Alzheimer's Disease Patients Research Articles

Subtype-specific neurons from patient iPSCs display distinct neuropathological features of Alzheimer’s disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by massive neuronal loss in the brain. Both cortical glutamatergic neurons and basal forebrain cholinergic neurons (BFCNs) in the AD brain are selectively vulnerable. The degeneration and dysfunction of these two subtypes of neurons are closely associated with the cognitive decline of AD patients. The determination of cellular and molecular mechanisms involved in AD pathogenesis, especially in the early stage, will largely facilitate the understanding of this disease and the development of proper intervention strategies. However, due to the inaccessibility of living neurons in the brains of patients, it remains unclear how cortical glutamatergic neurons and BFCNs respond to pathological stress in the early stage of AD. In this study, we established in vitro differentiation systems that can efficiently differentiate patient-derived iPSCs into BFCNs. We found that AD-BFCNs secreted less Aβ peptide than cortical glutamatergic neurons did, even though the Aβ42/Aβ40 ratio was comparable to that of cortical glutamatergic neurons. To further mimic the neurotoxic niche in AD brain, we treated iPSC-derived neurons with Aβ42 oligomer (AβO). BFCNs are less sensitive to AβO induced tau phosphorylation and expression than cortical glutamatergic neurons. However, AβO could trigger apoptosis in both AD-cortical glutamatergic neurons and AD-BFCNs. In addition, AD iPSC-derived BFCNs and cortical glutamatergic neurons exhibited distinct electrophysiological firing patterns and elicited different responses to AβO treatment. These observations revealed that subtype-specific neurons display distinct neuropathological changes during the progression of AD, which might help to understand AD pathogenesis at the cellular level.

Gut Microbiota Alterations in Alzheimer's Disease: Relation with Cognitive Impairment and Mediterranean Lifestyle.

Recently, an association between dysbiosis of the gut microbiota (GMB) and the development of several diseases, such as Alzheimer's disease (AD), has been proposed. Dysbiosis involves changes in microbial diversity influenced by environmental factors, like diet or lifestyle. In this study, we investigated the role of GMB parameters in Spanish AD patients, assessing the impact of adherence to the Mediterranean lifestyle (ML), as well as to characterize these parameters in relation to neuropsychological, neuropsychiatric, emotional, and functionality parameters. A case-control study was conducted to investigate the association between the composition of the GMB and cognitive, emotional, neuropsychiatric, and functionality status in Spanish AD patients, along with a shotgun metagenomics approach. Richness and alpha-diversity were significantly lower in the AD group compared to the controls. PERMANOVA and ANOSIM tests of Bray-Curtis dissimilarity, Aitchison distance, and Jaccard similarity did not showed significant differences in beta-diversity between the two groups. Moreover, associations between various phyla of the AD group and orientation performance, food consumption, and activities of daily living were identified. Dysbiosis observed in Spanish AD patients is characterized by reductions in richness and alpha-diversity, alongside alterations in GMB composition, which may be linked to adherence to the ML and cognitive and functionality symptoms.

Drug Repurposing for Effective Alzheimer's Disease Medicines: Existing Methods and Novel Pharmacoepidemiological Approaches.

Drug repurposing is a methodology used to identify new clinical indications for existing drugs developed for other indications and has been successfully applied in the treatment of numerous conditions. Alzheimer's disease (AD) may be particularly well-suited to the application of drug repurposing methods given the absence of effective therapies and abundance of multi-omic data that has been generated in AD patients recently that may facilitate discovery of candidate AD drugs. A recent focus of drug repurposing has been in the application of pharmacoepidemiologic approaches to drug evaluation. Here, real-world clinical datasets with large numbers of patients are leveraged to establish observational efficacy of candidate drugs for further evaluation in disease models and clinical trials. In this review, we provide a selected overview of methods for drug repurposing, including signature matching, network analysis, molecular docking, phenotypic screening, semantic network, and pharmacoepidemiological analyses. Numerous methods have also been applied specifically to AD with the aim of nominating novel drug candidates for evaluation. These approaches, however, are prone to numerous limitations and potential biases that we have sought to address in the Drug Repurposing for Effective Alzheimer's Medicines (DREAM) study, a multi-step framework for selection and validation of potential drug candidates that has demonstrated the promise of STAT3 inhibitors and re-evaluated evidence for other drug candidates, such as phosphodiesterase inhibitors. Taken together, drug repurposing holds significant promise for development of novel AD therapeutics, particularly as the pace of data generation and development of analytical methods continue to accelerate.

