Incident Alzheimer's Disease Research Articles

Associations of circulating saturated long-chain fatty acids with risk of mild cognitive impairment and Alzheimer’s disease in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort

No study has examined the associations between peripheral saturated long-chain fatty acids (LCFAs) and conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD). This study aimed to examine whether circulating saturated LCFAs are associated with both risks of incident MCI from cognitively normal (CN) participants and incident AD progressed from MCI in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. We conducted analysis of data from older adults aged 55-90 years who were recruited at 63 sites across the USA and Canada. We examined associations between circulating saturated LCFAs (i.e., C14:0, C16:0, C18:0, C20:0) and risk for incident MCI in CN participants, and incident AD progressed from MCI. 829 participants who were enrolled in ADNI-1 had data on plasma saturated LCFAs, of which 618 AD-free participants were included in our analysis (226 with normal cognition and 392 with MCI; 60.2% were men). Cox proportional-hazards models were used to account for time-to-event/censor with a 48-month follow-up period for the primary analysis. Other than C20:0, saturated LCFAs were associated with an increased risk for AD among participants with MCI at baseline (Hazard ratios (HRs)=1.3 to 2.2, P=0.0005 to 0.003 in fully-adjusted models). No association of C20:0 with risk of AD among participants with MCI was observed. No associations were observed between saturated LCFAs and risk for MCI among participants with normal cognition. Saturated LCFAs are associated with increased risk of progressing from MCI to AD. This finding holds the potential to facilitate precision prevention of AD among patients with MCI. National Institutes of Health.

Plasma p-tau217, p-tau181, and NfL as early indicators of dementia risk in a community cohort: The Shanghai Aging Study.

Blood biomarkers showed values for predicting future cognitive impairment. Evidence from the community-based cohort was limited only in high-income countries. This study included 1857 dementia-free community residents recruited in 2009-2011 and followed up in waves 2014-2016 and 2019-2023 in the Shanghai Aging Study. We intended to explore the relationships of baseline plasma ALZpath phosphorylated tau 217 (p-tau217), p-tau181, neurofilament light chain (NfL) with follow-up incident dementia, Alzheimer's disease (AD), and amyloidosis. Higher concentrations of plasma p-tau217, p-tau181, and NfL were correlated to higher decline speed of Mini-Mental State Examination score, and higher risk of incident dementia and AD. The p-tau217 demonstrated a significant correlation with longitudinal neocortical amyloid-beta (Aβ) deposition (r=0.57 [0.30, 0.76]) and a high accuracy differentiating Aβ+ from Aβ- at follow-ups (area under the receiver operating characteristic curve=0.821 [0.703, 0.940]). Plasma p-tau217 may be an early predictive marker of AD and Aβ pathology in older community-dwelling individuals.Highlights: Plasma p-tau217, p-tau181, and NfL were positively associated with long-term cognitive decline and risk of incident dementia.Plasma p-tau217 showed a better performance distinguishing Aβ+ individuals from Aβ- individuals at follow-ups.Plasma NfL may be a suitable predictor of general cognitive decline in older community-dwelling individuals.

Neuropathological substrate of incident dementia in older patients with schizophrenia: A clinicopathological study.

Clinical studies reported that patients with schizophrenia are at a higher risk of developing dementia than people without schizophrenia. However, early neuropathological studies have shown that the incidence of Alzheimer's disease (AD) in schizophrenia patients does not differ from that in controls. These inconsistent results may be attributable to the inclusion of non-AD dementia, but there have been few clinicopathological studies in older patients with schizophrenia based on the current neuropathological classification. This study aimed to investigate the neuropathological basis of incident dementia in older patients with schizophrenia. We systematically examined 32 brains of old patients with schizophrenia using standardized pathological methods. The severity of dementia-related neuropathologies was analyzed using standardized semiquantitative assessments. After excluding patients who fulfilled the neuropathological criteria, clinicopathological variables were compared between patients with and without incident dementia to identify potential differences. Seven patients fulfilled the pathological criteria for AD (n = 3), argyrophilic grain disease (AGD) (n = 2), dementia with Lewy bodies (n = 1), and AGD/progressive supranuclear palsy (n = 1). Among 25 patients for whom a neuropathological diagnosis was not obtained, 10 had dementia, but the clinicopathological findings did not differ from the remaining 15 patients without dementia. Two types of older schizophrenia patient present dementia: patients with co-existing neurodegenerative disease and patients who do not meet pathological criteria based on the current classification. To understand the neurobiological aspects of incident dementia in older patients with schizophrenia, further clinicopathological studies are needed that do not simply analyze incident dementia as a comorbidity of conventional dementia-related neuropathologies.

