL10, CX3CR1, IL1B, and IL6) that were finally selected as AD hub genes. Screening identified potential traditional Chinese medicine to intervene in the transformation process of AD, including Radix Salviae, ginseng, Ganoderma, licorice, Coptidis Rhizoma, and Scutellariae Radix, in addition to promising therapeutic targets, such as PTGS1, PTGS2, and RXRA. Finally, it was shown that IL1B directly correlated with immune cell infiltration in AD. In inverse variance weighting, we found that IL1B was associated with a higher risk of AD, with an OR of 1.003 (95% CI = 1.001-1.006, p = 0.038). Our research combined network pharmacology and the scRNA-seq computational framework to uncover pertinent hub genes and prospective traditional Chinese medicine potential therapeutic targets for AD. These discoveries may aid in understanding the molecular processes behind AD genes and the development of novel medications to treat the condition.

Association of soluble TREM2 with Alzheimer's disease and mild cognitive impairment: a systematic review and meta-analysis.

Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) is a potential neuroinflammatory biomarker linked to the pathogenesis of Alzheimer's disease (AD) and mild cognitive impairment (MCI). Previous studies have produced inconsistent results regarding sTREM2 levels in various clinical stages of AD. This study aims to establish the correlation between sTREM2 levels and AD progression through a meta-analysis of sTREM2 levels in cerebrospinal fluid (CSF) and blood. Comprehensive searches were conducted in PubMed, Embase, Web of Science, and the Cochrane Library to identify observational studies reporting CSF and blood sTREM2 levels in AD patients, MCI patients, and healthy controls. A random effects meta-analysis was used to calculate the standardized mean difference (SMD) and 95% confidence intervals (CIs). Thirty-six observational studies involving 3,016 AD patients, 3,533 MCI patients, and 4,510 healthy controls were included. CSF sTREM2 levels were significantly higher in both the AD [SMD = 0.28, 95% CI (0.15, 0.41)] and MCI groups [SMD = 0.30, 95% CI (0.13, 0.47)] compared to the healthy control group. However, no significant differences in expression were detected between the AD and MCI groups [SMD = 0.09, 95% CI (-0.09, 0.26)]. Furthermore, increased plasma sTREM2 levels were associated with a higher risk of AD [SMD = 0.42, 95% CI (0.01, 0.83)]. CSF sTREM2 levels are positively associated with an increased risk of AD and MCI. Plasma sTREM2 levels were notably higher in the AD group than in the control group and may serve as a promising biomarker for diagnosing AD. However, sTREM2 levels are not effective for distinguishing between different disease stages of AD. Further investigations are needed to explore the longitudinal changes in sTREM2 levels, particularly plasma sTREM2 levels, during AD progression. https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024514593.

Genetic characterization of the ALFA study: Uncovering genetic profiles in the Alzheimer's continuum.

In 2013, the ALzheimer's and FAmilies (ALFA) project was established to investigate pathophysiological changes in preclinical Alzheimer's disease (AD), and to foster research on early detection and preventive interventions. We conducted a comprehensive genetic characterization of ALFA participants with respect to neurodegenerative/cerebrovascular diseases, AD biomarkers, brain endophenotypes, risk factors and aging biomarkers. We placed particular emphasis on amyloid/tau status and assessed gender differences. Multiple polygenic risk scores were computed to capture different aspects of genetic predisposition. We additionally compared AD risk in ALFA to that across the full disease spectrum from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Results show that the ALFA project has been successful at establishing a cohort of cognitively unimpaired individuals at high genetic predisposition of AD. It is, therefore, well-suited to study early pathophysiological changes in the preclinical ADcontinuum. Highlights Prevalence of ε4 carriers in ALzheimer and FAmilies (ALFA) is higher than in the general European population The ALFA study is highly enriched in Alzheimer's disease (AD) genetic risk factors beyond APOE AD genetic profiles in ALFA are similar to clinical groups along the continuum ALFA has succeeded in establishing a cohort of cognitively unimpaired individuals at high genetic AD risk ALFA is well suited to study pathogenic events/early pathophysiological changes in AD.

Two‐year longitudinal outcomes of subjective cognitive decline in Hispanics compared to non‐Hispanic Whites