Exploration of plasma biomarkers for Alzheimer's disease by targeted lipid metabolomics based on nuclear magnetic resonance (NMR) spectroscopy.

Alzheimer's disease (AD) is the most common cause of dementia, but the disease lacks convenient and cost-effective alternative biomarkers currently. We utilized targeted lipid metabolomics based on nuclear magnetic resonance (NMR) spectroscopy to identify plasma biomarkers in AD patients. Our study was a cross-sectional study that enrolled 58 AD patients and 40 matched health controls (HCs). Firstly, we identified plasma lipid metabolites that were significantly different between the two groups based on P < 0.05 and variable importance in the projection (VIP) > 1. Then we examined the correlation between the lipid metabolites and cognitive function using partial correlation analysis and assessed the diagnostic ability of the lipid metabolites using receiver operating characteristic (ROC) curves. Seventeen lipoproteins showed significant differences between AD patients and HCs among 114 lipid metabolites. All 17 lipoproteins were subtypes of low-density lipoprotein (LDL). Among them, LDL-3 particle number, LDL-3 apolipoprotein-B, LDL-3 phospholipids, LDL free cholesterol and LDL phospholipids were significantly correlated with cognitive function. The ROC curves showed that LDL-2 triglycerides (TG) and LDL-3 TG could significantly distinguish AD patients from HCs, with the area under the curve (AUC) above 0.7. In addition, we explored a strategy of combined diagnosis that significantly improved the diagnostic efficacy for AD (AUC = 0.879). Our study provides insight into the lipoprotein alterations associated with AD and potential biomarkers for its diagnosis and cognitive function assessment.

Sex- and dose-dependent catalase increase and its clinical impact in a benzoate dose-finding, randomized, double-blind, placebo-controlled trial for Alzheimer's disease

BackgroundSex differences in Alzheimer's disease (AD) are gaining increasing attention. Previously research has shown that sodium benzoate treatment can improve cognitive function in AD patients, particularly in the female patients; and 1000 mg/day of benzoate appears more efficacious than lower doses. Catalase is a crucial endogenous antioxidant; and deficiency of catalase is regarded to be related to the pathogenesis of AD. The current study aimed to explore the role of sex and benzoate dose in the change of catalase activity among benzoate-treated AD patients. MethodsThis secondary analysis used data from a double-blind trial, in which 149 CE patients were randomized to receive placebo or one of three benzoate doses (500, 750, or 1000 mg/day) and measured with Alzheimer's disease assessment scale-cognitive subscale. Plasma catalase was assayed before and after treatment. ResultsBenzoate treatment, particularly at 1000 mg/day, increased catalase among female patients, but not among male. The increases in the catalase activity among the benzoate-treated women were correlated with their cognitive improvements. In addition, higher baseline catalase activity was associated with more cognitive improvement after benzoate treatment among both female and male patients. ConclusionsSupporting the oxidative stress theory and sex difference in AD, the finding suggest that sex (female) and benzoate dose co-determine catalase increase in benzoate-treated AD patients and the catalase increment contributes to cognitive improvement of benzoate-treated women.Trial Registration: ClinicalTrials.gov Identifier: NCT03752463.

Mediterranean Diet and Lifestyle in Persons with Mild to Moderate Alzheimer's Disease.