Chronic pain is a risk factor for incident Alzheimer's disease: a nationwide propensity-matched cohort using administrative data.

Chronic pain (CP) is one of the most disabling conditions in the elderly and seems to be a risk factor for the development of Alzheimer's disease and related dementias (ADRD). Only one study, using national administrative health databases, assessed and demonstrated that chronic pain (all types of pain) was a risk factor for dementia, but without assessing the impact of pain medications. To assess the impact of all types of chronic pain and the long-term use of pain medications on the person-years incidence of ADRD, a retrospective nationwide healthcare administrative data study was performed using the national inter-regime health insurance information system (SNIIRAM) to the French national health data system (SNDS). Incident people >50 years old with chronic pain, defined by at least 6-months duration analgesics treatment or by a diagnosis/long-term illness of chronic pain between 2006 and 2010, were included. Chronic pain individuals were matched with non-CP individuals by a propensity score. Individuals were followed up from 9 to 13 years to identify occurrences of ADRD from 2006. Among 64,496 French individuals, the incidence of ADRD was higher in the chronic pain population than control (1.13% vs. 0.95%, p <0.001). Chronic pain increases the risk of ADRD (HR = 1.23) and the incidence of ADRD was higher for women and increased significantly with age. Our study highlights the importance of prevention, diagnosis, and management of chronic pain in elderly to reduce the risk of development and/or worsening of dementia.

Identification and verification of genes associated with hypoxia microenvironment in Alzheimer’s disease

As the incidence of Alzheimer's disease (AD) increases year by year, more people begin to study this disease. In recent years, many studies on reactive oxygen species (ROS), neuroinflammation, autophagy, and other fields have confirmed that hypoxia is closely related to AD. However, no researchers have used bioinformatics methods to study the relationship between AD and hypoxia. Therefore, our study aimed to screen the role of hypoxia-related genes in AD and clarify their diagnostic significance. A total of 7681 differentially expressed genes (DEGs) were identified in GSE33000 by differential expression analysis and cluster analysis. Weighted gene co-expression network analysis (WGCNA) was used to detect 9 modules and 205 hub genes with high correlation coefficients. Next, machine learning algorithms were applied to 205 hub genes and four key genes were selected. Through the verification of external dataset and quantitative real-time PCR (qRT-PCR), the AD diagnostic model was established by ANTXR2, BDNF and NFKBIA. The bioinformatics analysis results suggest that hypoxia-related genes may increase the risk of AD. However, more in-depth studies are still needed to investigate their association, this article would guide the insights and directions for further research.

Age at Onset of Heart Failure and Subsequent Risk of Dementia: A Longitudinal Cohort Study

BackgroundThe average age at onset of heart failure (HF) shows a progressive decrease in recent years; however, the association between age at onset of HF and risk of subsequent dementia remains undetermined. ObjectivesThis study sought to examine whether younger onset age of HF is associated with a higher risk of incident dementia. MethodsIndividual-level data from the UK Biobank cohort study were analyzed in the present study. Cox regression models and the propensity score matching method were used to analyze the associations of HF and its onset age with subsequent all-cause dementia, Alzheimer disease (AD), and vascular dementia (VD). ResultsCompared with 442,791 participants without HF, those with HF had a higher risk of all-cause dementia (HR: 1.14). Among 14,413 participants with HF, multivariable-adjusted HRs for all-cause dementia, AD, and VD were 1.18, 1.64, and 1.27, respectively, per 10-year decrease in age at HF onset. The propensity score matching analyses found that the strength of association between HF and all-cause dementia increased with decreasing onset age of HF (≥75 years, HR: 1.05; 65-74 years, HR: 1.10; <65 years, HR: 1.67) after multivariable adjustment. Similarly, participants with onset age of HF <65 years had the greatest HRs for incident AD and VD, compared with their matched control subjects. ConclusionsYounger age at HF onset was associated with increased risk of dementia. Individuals with an onset age of HF before 65 years of age may represent a particularly vulnerable population for dementia irrespective of subtypes and need careful monitoring and timely intervention to attenuate subsequent risk of incident dementia.

