Prevention Of Alzheimer's Disease Research Articles

Associations between sex and lifestyle activities with cognitive reserve in mid-life adults with genetic risk for Alzheimer's disease.

Females have a higher age-adjusted incidence of Alzheimer's Disease (AD) than males, even when accounting for longer lifespan and, therefore, stand to benefit the most from dementia prevention efforts. As exposure to many modifiable risk factors for dementia begins in mid-life, interventions must be implemented from middle-age. Building cognitive reserve, particularly through stimulating avocational activities and occupational attainment presents a crucial, underexplored, dementia prevention approach for mid-life. It is currently unknown, however, whether modifiable lifestyle factors can protect against AD processes, from mid-life, differentially for females and males who carry inherited risk for late-life dementia. To address this gap, this study investigated the impact of biological sex and APOE4 carrier status on the relationship between stimulating activities, occupational attainment, and cognition in mid-life. We leveraged the PREVENT-Dementia program, the world's largest study investigating the origins and early diagnosis of dementia in mid-life at-risk individuals (N = 700; 40-59 years). Cognitive performance was measured using the Cognito Battery and the Visual Short Term Memory Binding task. Mid-life specific reserve contributors were assessed via the Lifetime of Experiences Questionnaire. Females had significantly better episodic and relational memory (p < 0.001), and lower occupational attainment than males (p < 0.001). Engagement in stimulating activities was positively associated with episodic and relational memory, regardless of sex and APOE4 status (β = 0.05, CI 0.03-0.07, p < 0.001). APOE4 carriers showed significant sex differences in the association between occupational attainment and episodic and relational memory (β = 0.38, CI 0.12-0.63, p = 0.003). APOE4 carrier females with higher occupational attainment showed better cognition (β = 0.16, CI -0.002-0.32, p = 0.053), whereas APOE4 carrier males showed the opposite effect (β = -0.20, CI -0.40 - -0.001, p = 0.049). Our findings suggest that occupational attainment in mid-life contributes to cognitive reserve against inherited risk of dementia in females, but not males. They highlight the need for high precision approaches that consider biological sex and APOE4 carrier status to inform Alzheimer's disease prevention strategies and clinical trials.

Lifestyle empowerment for Alzheimer's prevention prescribed by physicians: Methods and adaptations to COVID-19

The health care system is insufficiently capitalizing on the benefits of physical exercise in America's aging population. Few tools exist to help clinicians incorporate physical activity into their clinical care, and barriers limit older adults from initiating and maintaining exercise programs. The Lifestyle Empowerment for Alzheimer's Prevention (LEAP! Rx) Program has been designed to support providers and participants in lifestyle change. LEAP! Rx uses two forms of participant enrollment: physician referrals through electronic health records and self-referrals to test the efficacy of delivering a community-based exercise and healthy lifestyle program to older adults. After referral into the program, participants are randomized to receive the LEAP! Rx Program or are placed in a standard-of-care group to receive the program later. The LEAP! Rx program consists of a personalized and structured exercise program, lifestyle education, and mobile health monitoring. This includes a 12-week Empowerment phase with coaching and supervised exercise training, followed by a 40-week Lifestyle phase with intermittent supervised exercise and coaching. Lifestyle education includes monthly, evidence-based classes on optimal aging. The evaluation of LEAP! Rx focuses on 1) the assessment of implementation and scalability of the LEAP!Rx Program for clinicians and patients 2) the effect of the LEAP! Rx Program on cardiorespiratory fitness, 3) the impact of the LEAP! Rx Program on secondary intervention outcome measures of chronic disease risk factors, including insulin resistance, body composition, and lipids. If successful, this study's findings could advance future healthcare practices, providing a new and practical approach to aging and chronic disease prevention.

Microbiota-derived lysophosphatidylcholine alleviates Alzheimer's disease pathology via suppressing ferroptosis.