Due to the continuous aging of the population and consequent increase in dementia, focus on its prevention is of growing importance for public health. Since effective pharmacological treatments are not yet available, other determinants of cognitive decline have become fundamental. Several studies have indicated that the Mediterranean diet (MedDiet) is associated with reduced incident cognitive decline and dementia, but few studies have been conducted in persons already diagnosed with Alzheimer's disease (AD). We age-matched 73 patients with mild-moderate AD with 73 controls (mean age for the whole group = 76.5 ± 6.5; 67.5% women). The cases had a significantly lower adherence to the MedDiet and lower physical activity vs. controls, where only one participant (1.4%) had a high adherence to the MedDiet among cases compared to 5.5% among controls, while 52.5% of the cases had a moderate adherence to the MedDiet vs. 82.2% in controls. In multivariate analysis, only the presence of AD was significantly associated with a lower adherence to the MedDiet vs. controls. Other factors examined (gender, age, physical activity level, multimorbidity, and polypharmacy) were not significantly associated with adherence to the MedDiet. Thus, AD patients had a low adherence to the MedDiet and very low physical activity. Public health strategies aimed at promoting the Mediterranean diet and physical activity for older people should be a priority.

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.

Evaluating dysphagia in Alzheimer's disease: the significance of age and medical comorbidities,a cross-sectional study from a tertiary psychiatric hospital in Guangzhou China.

To investigate the influencing factors of dysphagia in Alzheimer's disease (AD) patients. The study evaluated the demographic characteristics, nutritional status, social functioning, and swallowing dysfunction of 109 hospitalized AD patients. The sample include 65.1% of female patients, mainly concentrate in >70 years old (72.5%). The illness duration is mainly 0~5 years (62.4%). After adjusting for confounding factors such as gender, poor lifestyle habits, illness duration, marital status, route to admission, concomitant medical illness, nutritional status, and social functioning, we find that the swallowing function in patients with AD is related to route to admission and concomitant medical illness (mainly includes: circulatory disease and respiratory disease). Age ≥90 years old and more concomitant medical illness contribute to a lower swallowing dysfunction score in patients with AD (P<0.05). Age and concomitant medical illness are the important influencing factors in swallowing dysfunction in patients with AD. Therefore, we believe that future research should focus on the treatment and care of patients with medical conditions in order to enhance the swallowing function in patients with AD.

Diagnosis of Alzheimer's Disease in Clinical Practice: Time to Incorporate Biomarkers?

Hippocampal dysfunction is associated with early clinical signs of Alzheimer's disease (AD). Due to the limited availability or invasiveness of current biomarkers, the AD diagnosis is usually based on cognitive assessment and structural brain imaging. The recent study by Lalive and colleagues examined the specificity of brain morphometry for the AD diagnosis in a memory clinic cohort with hippocampal-type amnestic syndrome. The results indicate that memory deficits and hippocampal atrophy are similar in AD and non-AD patients, highlighting their low diagnostic specificity. These findings challenge the traditional AD diagnosis and underscore the need for biomarkers to differentiate specific neuropathological entities.

Potential Mechanisms of Tunneling Nanotube Formation and Their Role in Pathology Spread in Alzheimer's Disease and Other Proteinopathies.

Alzheimer's disease (AD) is the most common type of dementia worldwide. The etiopathogenesis of this disease remains unknown. Currently, several hypotheses attempt to explain its cause, with the most well-studied being the cholinergic, beta-amyloid (Aβ), and Tau hypotheses. Lately, there has been increasing interest in the role of immunological factors and other proteins such as alpha-synuclein (α-syn) and transactive response DNA-binding protein of 43 kDa (TDP-43). Recent studies emphasize the role of tunneling nanotubes (TNTs) in the spread of pathological proteins within the brains of AD patients. TNTs are small membrane protrusions composed of F-actin that connect non-adjacent cells. Conditions such as pathogen infections, oxidative stress, inflammation, and misfolded protein accumulation lead to the formation of TNTs. These structures have been shown to transport pathological proteins such as Aβ, Tau, α-syn, and TDP-43 between central nervous system (CNS) cells, as confirmed by in vitro studies. Besides their role in spreading pathology, TNTs may also have protective functions. Neurons burdened with α-syn can transfer protein aggregates to glial cells and receive healthy mitochondria, thereby reducing cellular stress associated with α-syn accumulation. Current AD treatments focus on alleviating symptoms, and clinical trials with Aβ-lowering drugs have proven ineffective. Therefore, intensifying research on TNTs could bring scientists closer to a better understanding of AD and the development of effective therapies.