Circadian rest-activity rhythms and cognitive decline and impairment in older Chinese adults: A multicohort study with prospective follow-up

BackgroundThe associations between rest-activity rhythms and cognitive health are inconclusive. The potential changes in rest-activity rhythms in older people with mild cognitive impairment (MCI) remains unclear. This study aimed to examine the association between rest-activity rhythms and cognitive health across different outcome measures in older Chinese people. MethodsA total of 710 community-dwelling participants (average age 81.1 ± 5.2 years) from two cohort studies. Wrist-worn accelerometer data was used to estimate the circadian rest-activity rhythms at baseline. Cognitive function was assessed and clinical diagnosis was made at baseline and follow-up. The two-way Analysis of Co-variance was used to compare the differences in rest-activity rhythms across participants with cognitively normal, MCI and Alzheimer's disease (AD). Logistic regression models were used to investigate the association between rest-activity rhythms and incidence of cognitive decline and impairment in a 4-year prospective follow-up of cognitively normal individuals. ResultsThere was a progressive trend of lower relative amplitude and higher activity level during the least active 5 h across participants with cognitively normal, MCI and Alzheimer's disease (AD). Among the cognitively normal participants, lower relative amplitude at baseline was associated with a greater risk of cognitive decline (per 1 SD decrease, odds ratio 1.66 [95 %CI 1.13–2.45]) and increased incidence of MCI or AD (per 1 SD decrease, 1.68 [1.12–2.50]). ConclusionsLower relative amplitude could potentially serve as a robust biomarker of cognitive decline and impairment. Further studies could evaluate the potential benefits of interventions associated with rest-activity relative amplitude to prevent or delay the progression of AD.

Can Speaking More Than One Language Help Prevent Alzheimer's Disease?

Alzheimer's disease (AD) is an age-related neurocognitive disorder that is epidemic in the elderly population. Currently, there are limited pharmacological interventions, and this has heightened the urgency to identify potential preventable or modifiable risk factors that promote resilience to the neuropathological effects of AD. The regular use of two or more languages is one such factor that may increases cognitive reserve through the long-standing executive control involved in managing multiple languages in the brain. There is also evidence that bilingualism is associated with increased brain reserve or maintenance, particularly in frontal-executive structures and networks. This review examines the current, sometimes conflicting literature on bi/multilingualism and AD. These studies have confounding variations in the assessment of age of second language onset, language proficiency, language usage, and whether determining incidence of AD or age of symptom onset. Despite these limitations, most publications support the presence of increased frontal-executive reserve that compensates for the development of AD neuropathology and, thereby, delays the emergence of clinical symptoms of dementia by about 4-5 years. Although regularly speaking more than one language does not protect against AD neuropathology, the delay in its clinical expression has a potentially significant impact on the lifelong morbidity from this age-related disease. Learning other languages may be an important modifiable factor for delaying the clinical expression of AD in later life.

Menopausal hormone therapy and risk of dementia: health insurance database in South Korea-based retrospective cohort study.

Menopausal hormone therapy (MHT) is used to alleviate the symptoms associated with menopause, despite the lack of recommendations for MHT in preventing dementia. Recent nationwide studies have explored the association between MHT and dementia risk, but the findings remain limited. This study aims to investigate the association between MHT and the incidence of Alzheimer's disease (AD) and non-AD dementia using national population data from Korea. We conducted a retrospective study using data from the National Health Insurance Service in Korea between January 1, 2002, and December 31, 2019. Women over 40 years were eligible for this study and classified into the MHT or non-MHT groups. The MHT group consisted of women who used Tibolone (TIB), combined estrogen plus progestin by the manufacturer (CEPM), estrogen, combined estrogen plus progestin by a physician (CEPP), and transdermal estrogen during menopause. We compared the risk of dementia between the MHT and non-MHT groups. The study included 1,399,256 patients, of whom 387,477 were in the MHT group, and 1,011,779 were in the non-MHT group. The median duration of MHT was 23 months (range: 10-55 months). After adjusting for available confounders, we found that different types of MHT had varying effects on the occurrence of dementia. TIB (HR 1.041, 95% confidence interval (CI) 1.01-1.072) and oral estrogen alone (HR 1.081, 95% CI 1.03-1.134) were associated with a higher risk of AD dementia. In contrast, there was no difference in the risk of AD dementia by CEPM (HR 0.975, 95% CI 0.93-1.019), CEPP (HR 1.131, 95% CI 0.997-1.283), and transdermal estrogen (HR 0.989, 95% CI 0.757-1.292) use. The use of TIB, CEPM, and oral estrogen alone increased the risk of non-AD dementia (HR 1.335, 95% CI 1.303-1.368; HR 1.25, 95% CI 1.21-1.292; and HR 1.128, 95% CI 1.079-1.179; respectively), but there was no risk of non-AD dementia in the other MHT groups (CEPP and topical estrogen). Our findings indicate that MHT has varying effects on the incidence of AD and non-AD dementia. Specifically, TIB, CEPM, and oral estrogen alone increase the risk of non-AD dementia, while transdermal estrogen is not associated with dementia risk. It is essential to consider the type of MHT used when assessing the risk of dementia in women.