Alzheimer's disease (AD) is a pervasive neurodegenerative disorder, and new approaches for its prevention and therapy are critically needed. Here, we elucidate a gut-microbiome-brain axis that offers actionable perspectives for achieving this objective. Using the 5xFAD mouse model, we identify increased Clostridium abundance and decreased Bacteroides abundance as key features associated with β-amyloid (Aβ) burden. Treatment with Bacteroides ovatus, or its associated metabolite lysophosphatidylcholine (LPC), significantly reduces Aβ load and ameliorates cognitive impairment. Mechanistically, LPC acts through the orphan receptor GPR119, inhibiting ACSL4 expression, thereby suppressing ferroptosis and ameliorating AD pathologies. Analysis of fecal and serum samples from individuals with AD also reveals diminished levels of Bacteroides and LPC. This study thus identifies a B.ovatus-triggered pathway regulating AD pathologies and indicates that the use of single gut microbiota, metabolite, or small molecule compound may complement current prevention and treatment approaches for AD.

Anti-Alzheimer's Disease Target and Beneficial Effect in Formononetin

Introduction: Alzheimer's Disease (AD), a common neurodegenerative relevance of dementia, is spreading in the world. Hitherto, the pharmacological treatment for AD is prescribed limitedly in clinical application. Recently, it has been found that naturally occurring extracts possess promising anti-neurodegenerative properties, including AD. Method: Our previous study indicated that formononetin (FMN) exerts the anti-AD benefits based on bioinformatics analysis. However, the experimental validation for bioinformatics findings has not been conducted. In this study, we primarily applied the molecule docking analysis to ascertain the pharmacological targets, including cytochrome P450 19A1 (CYP19A1). Transgenic AD mice were used to validate the bioinformatics findings in vivo experimentally. Molecular docking data showed that FMN acted directly on CYP19A1 target protein with effective binding sites and potent combining affinity/energy. Results: Meanwhile, FMN intervention contributed to an increased trend of body weight in transgenic AD mice reduced hippocampal expression of Aβ1-42, and elevated content of CYP19A1. Additionally, FMN intervention showed reduced terminal deoxynucleotidyl Transferase dUTP Nick-End Labeling (TUNEL) expression and increased CYP19A1 and Ki67 expressions in hippocampal sections of transgenic AD mice. Conclusion: Collectively, FMN may be used for the prevention of AD, and the pharmacological activities are possibly related to reducing Aβ1-42, and TUNEL expressions to increase Ki67 and CYP19A1 activities.

Assessing the Role of the Generative Pretrained Transformer (GPT) in Alzheimer's Disease Management: Comparative Study of Neurologist- and Artificial Intelligence-Generated Responses.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder posing challenges to patients, caregivers, and society. Accessible and accurate information is crucial for effective AD management. This study aimed to evaluate the accuracy, comprehensibility, clarity, and usefulness of the Generative Pretrained Transformer's (GPT) answers concerning the management and caregiving of patients with AD. In total, 14 questions related to the prevention, treatment, and care of AD were identified and posed to GPT-3.5 and GPT-4 in Chinese and English, respectively, and 4 respondent neurologists were asked to answer them. We generated 8 sets of responses (total 112) and randomly coded them in answer sheets. Next, 5 evaluator neurologists and 5 family members of patients were asked to rate the 112 responses using separate 5-point Likert scales. We evaluated the quality of the responses using a set of 8 questions rated on a 5-point Likert scale. To gauge comprehensibility and participant satisfaction, we included 3 questions dedicated to each aspect within the same set of 8 questions. As of April 10, 2023, the 5 evaluator neurologists and 5 family members of patients with AD rated the 112 responses: GPT-3.5: n=28, 25%, responses; GPT-4: n=28, 25%, responses; respondent neurologists: 56 (50%) responses. The top 5 (4.5%) responses rated by evaluator neurologists had 4 (80%) GPT (GPT-3.5+GPT-4) responses and 1 (20%) respondent neurologist's response. For the top 5 (4.5%) responses rated by patients' family members, all but the third response were GPT responses. Based on the evaluation by neurologists, the neurologist-generated responses achieved a mean score of 3.9 (SD 0.7), while the GPT-generated responses scored significantly higher (mean 4.4, SD 0.6; P<.001). Language and model analyses revealed no significant differences in response quality between the GPT-3.5 and GPT-4 models (GPT-3.5: mean 4.3, SD 0.7; GPT-4: mean 4.4, SD 0.5; P=.51). However, English responses outperformed Chinese responses in terms of comprehensibility (Chinese responses: mean 4.1, SD 0.7; English responses: mean 4.6, SD 0.5; P=.005) and participant satisfaction (Chinese responses: mean 4.2, SD 0.8; English responses: mean 4.5, SD 0.5; P=.04). According to the evaluator neurologists' review, Chinese responses had a mean score of 4.4 (SD 0.6), whereas English responses had a mean score of 4.5 (SD 0.5; P=.002). As for the family members of patients with AD, no significant differences were observed between GPT and neurologists, GPT-3.5 and GPT-4, or Chinese and English responses. GPT can provide patient education materials on AD for patients, their families and caregivers, nurses, and neurologists. This capability can contribute to the effective health care management of patients with AD, leading to enhanced patient outcomes.