Mannose-Functionalized Chitosan-Coated PLGA Nanoparticles for Brain-Targeted Codelivery of CBD and BDNF for the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is a common neurodegenerative disease causing cognitive and memory decline. AD is characterized by the deposition of amyloid-β and hypophosphorylated forms of tau protein. AD brains are found to be associated with neurodegeneration, oxidative stress, and inflammation. Cannabidiol (CBD) shows neuroprotective, antioxidant, and anti-inflammatory properties and simultaneously reduces amyloid-β production and tau hyperphosphorylation. The brain-derived neurotrophic factor (BDNF) plays a vital role in the development and maintenance of the plasticity of the central nervous system. A decline of BDNF levels in AD patients results in reduced plasticity and neuronal cell death. Current therapeutics against AD are limited to only symptomatic relief, necessitating a therapeutic strategy that reverses cognitive decline. In this scenario, combination therapy of CBD and BDNF could be a fruitful strategy for the treatment of AD. We designed mannose-conjugated chitosan-coated poly(d,l-lactide-co-glycolide (PLGA) (CHTMAN-PLGA) nanoparticles for the codelivery of CBD and BDNF to the brain. Chitosan is modified with mannose to specifically target the glucose transporter-1 (GLUT-1) receptor abundantly present in the blood-brain barrier for selectively delivering therapeutics to the brain. The CBD-encapsulated nanoparticles showed an average hydrodynamic diameter of 306 ± 8.12 nm and a zeta potential of 31.7 ± 1.53 mV. The coated nanoparticles prolonged encapsulated CBD release from the PLGA matrix. The coated nanoparticles exhibited sustained release of CBD for up to 22 days with 91.68 ± 2.91% release of the encapsulated drug. The coated nanoparticles, which had a high positive zeta potential (31.7 ± 1.53 mV), encapsulated the plasmid DNA. The qualitative transfection efficiency was investigated using CHTMAN-PLGA-CBD/pGFP in bEND.3, primary astrocytes, and primary neurons, while the quantitative transfection efficiency of the delivery system was determined using CHTMAN-PLGA-CBD/pBDNF. In vitro, the pBDNF transfection study revealed that the BDNF expression was 4-fold higher for CHTMAN-PLGA-CBD/pBDNF than for naked pBDNF in all of the cell lines. The cytotoxicity and hemocompatibility of the designed nanoparticles were tested in bEND.3 cells and red blood cells, respectively, and the nanoparticles were found to be nontoxic and hemocompatible. Hence, mannose-conjugated chitosan-coated PLGA nanoparticles could be useful as brain-targeting delivery vehicles for the codelivery of CBD and BDNF for possible AD treatment.

Defining Alzheimer's Disease through Proteomic CSF Profiling.

Alzheimer disease (AD) is the main cause of dementia, and its complexity is not yet completely understood. Proteomic profiles can provide useful information to explore the pathways involved and the heterogeneity among AD patients. A proteomic analysis was performed in cerebrospinal fluid (CSF) samples from mild cognitive impairment due to AD (MCI-AD) and control individuals; both groups were classified by amyloid β42/amyloid β40 levels in CSF (data available in BioStudies database (S-BSST1456)). The analysis based on PLS regression and volcano plot identified 7 proteins (FOLR2, PPP3CA, SMOC2, STMN1, TAGLN3, TMEM132B, and UCHL1) mainly related to protein phosphorylation, structure maintenance, inflammation, and protein degradation. Enrichment analysis revealed the involvement of different biological processes related to neuronal mechanisms and synapses, lipid and carbohydrate metabolism, immune system and inflammation, vascular, hormones, and response to stimuli, and cell signaling and adhesion. In addition, the proteomic profile showed some association with the levels of AD biomarkers in CSF. Regarding the subtypes, two MCI-AD subgroups were identified: one could be related to synapsis and neuronal functions and the other to innate immunity. The study of the proteomic profile in the CSF of AD patients reflects the heterogeneity of biochemical pathways involved in AD.