Causal relationship between Alzheimer's disease and cardiovascular disease: a bidirectional Mendelian randomization analysis.

Observational studies suggest that cardiovascular disease (CVD) increases the risk of developing Alzheimer's disease (AD). However, the causal relationship between the two is not clear. This study applied a two-sample bidirectional Mendelian randomization method to explore the causal relationship between CVD and AD. Genome-wide association study (GWAS) data from 46 datasets of European populations (21,982 cases of AD and 41,944 controls) were utilized to obtain genetic instrumental variables for AD. In addition, genetic instrumental variables for atrial fibrillation (AF), heart failure (HF), myocardial infarction (MI), coronary heart disease (CHD), angina pectoris (AP), and ischemic stroke (IS) (including large-artery atherosclerotic stroke [LAS] and cardioembolic stroke [CES]) were selected from GWAS data of European populations (P < 5E-8). The inverse variance weighting method was employed as the major Mendelian randomization analysis method. Genetically predicted AD odds ratios (OR) (1.06) (95% CI: 1.02-1.10, P = 0.003) were linked to higher AP analysis. A higher genetically predicted OR for CES (0.9) (95% CI 0.82-0.99, P = 0.02) was linked to a decreased AD risk. This Mendelian randomized study identified AD as a risk factor for AP. In addition, CES was related to a reduced incidence of AD. Therefore, these modifiable risk factors are crucial targets for preventing and treating AD.

Abstract P378.2: Association Of Foxo3 Longevity Genotype And Late-life Hypertension With Alzheimer’S Disease And Vascular Dementia

Genetic variants of the gene encoding the transcription factor FOXO3 are associated with cell resilience and longevity. Mid-life hypertension is associated with increased risk of vascular dementia and Alzheimer’s disease (AD) at older ages. But the findings for late life hypertension and AD are mixed. The aim of the present study was to determine whether FOXO3 genotype might influence the association between late-life hypertension and incident dementia. Subjects were 2,688 American men of Japanese ancestry free of prevalent dementia at baseline (1991-93, baseline age: 77.0 ± 4.1 years, range 71-93 years) from the Kuakini Honolulu Heart Program. Status was known for FOXO3 rs2802292 genotype, hypertension, and diagnosis of incident dementia to 2012. Association of FOXO3 genotype with late-life hypertension and incident dementia, vascular dementia (VD) and Alzheimer’s disease (AD) was assessed using Cox proportional hazards models. During 21 years of follow-up, 725 men were diagnosed with all-cause dementia, 513 with AD and 104 with VD. A multivariable Cox model, adjusting for age, education, APOE-ε4 and cardiovascular risk factors, showed late-life hypertension increased VD risk only (HR=1.71, 95%CI=1.08-2.71, p =0.022). We found no significant protective effect of FOXO3 longevity genotype on any type of dementia at the population level. However, in a full Cox model adjusting for age, education, APOE-ε4 and other cardiovascular risk factors, there was a significant interaction effect of late-life hypertension and FOXO3 longevity genotypes on incident AD (β= -0.52, p =0.0061). In men with FOXO3 rs2802292 longevity genotypes ( TG / GG ), late-life hypertension showed protection against AD (HR=0.72; 95% CI=0.55-0.95, p =0.021). The non-longevity genotype ( TT ) (HR=1.16; 95% CI=0.90-1.51, p =0.25) had no protective effect. In conclusion, our longitudinal study found that FOXO3 genotype modulates the effect of late-life hypertension on incident AD.