Risk of Alzheimer’s disease and genetically predicted levels of 1400 plasma metabolites: a Mendelian randomization study

Alzheimer’s disease (AD) is a metabolic disorder. Discovering the metabolic products involved in the development of AD may help not only in the early detection and prevention of AD but also in understanding its pathogenesis and treatment. This study investigated the causal association between the latest large-scale plasma metabolites (1091 metabolites and 309 metabolite ratios) and AD. Through the application of Mendelian randomization analysis methods such as inverse-variance weighted (IVW), MR-Egger, and weighted median models, 66 metabolites and metabolite ratios were identified as potentially having a causal association with AD, with 13 showing significant causal associations. During the replication validation phase, six metabolites and metabolite ratios were confirmed for their roles in AD: N-lactoyl tyrosine, argininate, and the adenosine 5’-monophosphate to flavin adenine dinucleotide ratio were found to exhibit protective effects against AD. In contrast, ergothioneine, piperine, and 1,7-dimethyluric acid were identified as contributing to an increased risk of AD. Among them, argininate showed a significant effect against AD. Replication and sensitivity analyses confirmed the robustness of these findings. Metabolic pathway analysis linked “Vitamin B6 metabolism” to AD risk. No genetic correlations were found, but colocalization analysis indicated potential AD risk elevation through top SNPs in APOE and PSEN2 genes. This provides novel insights into AD’s etiology from a metabolomic viewpoint, suggesting both protective and risk metabolites.

SV2A PET shows hippocampal synaptic loss in cognitively unimpaired APOE ε4/ε4 homozygotes.

We investigated hippocampal synaptic density using synaptic vesicle 2A positron emission tomography (PET), and its association with amyloid beta (Aβ) and cognitive performance in healthy apolipoprotein E (APOE) ε4 carriers. Synaptic density was assessed in 46 individuals (APOE ε4/ε4 n=14; APOE ε3/ε4 n=16; APOE ε3/ε3 n=16) with [11C]UCB-J-PET standardized uptake value ratios (SUVRs), by using the centrum semiovale as a reference region. Differences in hippocampal [11C]UCB-J SUVRs were analyzed with analysis of variance (ANOVA) and linear models. Associations among [11C]UCB-J SUVR, Aβ, hippocampal volume, and cognitive variables were analyzed with Spearman correlation. Hippocampal synaptic density was different among the APOE groups (PANOVA=0.016): APOE ε4/ε4 carriers had lower [11C]UCB-J SUVRs compared to APOE ε3/ε3 (p=0.013). Hippocampal synaptic density did not correlate with Consortium to Establish a Registry for Alzheimer's Disease (CERAD) total score (rho=-0.052, p=0.74), Alzheimer's Prevention Initiative Preclinical Cognitive Composite (APCC) score (rho=0.17, p=0.28), or [11C]PiB uptake (rho=-0.10, p=0.50). Hippocampal synaptic loss emerges early in the AD continuum and is measurable in vivo in cognitively unimpaired high-risk individuals. Synaptic density was studied in vivo in healthy older adults using [11C]UCB-J positron emission tomography. Apolipoprotein E (APOE) ε4/ε4 carriers had lower hippocampal synaptic density compared to APOE ε3/ε3. Synaptic density was not associated with cognitive performance in this population. Hippocampal synaptic alterations occur before clinical symptoms in APOE ε4/ε4 carriers.