AbstractBackgroundHispanics are at higher risk for Alzheimer disease (AD) than non‐Hispanic Whites (NHW), motivating further study of differences and risk factors at the preclinical level. Subjective cognitive decline (SCD) is considered a preclinical AD stage, but its features and outcomes in Hispanics are less studied. We investigated the differences in longitudinal change in SCD phenotype, cognition, and function among Hispanics compared to NHW.MethodLongitudinal analyses were performed on consecutive participants with SCD who were evaluated at the NYU Alzheimer’s Disease Research Center. Inclusion criteria were self‐identification as Hispanic (n = 23) or NWH (n = 165) and a 2‐year follow‐up visit. Demographics, conversion rate to mild cognitive impairment (MCI), SCD characteristics, and psychometric performance were analyzed by t‐test, multiple linear regression models, or Cox models as appropriate. Models were adjusted for age, sex, education, depression, and baseline values.ResultHispanics were at higher risk for conversion to MCI (HR: 6.57, 95% CI 1.25‐34.47, p = 0.02596). Hispanic ethnicity was associated with increased SCD severity in time as measured via the total Brief Cognitive Rating Scale (BCRS) score (OR: 4.28, 95% CI 1.42‐12.83, p = 0.0094), and in specific BCRS domains: mood and behavior (OR: 0.18, 95% CI 0.03‐0.89, p = 0.0355) and calculation (OR: 29.68, 95% CI 4.02‐219.18, p = 0.0009). Global cognitive function by Mini‐Mental State Examination had a higher risk of declining in time in Hispanics (HR: 2.83, CI 1.09‐7.35, p = 0.0320). Likelihood of decline in domain‐specific tests associated with Hispanic ethnicity for Trails A (HR: 4.05, 95% CI 1.93‐8.47, p = 0.0002), Trails B (HR: 3.16, 95% CI 1.62‐6.14, p = 0.0007), and delayed paragraph recall (HR: 2.08, 95% CI 1.01‐4.24, p = 0.0444).ConclusionHispanics present a higher risk of conversion from SCD to MCI than NHW. Apart from stage conversion, subjective and objective measure of cognition worsen more in Hispanics, but in a domain‐specific manner. These findings suggests that Hispanics not only decline at a faster rate, but that this decline is expressed with a different phenotype. This should be considered when studying this population in preclinical investigations.

Examining sex differences in Alzheimer Disease neuropathology in Down Syndrome

AbstractBackgroundPeople with Down syndrome (DS) have a higher risk of developing Alzheimer disease (AD), due to an extra copy of the amyloid precursor protein (APP) gene on chromosome 21. Overexpression of APP is associated with increased production of amyloid beta (Aβ) in DS, and contributes to early onset of AD. Some studies suggest women with DS are at a higher risk for AD, while others find the opposite. Sex differences may be mediated by estrogen, which is critically involved in neuronal survival and modulation. We hypothesized that lower levels of ERα protein would correlate with increasing AD pathology in DS.MethodWe examined 35 brains (frontal and occipital cortices) of people with DS and DS with AD. Serial sections were immunostained for phosphorylated tau (pTau ‐AT8) and Aβ (6E10) along with ERα and quantified using QuPath. Spearman rank correlations using log transformed % load data were calculated, Kruskal‐Wallis was used to compare men and women.ResultNo significant differences in protein levels of ERα, Aβ, or tau were observed when comparing men and women with DS. However, we found higher levels of ERα protein were associated with higher levels of Aβ in the gray matter of the occipital cortex (R = 0.7078; p = 0.0005) in all cases. This positive correlation was driven primarily by women. Females with DS showed a significant positive association with Aβ and ERα (R = 0.93; p = 0.00012) whereas men showed a weaker trend (R = 0.62; p = 0.057). In contrast, no significant associations between ERα, Aβ or pTau were observed in the frontal cortex. PTau measures in the occipital cortex in women with DS were positively associated with ERα (R = 0.61; p = 0.055), whereas men with DS showed a slight negative, though not significant association (R = ‐0.29; p = 0.41). There was no such trend in the frontal cortex.ConclusionThese results suggest ERα, in contrast to our original hypothesis, may be increasing in response to AD pathology to preserve neuronal health in the occipital cortex. Lack of similar positive associations in the frontal cortex may be related to AD progression, with the occipital cortex being affected later in disease, giving us the opportunity to observe increased ERα.

Investigating the Role of Estrogen Receptor Alpha in Alzheimer’s Disease Pathogenesis in Down Syndrome

AbstractBackgroundPeople with Down syndrome (DS) have a higher risk of developing Alzheimer disease (AD), due to an extra copy of the amyloid precursor protein (APP) gene on chromosome 21. Overexpression of APP is associated with increased production of amyloid beta (Aβ) in DS, and contributes to early onset of AD. Some studies suggest women with DS are at a higher risk for AD, while others find the opposite. Sex differences may be mediated by estrogen, which is critically involved in neuronal survival and modulation. We hypothesized that lower levels of ERα protein would correlate with increasing AD pathology in DS.MethodWe examined 34 brains (frontal and occipital cortices) of people with DS and DS with AD. Serial sections were immunostained for phosphorylated tau (pTau ‐AT8) and Aβ (6E10) along with ERα and quantified using QuPath. Spearman rank correlations using log transformed % load data were calculated, Kruskal‐Wallis was used to compare men (n = 19) and women(n = 15).ResultNo significant differences in protein levels of ERα, Aβ, or tau were observed when comparing men and women with DS. However, we found higher levels of ERα protein were associated with higher levels of Aβ in the gray matter of the occipital cortex (r = 0.7078; p = 0.0005) in all cases. This positive correlation was driven primarily by women. Females with DS showed a significant positive association with Aβ and ERα (r = 0.93; p = 0.00012) whereas men showed a weaker trend (r = 0.62; p = 0.057). In contrast, no significant associations between ERα, Aβ or pTau were observed in the frontal cortex. PTau measures in the occipital cortex in women with DS were positively associated with ERα (r = 0.61; p = 0.055), whereas men with DS showed a slight negative, though not significant association (r = ‐0.29; p = 0.41). There was no such trend in the frontal cortex.ConclusionThese results suggest ERα, in contrast to our original hypothesis, may be increasing in response to AD pathology to preserve neuronal health in the occipital cortex. Lack of similar positive associations in the frontal cortex may be related to AD progression, with the occipital cortex being affected later in disease, giving us the opportunity to observe increased ERα.