Non-Genetic Risk Factors for Dementia and Alzheimer’s Disease

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder linked to multiple genetic and environmental factors. Despite its complex pathology and still undetermined etiology, a number of factors have been found to be closely associated with the incidence of AD. Although the molecular mechanisms linking many of these factors with AD are unclear and not necessarily causative, their identification and control might be key preventative measures. Cardiovascular diseases, diabetes, obesity and other life-style habits are recognized as established risk factors for AD. Other emerging factors investigated as potential contributors to the overall risk of dementia include anemia, obstructive respiratory diseases, vitamin D deficiency, thyroid imbalance, inflammation and depression. This review summarizes established risk factors; it also provides an insight into emerging factors as modifiable elements, the control of which may reduce the risk of AD and dementia.

Incidence of Alzheimer's Disease in Men with Late-Life Hypertension Is Ameliorated by FOXO3 Longevity Genotype.

It is well established that mid-life hypertension increases risk of dementia, whereas the association of late-life hypertension with dementia is unclear. To determine whether FOXO3 longevity-associated genotype influences the association between late-life hypertension and incident dementia. Subjects were 2,688 American men of Japanese ancestry (baseline age: 77.0±4.1 years, range 71-93 years) from the Kuakini Honolulu Heart Program. Status was known for FOXO3 rs2802292 genotype, hypertension, and diagnosis of incident dementia to 2012. Association of FOXO3 genotype with late-life hypertension and incident dementia, vascular dementia (VaD) and Alzheimer's disease (AD) was assessed using Cox proportional hazards models. During 21 years of follow-up, 725 men were diagnosed with all-cause dementia, 513 with AD, and 104 with VaD. A multivariable Cox model, adjusting for age, education, APOEɛ4, and cardiovascular risk factors, showed late-life hypertension increased VaD risk only (HR = 1.71, 95% CI = 1.08-2.71, p = 0.022). We found no significant protective effect of FOXO3 longevity genotype on any type of dementia at the population level. However, in a full Cox model adjusting for age, education, APOEɛ4, and other cardiovascular risk factors, there was a significant interaction effect of late-life hypertension and FOXO3 longevity genotype on incident AD (β= -0.52, p = 0.0061). In men with FOXO3 rs2802292 longevity genotype (TG/GG), late-life hypertension showed protection against AD (HR = 0.72; 95% CI = 0.55-0.95, p = 0.021). The non-longevity genotype (TT) (HR = 1.16; 95% CI = 0.90-1.51, p = 0.25) had no protective effect. This longitudinal study found late-life hypertension was associated with lower incident AD in subjects with FOXO3 genotype.

Education counteracts the genetic risk of Alzheimer's disease without an interaction effect.

Alzheimer's disease (AD) is a major cause of disability and mortality in older adults. This study aimed to investigate the association of AD with education and genetic factors. We conducted a prospective cohort study using data from the UK Biobank. Genetic risk was assessed using a polygenic risk score for AD. The educational level was categorized as either low, intermediate, or high. AD was defined using the International Classification of Diseases and Related Health Problems, 10th revision. Logistic regression models were used to investigate the independent and combined effects of genetic factors and educational levels on the risk of AD. We included 318,535 participants in this study (age: 56.53 ± 8.09 years; male: 44.81%). Compared with a low genetic risk, a high genetic risk was associated with a significantly greater risk of AD (OR = 7.09, 95% CI: 6.09-8.26). A high educational level was associated with a 30% lower risk of AD compared with a low educational level (OR = 0.70, 95% CI: 0.60-0.81). Combining genetic risk and education categories, individuals with a low genetic risk and high educational level had a more than 90% (OR = 0.09, 95% CI: 0.05-0.16) lower risk of AD compared to those with a high genetic risk and low educational level. There was no significant interaction between genetic risk and educational level regarding AD risk (p for interaction = 0.359). Education counteracts the genetic risk of AD, without an interaction effect. Increasing education to reduce the incidence of AD is of same importance across individuals with different genetic risk.

Peripheral inflammatory biomarkers are associated with cognitive function and dementia: Framingham Heart Study Offspring cohort.