Identification of mild cognitive impairment using multimodal 3D imaging data and graph convolutional networks

Abstract Objective. Mild cognitive impairment (MCI) is a precursor stage of dementia characterized by mild cognitive decline in one or more cognitive domains, without meeting the criteria for dementia. MCI is considered a prodromal form of Alzheimer's disease (AD). Early identification of MCI is crucial for both intervention and prevention of AD. To accurately identify MCI, a novel multimodal 3D imaging data integration graph convolutional network model is designed in this paper. Approach. The proposed model utilizes 3D-VGGNet to extract three-dimensional features from multimodal imaging data (such as sMRI and FDG-PET), which are then fused into feature vectors as the node features of a population graph. Non-imaging features of participants are combined with the multimodal imaging data to construct a population sparse graph. Additionally, in order to optimize the connectivity of the graph, we employed the Pairwise Attribute Estimation (PAE) method to compute the edge weights based on non-imaging data, thereby enhancing the effectiveness of the graph structure. Subsequently, a population-based graph convolutional network (GCN) integrates the structural and functional features of different modal images into the features of each participant for MCI classification. Main results. Experiments on the ADNI demonstrated accuracies of 98.57%, 96.03%, and 96.83% for the NC-EMCI, NC-LMCI, and EMCI-LMCI classification tasks, respectively. The AUC, specificity, sensitivity, and F1-score are also superior to state-of-the-art models, demonstrating the effectiveness of the proposed model. Furthermore, the proposed model is applied to the ABIDE dataset for autism diagnosis, achieving an accuracy of 91.43% and outperforming the state-of-the-art models, indicating excellent generalization capabilities of the proposed model. Significance. This study demonstrate the proposed model’s ability to integrate multimodal imaging data and its excellent ability to recognize MCI. This will help achieve early warning for AD and intelligent diagnosis of other brain neurodegenerative diseases.

The relationship between micronutrients and cognitive ability in an elderly population with mild cognitive impairment and Alzheimer’s disease: a cross-sectional study

BackgroundMild cognitive impairment (MCI) and Alzheimer’s disease (AD) are significant neurodegenerative disorders with increasing prevalence worldwide. Lifestyle and dietary factors, including micronutrients, have been suggested as modifiable risk factors for disease development. This study aims to investigate the association between micronutrients and cognitive ability in these diseases.MethodsA cross-sectional study involving 105 participants with MCI and AD was conducted. Dietary assessments were performed using a validated food frequency questionnaire (FFQ), and micronutrient intake was calculated based on nutrient content. Disease severity was evaluated using the Functional Assessment Staging Tool (FAST). Statistical analyses, including correlation coefficients and multiple regression models, were employed to examine the association between micronutrients and disease progression.ResultsThe results revealed significant correlations between disease severity and several micronutrients, including omega-3 fatty acids (B = -0.2, P = 0.01), carotenoids (B = -0.19, P = 0.02), dietary antioxidant compounds, including vitamins A, C, D, E (B = -0.19, P = 0.02), selenium (B = -0.17, P = 0.03), alpha-carotene (B = -0.16, P = 0.04), beta-carotene (B = -0.17, P = 0.03), and lycopene (B = -0.16, P = 0.04). Multivariate regression analysis showed that higher intake of omega-3 fatty acids was associated with slower disease progression. Furthermore, the levels of these micronutrients declined in advanced stages of the disease.ConclusionOmega-3 fatty acids and carotenoids may affect the cognitive ability and disease progression. Further longitudinal studies are warranted to establish causality and explore the therapeutic implications of these findings for the prevention and management of MCI and AD.