Associations of Folate/Folic Acid Supplementation Alone and in Combination With Other B Vitamins on Dementia Risk and Brain Structure: Evidence From 466 224 UK Biobank Participants.

Previous researchers have tried to explore the association between folate/folic acid intake and dementia incidence, but the results remain controversial. We evaluated the associations of folate/folic acid supplementation alone and in combination with other B vitamins on dementia risk and brain structure. A total of 466 224 UK Biobank participants were investigated. Cox proportional hazards models were used to assess the associations between folate/folic acid supplementation status and the risk of Alzheimer's disease (AD) and vascular dementia (VD). Multivariable linear regression models were employed to evaluate the association between folate/folic acid supplementation status and brain structure. In the final model, folate/folic acid supplementation alone was significantly associated with a higher risk of AD (hazard ratio [HR] = 1.34, 95% confidence interval [CI] = 1.06-1.69, p = .015) and VD (HR = 1.61, 95% CI = 1.21-2.13, p = .001). Folate/folic acid supplementation alone was associated with a reduction in the hippocampus (β = -95.25 mm3, 95% CI = -165.31 to -25.19 mm3, p = .014) and amygdala (β = -51.85 mm3, 95% CI = -88.02 to -15.68 mm3, p = .012). The risk of AD and VD, as well as brain structure, in the group with combined folate/folic acid supplementation and other B vitamins did not show a statistically significant difference compared to the reference group (all p > .05). Folate/folic acid supplementation alone is significantly associated with a higher risk of AD and VD, as well as adverse alterations in brain structure. However, when combined with other B vitamins, these detrimental effects can be counteracted.

Associations of screen-based sedentary activities with all cause dementia, Alzheimer’s disease, vascular dementia: a longitudinal study based on 462,524 participants from the UK Biobank

BackgroundCurrent drug treatments for dementia aren't effective. Studying gene-environment interactions can help develop personalized early intervention strategies for Alzheimer's disease (AD). However, no studies have examined the relationship between screen-based sedentary activities and genetic susceptibility to AD risk, and further understanding of the causal relationship is also crucial.MethodsThis study included 462,524 participants from the UK Biobank with a follow-up of 13.6 years. Participants' screen-based sedentary activities time was categorized into three groups based on recorded time: ≥ 4 h/day, 2–3 h/day, and ≤ 1 h/day. Cox proportional risk models were used to analyze the association between computer use/TV viewing groups and the risk of all-cause dementia, AD and vascular dementia (VD). Generalized linear model (GLM) were used to examine the relationship between screen-based sedentary activities and brain structure. Bidirectional Mendelian randomization (MR) was used to validate the causal relationship between TV viewing and AD.ResultsCompared to TV viewing ≤ 1 h/day, 1)TV viewing 2–3 h/day was correlated with a higher risk of all-cause dementia (HR = 1.09, 95% CI:1.01–1.18, P < 0.05), and TV viewing ≥ 4 h/day was associated with a higher risk of all-cause dementia (HR = 1.29, 95% CI: 1.19–1.40, P < 0.001), AD (HR = 1.25, 95% CI:1.1–1.42, P < 0.001), and VD (HR = 1.24, 95% CI: 1.04–1.49, P < 0.05); 2) TV viewing ≥ 4 h/day was correlated with a higher AD risk at intermediate (HR = 1.34, 95% CI: 1.03–1.75, P < 0.001) and high AD genetic risk score (AD-GRS) (HR = 2.18, 95% CI: 1.65–2.87, P < 0.001);3) TV viewing 2–3 h/day [β = (-94.8), 95% CI: (-37.9) -(-151.7), P < 0.01] and TV viewing ≥ 4 h/day [β = (-92.94), 95% CI: (-17.42) -(-168.46), P < 0.05] were correlated with a less hippocampus volume. In addition, a causal effect of TV viewing times was observed on AD analyzed using MR Egger (OR = 5.618, 95%CI:1.502–21.013, P < 0.05).ConclusionsThere was a causal effect between TV viewing time and AD analyzed using bidirectional MR, and more TV viewing time exposure was correlated with a higher AD risk. Therefore, it is recommended that people with intermediate and high AD-GRS should control their TV viewing time to be less than 4 h/ day or even less than 1 h/day.