Alzheimer's disease-associated genotypes differentially influence chronic evoked seizure outcomes and antiseizure medicine activity in aged mice.

Alzheimer's disease (AD) patients are at greater risk of focal seizures than similarly aged adults; these seizures, left untreated, may worsen functional decline. Older people with epilepsy generally respond well to antiseizure medications (ASMs). However, whether specific ASMs can differentially control seizures in AD is unknown. The corneal kindled mouse model of acquired chronic secondarily generalized focal seizures allows for precisely timed drug administration studies to quantify the efficacy and tolerability of ASMs in an AD-associated genetic model. We hypothesized that mechanistically distinct ASMs would exert differential anticonvulsant activity and tolerability in aged AD mice (8-15 months) to define whether rational ASM selection may benefit specific AD genotypes. Aged male and female PSEN2-N141I versus age-matched non-transgenic control (PSEN2 control) C57Bl/6J mice, and APP swe /PS1 dE9 versus transgene negative (APP control) littermates underwent corneal kindling to quantify latency to fully kindled criterion. Dose-related ASM efficacy was then compared in each AD model versus matched control over 1-2 months using ASMs commonly prescribed in older adults with epilepsy: valproic acid, levetiracetam, lamotrigine, phenobarbital, and gabapentin. Sex and AD genotype differentially impacted seizure susceptibility. Male PSEN2-N141I mice required more stimulations to attain kindling criterion (X 2 =5.521; p<0.05). Male APP/PS1 mice did not differ in kindling rate versus APP control mice, but they did have more severe seizures. There were significant ASM class-specific differences in acute seizure control and dose-related tolerability. APP/PS1 mice were more sensitive than APP controls to valproic acid, levetiracetam, and gabapentin. PSEN2-N141I mice were more sensitive than PSEN2 controls to valproic acid and lamotrigine. AD genotypes may differentially impact ASMs activity and tolerability in vivo with advanced biological age. These findings highlight the heterogeneity of seizure risk in AD and suggest that precisely selected ASMs may beneficially control seizures in AD, thus reducing functional decline.

Genome-wide scan of Flortaucipir PET levels finds JARID2 associated with cerebral tau deposition.

Genetic research on Alzheimer's disease (AD) has primarily focused on amyloid-β (Aβ) pathogenesis, with fewer studies exploring tau pathology. Elucidating the genetic basis of tau pathology could identify novel pathways in AD. We conducted a genome-wide association study of tau standard uptake value ratios (SUVRs) from [18] F-flortaucipir positron emission tomography (PET) images to identify genetic variants underlying Tau pathology. Genetic data and tau-SUVRs from [18] F-flortaucipir PET images were acquired from the A4 (311 with preclinical AD) and ADNI (280 cognitively normal, 76 with mild cognitive impairment, and 19 AD patients) studies. Circulating plasma proteins in UK Biobank Pharma Proteomics Project (UKBPPP, N=54,129) were used to validate genetic findings. SNP genotypes were tested for association with Tau-SUVR levels adjusting for age, sex and population substructure variables. AD association of polygenic risk scores (PRS) of tau and amyloid-SUVRs were assessed. Causal effect of plasma protein levels on Tau pathology were tested using Mendelian randomization analyses. GWAS of tau-SUVR revealed two significant loci: rs78636169 ( P =5.76×10 -10 ) in JARID2 and rs7292124 ( P =2.20×10 -8 ) near ISX . Gene-based analysis of tau deposition highlighted APOE ( P =2.55×10 -6 ), CTNNA3 ( P =2.86×10 -6 ) and JARID2 ( P =1.23×10 -4 ), a component of the PRC2 multi-protein complex which regulates gene expression. Mendelian randomization analysis of available circulating plasma proteins in the UK Biobank Pharma Proteomics Project (UKBPPP) identified LRRFIP1, a protein that binds with PRC2 multi-protein complex, as potentially causally linked to tau pathology. Genes associated with both amyloid and tau pathologies were enriched in endocytosis and signal transduction pathways. AD polygenic risk score (PRS) was associated with amyloid-SUVR but not with tau-SUVR. Amyloid-SUVR PRS had a notable association with AD clinical status, particularly in younger APOE -ε4 carriers, whereas tau-SUVR PRS showed a stronger association in older carriers. We identified a novel potential therapeutic target, JARID2 in the PRC2 multi-protein complex, for tau pathology. Furthermore, gene pathway analysis clarified the distinct roles of Aβ and tau in AD progression, underscoring the complexity of genetic influences across different stages of the disease.