Longitudinal and Multi-Kingdom Gut Microbiome Alterations in a Mouse Model of Alzheimer's Disease.

Gut microbial dysbiosis, especially bacteriome, has been implicated in Alzheimer's disease (AD). However, nonbacterial members of the gut microbiome in AD, such as the mycobiome, archaeome, and virome, are unexplored. Here, we perform higher-resolution shotgun metagenomic sequencing on fecal samples collected longitudinally from a mouse model of AD to investigate longitudinal and multi-kingdom gut microbiome profiling. Shotgun metagenomic sequencing of fecal samples from AD mice and healthy mice returns 41,222 bacterial, 414 fungal, 1836 archaeal, and 1916 viral species across all time points. The ecological network pattern of the gut microbiome in AD mice is characterized by more complex bacterial-bacterial interactions and fungal-fungal interactions, as well as simpler archaeal-archaeal interactions and viral-viral interactions. The development of AD is accompanied by multi-kingdom shifts in the gut microbiome composition, as evidenced by the identification of 1177 differential bacterial, 84 differential fungal, 59 differential archaeal, and 10 differential viral species between healthy and AD mice across all time points. In addition, the functional potential of the gut microbiome is partially altered in the development of AD. Collectively, our findings uncover longitudinal and multi-kingdom gut microbiome alterations in AD and provide a motivation for considering microbiome-based therapeutics during the prevention and treatment of AD.

Mendelian Randomization Study of the Causal Relationship between PM2.5 and Neurodegenerative Diseases

Background: In recent years, a large number of studies have evaluated the relationship between particulate matter 2.5 (PM2.5) and the incidence rate and mortality of neurodegenerative diseases (NDDs), but the conclusion is controversial. Methods: The publicly available statistical data from genome-wide association studies were used for two sample MR. Inverse variance weighted is used as the main analysis, MR Egger regression, maximum likelihood, simple median, and weighted median are used for supplementary validation. Results: MR analysis results indicate that for every standard deviation increase in PM2.5 exposure, the risk of Alzheimer's disease (AD) increases by 41% (95% CI: 1.10～1.82, P=0.008). However, there is no causal association between PM2.5 and NDDs such as Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and Dementia with Lewy bodies. Sensitivity analysis did not detect heterogeneity and pleiotropy, indicating that the analysis results are robust. Conclusion: There is a causal relationship between PM2.5 and the risk of AD, and reducing PM2.5 exposure may be of great significance for the prevention of AD.

Blood‐based biomarkers of Alzheimer's disease: Standardization and comprehensiveness

AbstractPopulation aging is sweeping across the globe, resulting in a striking prevalence of Alzheimer's disease (AD) and dementia and a heavy economic burden. Given the time window of 10–20 years from pathological initiation to clinically detected cognitive impairment, early detection can significantly impact the prevention and control of AD. The invasiveness and high cost of cerebrospinal fluid biomarkers and positron emission tomography‐computed tomography imaging limit large‐scale disease screening. However, blood‐based biomarkers (BBMs) lack these disadvantages, shedding light on their usefulness in the large‐scale identification and prevention of AD. Prominent advancement has recently been made regarding BBMs of AD co‐pathology (amyloid β, tau protein, neurofilament light polypeptide, and glial fibrillary acidic protein) to improve their accuracy as clinical diagnostics of AD to a level comparable to that of canonical methods, facilitating the large‐scale clinical implementation of diagnostic tests with higher precision. To briefly summarize, the prospects of AD BBMs rely on standardization and comprehensiveness. Calibrating the sample collection procedure and clarifying the boundaries for indices and abnormalities are beneficial for constructing a canonical diagnostic assay. The comprehensive assembly of heterogeneous clinical evidence guarantees the accuracy of diagnosis and improves the workflow for early identification.

Response Surface Methodology Optimization of Exosome-like Nanovesicles Extraction from Lycium ruthenicum Murray and Their Inhibitory Effects on Aβ-Induced Apoptosis and Oxidative Stress in HT22 Cells.