Inflammatory protein biomarkers induced by immune responses have been associated with cognitive decline and the pathogenesis of Alzheimer's disease (AD). Here, we investigate associations between a panel of inflammatory biomarkers and cognitive function and incident dementia outcomes in the well-characterized Framingham Heart Study Offspring cohort. Participants aged ≥40 years and dementia-free at Exam 7 who had a stored plasma sample were selected for profiling using the OLINK proteomics inflammation panel. Cross-sectional associations of the biomarkers with cognitive domain scores (N = 708, 53% female, 22% apolipoprotein E (APOE) ε4 carriers, 15% APOE ε2 carriers, mean age 61) and incident all-cause and AD dementia during up to 20 years of follow-up were tested. APOE genotype-stratified analyses were performed to explore effect modification. Higher levels of 12 and 3 proteins were associated with worse executive function and language domain factor scores, respectively. Several proteins were associated with more than one cognitive domain, including IL10, LIF-R, TWEAK, CCL19, IL-17C, MCP-4, and TGF-alpha. Stratified analyses suggested differential effects between APOE ε2 and ε4 carriers: most ε4 carrier associations were with executive function and memory domains, whereas most ε2 associations were with the visuospatial domain. Higher levels of TNFB and CDCP1 were associated with higher risks of incident all-cause and AD dementia. Our study found that TWEAK concentration was associated both with cognitive function and risks for AD dementia. The association of these inflammatory biomarkers with cognitive function and incident dementia may contribute to the discovery of therapeutic interventions for the prevention and treatment of cognitive decline.

Aerobic Exercise Facilitates the Nuclear Translocation of SREBP2 by Activating AKT/SEC24D to Contribute Cholesterol Homeostasis for Improving Cognition in APP/PS1 Mice.

Impaired cholesterol synthesizing ability is considered a risk factor for the development of Alzheimer's disease (AD), as evidenced by reduced levels of key proteases in the brain that mediate cholesterol synthesis; however, cholesterol deposition has been found in neurons in tangles in the brains of AD patients. Although it has been shown that statins, which inhibit cholesterol synthesis, reduce the incidence of AD, this seems paradoxical for AD patients whose cholesterol synthesizing capacity is already impaired. In this study, we aimed to investigate the effects of aerobic exercise on cholesterol metabolism in the brains of APP/PS1 mice and to reveal the mechanisms by which aerobic exercise improves cognitive function in APP/PS1 mice. Our study demonstrates that the reduction of SEC24D protein, a component of coat protein complex II (COPII), is a key factor in the reduction of cholesterol synthesis in the brain of APP/PS1 mice. 12 weeks of aerobic exercise was able to promote the recovery of SEC24D protein levels in the brain through activation of protein kinase B (AKT), which in turn promoted the expression of mem-brane-bound sterol regulatory element-binding protein 2 (SREBP2) nuclear translocation and the expression of key proteases mediating cholesterol synthesis. Simultaneous aerobic exercise restored cholesterol transport capacity in the brain of APP/PS1 mice with the ability to efflux excess cholesterol from neurons and reduced neuronal lipid rafts, thereby reducing cleavage of the APP amyloid pathway. Our study emphasizes the potential of restoring intracerebral cholesterol homeostasis as a therapeutic strategy to alleviate cognitive impairment in AD patients.

DNA methylation: The epigenetic mechanism of Alzheimer's disease.

Nowadays, with the development of the social health care system, there is an increasing trend towards an aging society. The incidence of Alzheimer's disease (AD) is also on the rise. AD is a kind of neurodegenerative disease that can be found in any age group. For years, scientists have been committing to discovering the cause of AD. DNA methylation is one of the most common epigenetic mechanisms in mammals and plays a vital role in the pathogenesis of several diseases, including tumors. Studying chemical changes in the epigenome, or DNA methylation can help us understand the effects of our environment and life on diseases, such as smoking, depression, and menopause, which may affect people's chances of developing Alzheimer's or other diseases. Recent studies have identified some crucial genes like ANK1, RHBDF2, ABCA7, and BIN1, linking DNA methylation to AD. This review focuses on elucidating the relationship between DNA methylation and the pathogenesis of AD and provides an outlook on possible targeted therapeutic modalities.

Associations of inner retinal layers with risk of incident dementia: An individual participant data analysis of four prospective cohort studies.