CSF complement proteins are elevated in prodromal to moderate Alzheimer's disease patients and are not altered by the anti-tau antibody semorinemab.

Growing evidence suggests a role for neuroinflammation in Alzheimer's disease (AD). We investigated complement pathway activity in AD patient cerebrospinal fluid (CSF) and evaluated its modulation by the anti-tau antibody semorinemab. Immunoassays were applied to measure CSF complement proteins C4, factor B (FB), C3 and their cleavage fragments C4a, C3a, and factor Bb (Bb) in AD patients and a separate cognitively unimpaired (CU) cohort. All measured CSF complement proteins were increased in AD versus CU subjects, with C4a displaying the most robust increase. Finally, semorinemab did not have a significant pharmacodynamic effect on CSF complement proteins. Elevated levels of CSF C4a, C4, C3a, C3, Bb, and FB are consistent with complement activation in AD brains. Despite showing a reduction in CSF soluble tau species, semorinemab did not impact complement protein levels or activity. Further studies are needed to determine the value of complement proteins as neuroinflammation biomarkers in AD. Cerebrospinal fluid (CSF) complement proteins C4a, C3a, Bb, C4, C3, and factor B levels were increased in Alzheimer's disease (AD) patients compared to a separate cognitively unimpaired (CU) cohort. Baseline CSF complement protein levels were correlated with neuro-axonal degeneration and glial activation biomarkers in AD patients. The investigational anti-tau antibody semorinemab did not impact CSF complement protein levels or activity relative to the placebo arm.

Genetic and clinical correlates of two neuroanatomical AI dimensions in the Alzheimer’s disease continuum

Alzheimer’s disease (AD) is associated with heterogeneous atrophy patterns. We employed a semi-supervised representation learning technique known as Surreal-GAN, through which we identified two latent dimensional representations of brain atrophy in symptomatic mild cognitive impairment (MCI) and AD patients: the “diffuse-AD” (R1) dimension shows widespread brain atrophy, and the “MTL-AD” (R2) dimension displays focal medial temporal lobe (MTL) atrophy. Critically, only R2 was associated with widely known sporadic AD genetic risk factors (e.g., APOE ε4) in MCI and AD patients at baseline. We then independently detected the presence of the two dimensions in the early stages by deploying the trained model in the general population and two cognitively unimpaired cohorts of asymptomatic participants. In the general population, genome-wide association studies found 77 genes unrelated to APOE differentially associated with R1 and R2. Functional analyses revealed that these genes were overrepresented in differentially expressed gene sets in organs beyond the brain (R1 and R2), including the heart (R1) and the pituitary gland, muscle, and kidney (R2). These genes were enriched in biological pathways implicated in dendritic cells (R2), macrophage functions (R1), and cancer (R1 and R2). Several of them were “druggable genes” for cancer (R1), inflammation (R1), cardiovascular diseases (R1), and diseases of the nervous system (R2). The longitudinal progression showed that APOEε4, amyloid, and tau were associated with R2 at early asymptomatic stages, but this longitudinal association occurs only at late symptomatic stages in R1. Our findings deepen our understanding of the multifaceted pathogenesis of AD beyond the brain. In early asymptomatic stages, the two dimensions are associated with diverse pathological mechanisms, including cardiovascular diseases, inflammation, and hormonal dysfunction—driven by genes different from APOE—which may collectively contribute to the early pathogenesis of AD. All results are publicly available at https://labs-laboratory.com/medicine/.