Exosome-like nanovesicles (ELNs) derived from plants are nanoscale vesicles isolated from edible plant sources. Lycium ruthenicum Murray (LRM) has garnered growing attention for its dietary value and therapeutic benefits. In this study, a PEG6000-based method was developed to isolate LRM-ELNs. Response surface methodology (RSM) was used to optimize the extraction conditions to obtain the optimal extraction efficiency. When PEG6000 concentration was at 11.93%, relative centrifugal force was 9720 g, and incubation time was 21.12 h, the maximum LRM-ELN yield was 4.24 g/kg. This optimization process yielded LRM-ELNs with a particle size of 114.1 nm and a surface charge of -6.36 mV. Additionally, LRM-ELNs mitigated Aβ-induced apoptosis in HT22 cells by enhancing mitochondrial membrane potential (MMP), lowering the Bax/Bcl-2 ratio, and reducing Cleaved Caspase-3 expression. Furthermore, LRM-ELNs alleviated Aβ-induced oxidative stress in HT22 cells by promoting the nuclear translocation of Nrf2 and upregulating the expression of HO-1 and NQO1. These findings indicate that LRM-ELNs exert protective effects against Aβ-induced damage in HT22 cells and may be considered as a potential dietary supplement for Alzheimer's disease prevention.

Olive Oil Industry By-Products as a Novel Source of Biophenols with a Promising Role in Alzheimer Disease Prevention.

This review explores the potential health benefits and applications of phenolic secoiridoids derived from olive oil by-products in the prevention of Alzheimer's disease (AD). As reviewed herein, polyphenols, such as epigallocatechin-3-gallate, epicatechin, and resveratrol, show in vitro and in vivo antioxidant, anti-inflammatory, and neuroprotective properties, and are particularly relevant in the context of AD, a leading cause of dementia globally. The olive oil industry, particularly in the Mediterranean region, produces significant amounts of waste, including leaves, pomace, and wastewater, which pose environmental challenges but also offer an untapped source of bioactive compounds. Despite promising in vitro and in vivo studies indicating that olive-derived polyphenols, such as oleuropein and hydroxytyrosol, may mitigate AD pathology, human clinical trials remain limited. The variability in extraction methods and the complex nature of AD further complicate research. Future studies should focus on standardizing the protocols and conducting robust clinical trials to fully assess the therapeutic potential of these compounds. This approach not only supports the development of new treatments for AD but also promotes environmental sustainability by valorizing olive oil industry waste.

Dual-Carbon Dots Composite: A Multifunctional Photo-Propelled Nanomotor Against Alzheimer's β-Amyloid.

The abnormal accumulation of β-amyloid protein (Aβ) is considered as the main pathological hallmark of Alzheimer's disease (AD). The design of potent multifunctional theranostic agents targeting Aβ is one of the effective strategies for AD prevention and treatment. Nanomotors as intelligent, advanced, and multifunctional nanoplatforms can perform many complex tasks, but their application in AD theranostics is rare. Herein, sub-10nm multifunctional dual-carbon dots composites (ERCD) with photo-propelled nanomotor behavior are fabricated by conjugating near-infrared (NIR) carbon dots (RCD) of thermogenic and photodynamic capability with the previously reported epigallocatechin gallate-derived carbonized polymer dots (ECD). ERCD-1 (ECD:RCD = 1:2.5) showed potent inhibitory capability similar to ECD in the absence of NIR light, and exhibited photooxygenation activity and nanomotor behavior powered by "self-thermophoretic force" under NIR irradiation, significantly enhancing the inhibition, disaggregation, and photooxygenation capabilities. The nanomotor suppressed Aβ fibrillization and rapidly disaggregated mature Aβ fibrils at very low concentrations (0.5µg mL-1). Moreover, the NIR-activated ERCD-1 imaged Aβ plaques in vivo and prolonged nematode lifespan by 6 d at 2µg mL-1. As a proof-of-concept, this work opened a new avenue to the design of multifunctional sub-10nm nanomotors targeting Aβ for AD theranostics.

LEAP! Rx: A randomized trial of a pragmatic approach to lifestyle medicine.