Our main objectivewas to investigate whether retinal neurodegeneration, estimated from lower thickness of inner retinal layers, was associated with incident all-cause dementia and Alzheimer's disease (AD). We performed an individual participant data meta-analysis using unpublished data from four prospective cohort studies with a total of 69,955 participants (n=1087 cases of incident all-cause dementia; n=520 cases incident AD; follow-up time median [interquartile range] 11.3 [8.8-11.5] years). General baseline characteristics of the study population were mean (standard deviation) age, 58.1 (8.8) years; 47% women. After adjustment, lower baseline macular retinal nerve fiber layer thickness was significantly associated with a 10% and 11% higher incidence of all-cause dementia and AD, respectively. Lower baseline macular ganglion cell-inner plexiform layer thickness was not significantly associated with these outcomes. These findings suggest that retinal neurodegeneration precedes the onset of clinical dementia. Retinal imaging tools may be informative biomarkers for the study of the early pathophysiology of dementia.

Cardiovascular health, infection burden, and incident dementia in the UK Biobank.

Among older adults, total and hospitalized infection may be associated with incidence of all-cause and Alzheimer's disease (AD) dementias, with variation by cardiovascular health (CVH). We used Cox proportional hazards (PH) models to examine the relationships between International Classification of Diseases-10th revision(ICD-10)-specific viral and bacterial infectious agents and incident all-cause and AD dementia among 355,046 UK Biobank participants ≥50 years at baseline. Life's Essential 8 (LE8) index reflected CVH. In both sexes, total infection burden (yes vs. no) was associated with all-cause dementia, with significant interactions by LE8 tertiles, whereby this relationship was significant only in the lowest LE8 tertile. Hospital-treated infection burden (yes vs no) was significantly related to all-cause and AD dementia, with no significant interaction with LE8 tertile. Age group patterns were detected. AD and all-cause dementia were related to hospital-treated infections, while CVH modified the relationship of total infection burden with all-cause dementia. Highlights Secondary analysis on>355,000 UK Biobank participants ≥50 years at baseline. Alzheimer's disease and all-cause dementia are both related to hospital-treated infection. Cardiovascular health modifies association of infection burden with all-cause dementia.

Evaluation of bumetanide as a potential therapeutic agent for Alzheimer's disease.

Therapeutics discovery and development for Alzheimer's disease (AD) has been an area of intense research to alleviate memory loss and the underlying pathogenic processes. Recent drug discovery approaches have utilized in silico computational strategies for drug candidate selection which has opened the door to repurposing drugs for AD. Computational analysis of gene expression signatures of patients stratified by the APOE4 risk allele of AD led to the discovery of the FDA-approved drug bumetanide as a top candidate agent that reverses APOE4 transcriptomic brain signatures and improves memory deficits in APOE4 animal models of AD. Bumetanide is a loop diuretic which inhibits the kidney Na+-K+-2Cl- cotransporter isoform, NKCC2, for the treatment of hypertension and edema in cardiovascular, liver, and renal disease. Electronic health record data revealed that patients exposed to bumetanide have lower incidences of AD by 35%-70%. In the brain, bumetanide has been proposed to antagonize the NKCC1 isoform which mediates cellular uptake of chloride ions. Blocking neuronal NKCC1 leads to a decrease in intracellular chloride and thus promotes GABAergic receptor mediated hyperpolarization, which may ameliorate disease conditions associated with GABAergic-mediated depolarization. NKCC1 is expressed in neurons and in all brain cells including glia (oligodendrocytes, microglia, and astrocytes) and the vasculature. In consideration of bumetanide as a repurposed drug for AD, this review evaluates its pharmaceutical properties with respect to its estimated brain levels across doses that can improve neurologic disease deficits of animal models to distinguish between NKCC1 and non-NKCC1 mechanisms. The available data indicate that bumetanide efficacy may occur at brain drug levels that are below those required for inhibition of the NKCC1 transporter which implicates non-NKCC1 brain mechansims for improvement of brain dysfunctions and memory deficits. Alternatively, peripheral bumetanide mechanisms may involve cells outside the central nervous system (e.g., in epithelia and the immune system). Clinical bumetanide doses for improved neurological deficits are reviewed. Regardless of mechanism, the efficacy of bumetanide to improve memory deficits in the APOE4 model of AD and its potential to reduce the incidence of AD provide support for clinical investigation of bumetanide as a repurposed AD therapeutic agent.