Calycosin-7-O-β-D-Glucoside Ameliorates Palmitate-Induced Lipid Accumulation in HT22 Cells.

The pathogenesis of Alzheimer's disease (AD) is complex. Recent research suggests that AD patients have early disorders in brain cholesterol metabolism. Cholesterol and its derivatives accumulate in neurons, leading to p-Tau overproduction and synaptic dysfunction, initiating AD progression. Calycosin-7-O-β-D-glucoside (CG), a distinctive constituent of Astragali Radix, holds a representative position. Many clinical trials have demonstrated that CG can attenuate cerebral ischemia/reperfusion injury and preserve the structural integrity of the blood-brain barrier. However, whether CG alleviates tau-mediated neurodegeneration by increasing cholesterol efflux after lipid accumulation remains unexplored. Ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS/MS) and multivariate data analysis were employed to investigate metabolic changes in HT22 cells induced by sodium palmitate following 24 hours of CG treatment. The potential therapeutic mechanisms of CG on AD were further examined through Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Metabolomic analysis characterized 24 potential biomarkers, revealing that CG could ameliorate cholesterol metabolic pathways. The results of cell experiments revealed that CG can increase the expression of enzyme cholesterol 24-hydroxylase (CYP46A1) (p < 0.05) and the level of 24 hydroxycholesterol (24-OHC) (p < 0.05), reduce the expression of p-Tau (Thr231)/Tau (p < 0.01), inhibit the formation of lipid droplets. CG may inhibit the accumulation of cholesterol and its derivatives in neurons by affecting the CYP46A1-CE-Tau axis, offering a potential therapeutic strategy for AD.

Lateral Entorhinal Cortex Dysfunction in Alzheimer's Disease Mice.

In Alzheimer's disease (AD), the formation of amyloid beta and neurofibrillary tangles (NFTs) leads to neuronal loss in entorhinal cortex (EC), a crucial brain region involved in memory and navigation. These pathological changes are concurrent with the onset of memory-related issues in AD patients with symptoms of forgetfulness such as misplacing items, disorientation in familiar environments etc. The lateral EC (LEC) is associated with non-spatial memory processing including object recognition. Since in LEC, neurons fire in response to objects (object cells) and at locations previously occupied by objects (trace cells), pathology in this region could lead to dysfunction in object location coding. In this paper we show that a transgenic mouse model, EC-App/Tau, which expresses both APP and tau primarily in the EC region, have deficits in LEC-specific memory tasks. Using in vivo single-unit electrophysiology recordings we show that the LEC neurons are hyperactive with low information content and high sparsity compared to the controls indicating poor firing fidelity. We finally show that object cells and trace cells fire less precisely in the EC-App/Tau mice compared to controls indicating poor encoding of objects. Overall, we show that AD pathology causes erratic firing of LEC neurons and object coding defects leading to LEC-specific memory impairment.

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.

Low-intensity transcranial ultrasound stimulation modulates neurovascular coupling in mouse models of Alzheimer's disease.

Neurovascular coupling plays an important role in the progression of Alzheimer's disease. However, it is unclear how ultrasound stimulation modulates neurovascular coupling in Alzheimer's disease. Here, we found that (i) transcranial ultrasound stimulation modulates the time domain and frequency domain characteristics of cerebral blood oxygen metabolism in Alzheimer's disease mice; (ii) transcranial ultrasound stimulation can significantly modulate the relative power of theta and gamma frequency of local field potential in Alzheimer's disease mice; and (iii) transcranial ultrasound stimulation can significantly modulate the neurovascular coupling in time domain and frequency domain induced by forepaw electrical stimulation in Alzheimer's disease mice. It provides a research basis for the clinical application of transcranial ultrasound stimulation in Alzheimer's disease patients.