Clinicians lack the tools to incorporate physical activity into clinical care for Alzheimer's disease prevention. We tested a 52-week exercise and health education program (Lifestyle Empowerment for Alzheimer's Prevention [LEAP! Rx]) that integrates clinician referrals and community-based fitness resources. We randomized 219 participants to the LEAP! Rx (ie, exercise and monthly brain health education) or a standard-of-care control group and tested the effects on cardiorespiratory fitness, insulin resistance, body composition, lipids, and cognitive performance. Physicians were able to connect their patients to a community lifestyle intervention. The intervention group increased in cardiorespiratory fitness at 12 and 52 weeks (p=0.005). We observed no effects on secondary measures. Participants meeting 80% of weekly goals (150 min, moderate to vigorous activity) saw greater fitness improvements than those with less than 80% (p<0.001). These results hold promise for broad implementation of exercise interventions into larger healthcare systems and have implications for improved research recruitment strategies. NCT No. NCT03253341. Our community-based exercise program increased cardiorespiratory fitness. Our digital physician referral method increased the diversity of the participant sample. Our findings have implications for personalized dementia risk reduction strategies.

Mechanisms and Functions of the Cerebral-Cognitive Reserve in Patients with Alzheimer's Disease: A Narrative Review.

The need for scientific knowledge about aging is predicated on the demand of modern society to extend the active life of a person. To maintain intellectual longevity, it is necessary to take into account not only the pathological, but also compensatory mechanisms that arise during aging. The cerebral-cognitive reserve (CCR) influences the rate of transition from pre-phenomenological stages to the clinical stage of the disease, thereby changing the prognosis of Alzheimer's disease (AD). The aim of this work was to review meta-analyses from studies that have examined the principles and functions of the CCR in people with AD. The work included 83 scientific publications devoted to the issues of the CCR in neurodegenerative diseases such as AD. The Results and Discussion sections of this article provide reviews of the results of 12 meta-analyses published from 2012 to 2024 and selected from the PubMed and eLibrary databases using the following keywords in English and Russian: "cerebral reserve", "cognitive "reserve", and "Alzheimer's disease". The scope of the definition was not limited, since the goal here was to determine the terminological boundaries of the concepts of "cognitive reserve" and "single brain reserve". The modern understanding of AD as a biological continuum covering the preclinical, prodromal, and clinical phases of the disease makes it possible to infer that insufficiency of protective factors underlies the progression of AD. The cognitive reserve is involved in the sanogenetic protective mechanism during neurodegeneration. The cognitive reserve is a theoretical concept that reflects modern research's understanding of how the integrative functioning of the brain (cerebral) and cognitive reserves extend the period of active intellectual longevity through energy-saving mechanisms. It considers these mechanisms as central to healthy mental activity and in slowing the progression of neurodegenerative diseases. At some point, an increase in excess interneuronal activity that reflects the hypercompensatory function of the reserve would accelerate the depletion of brain structures and contribute to clinical and psychopathological manifestations of AD. The concept of the CCR puts the spotlight on the need to determine the compensatory indicators of cognitive deficit in AD, assess the architecture and volume of the reserve, and develop and follow protocols for its maintenance. It appears just as crucial to adopt measures to prevent the Reserve's depletion as early as at the preclinical stages of the disease. Elaborating protective and compensatory mechanisms that help to maintain the functional activity of the brain in conditions of neurodegeneration, that is, CCR, require further research and can form a conceptual basis for the prevention of AD, starting from the preclinical stages of the disease.

Mitochondrial dysfunction gene expression, DNA methylation, and inflammatory cytokines interaction activate Alzheimer’s disease: a multi-omics Mendelian randomization study

BackgroundMitochondrial dysfunction (MD) is increasingly recognized as a key pathophysiological contributor in Alzheimer disease (AD). As differential MD genes expression may serve as either a causative factor or a consequence in AD, and expression of these genes could be influenced by epigenetic modifications or interact with inflammatory cytokines, hence, the precise role of MD in AD remains uncertain.MethodsMeta-analysis of brain transcriptome datasets was conducted to pinpoint differentially expressed genes (DEGs) associated with MD in AD. We utilized three-step SMR to analyze the AD genome-wide association study summaries with expression quantitative trait loci (eQTLs) and DNA methylation QTLs from the blood and brain tissues, respectively. Through SMR and colocalization analysis, we further explored the interactions between brain eQTLs and inflammatory cytokines.ResultsFive datasets were meta-analyzed to prioritize 825 DEGs in AD from 1339 MD-related genes. Among these, seven genes from blood samples such as NDUFS8 and SPG7 and thirty-two genes from brain tissue including CLU and MAPT were identified as candidate AD-causal MD genes and regulated by methylation level. Furthermore, we revealed 13 MD gene expression-inflammatory pathway pairs involving LDLR, ACE and PTPMT1 along with interleukin-17C, interleukin-18 and hepatocyte growth factor.ConclusionsThis study highlighted that the AD-causal MD genes could be regulated by epigenetic changes and interact with inflammatory cytokines, providing evidence for AD prevention and intervention.

Highly sensitive β-amyloid1–42 oligomer aptamer-based assay via dual cyclic amplifications of three-way catalytic hairpin assembly and palindrome polymerase reaction

β-amyloid1–42 oligomer (AβO1–42), a neurotoxic protein, is considered the key factor in the progression of Alzheimer's disease (AD). And, high sensitivity detection of AβO1–42 is of considerable importance for the early diagnosis and deterioration prevention of AD. We present here an ultrasensitive fluorescent AβO1–42 detection approach based on aptamer recognition probes and a new dual cyclic signal amplification strategy by combining three-way catalytic hairpin assembly (3W-CHA) with palindromic sequence-based polymerase amplification (PBPA). Once the aptamers bind to target AβO1–42 molecules, ssDNA sequences are released to initiate 3W-CHA between three hairpins to unfold the signal hairpins and to form Y-shaped DNA structures (Y-DNAs). Subsequently, the assistance ssDNAs bind the Y-DNAs to expose the palindromic sequences to yield Y-DNA dimers, which lead to cyclic PBPA reaction with presence of polymerase to further unfold more signal hairpins for yielding considerably magnified fluorescence recovery, enabling sensitive assay of AβO1–42 down to 2.4 pM within a dynamic range of 5 pM∼50 nM. Furthermore, this strategy has been validated for interrogation of low AβO1–42 levels in artificial cerebrospinal fluid (CSF), suggesting its promising potential for application in early diagnosis and prevention of AD.

TFEB agonist clomiphene citrate activates the autophagy-lysosomal pathway and ameliorates Alzheimer's disease symptoms in mice

Autophagy is a conserved eukaryotic cellular clearance and recycling process through the lysosome-mediated degradation of damaged organelles and protein aggregates to maintain homeostasis. Impairment of the autophagy-lysosomal pathway is implicated in the pathogenesis of Alzheimer’s disease (AD). Transcription factor EB (TFEB) is a master regulator of autophagy and lysosomal biogenesis. Therefore, activating TFEB and autophagy provides a novel strategy for AD treatment. We previously described that clomiphene citrate (CC) promotes nuclear translocation of TFEB and increases autophagy and lysosomal biogenesis. In this study, 7 and 3-month-old APP/PS1 mice were treated with TFEB agonist CC and assessed. The behavioral tests were performed using Morris water maze and open field test. Additional changes in Aβ pathology, autophagy and inflammatory response were determined. We found that CC activated TFEB and the autophagy-lysosomal pathway in neuronal cells. Moreover, using mouse model of Alzheimer's disease, CC treatment promoted clearance of Aβ plaques and ameliorated cognitive function in both 7 and 3-month-old APP/PS1 mice. The CC-induced activation of TFEB occurs by promoting acetylation of TFEB for nuclear translocation. These findings provide a molecular mechanism for the TFEB-mediated activation of the autophagy-lysosome pathway by CC, which has the potential to be repurposed and applied in the treatment or prevention of AD.