Journal of Alzheimer's Disease最新文献

Presenilin 1 (PSEN1) plays a pivotal role in early-onset Alzheimer's disease (EOAD). The clinical phenotype of EOAD is typically marked by cognitive decline, with ataxia rarely reported. We identified mutations at different positions of PSEN1 in two Chinese patients with EOAD. Interestingly, one patient carrying the PSEN1 p.P117L mutation manifested symptoms of ataxia, while another patient harboring the PSEN1 p.P264L mutation did not exhibit any signs of this disorder. Computational analyses using PolyPhen-2, SIFT, Provean, and Mutation Taster predicted both mutations as pathogenic, while structural predictions using SOPMA, TMHMM 2.0, and PyMOL. Our findings expand the spectrum of atypical PSEN1-associated phenotypes.

Transactive response DNA-binding protein of 43 kDa (TDP-43) type-A is associated with frontotemporal lobar degeneration (FTLD). In primary age-related tauopathy (PART), TDP-type-α displays similar features to FTLD-TDP type-A. We compared antemortem MRI volumes of amygdala nuclei and hippocampal subfields between 16 PART-TDP-α and 12 FTLD-TDP-A autopsy-confirmed cases. Hippocampal tail and CA1 body volumes were smaller in PART-TDP-α group, which also had smaller lateral and central amygdala nuclei compared to FTLD-TDP-A group, but differences were non-significant after FDR correction. There is no evidence suggesting that TDP-43 type-A in FTLD affects hippocampal and amygdala volume loss differently than TDP-43 type-α in PART.

BackgroundDepressive symptoms in older adults have become a major public health problem. Interventions targeting physical function and motoric cognitive risk syndrome (MCR), a pre-dementia (such as Alzheimer's disease) syndrome, may offer promising new avenues for addressing this problem.ObjectiveWe aim to explore the relationship between self-perceptions of aging (SPA) and depression among community-dwelling older adults and analyze whether physical function plays a mediating role in this association and whether motoric cognitive risk syndrome (MCR) can moderate this mediating effect.MethodsFrom March to November 2023, 861 community-dwelling older adults in Xinxiang City, China were investigated for their SPA, depression, physical function and MCR status. Descriptive statistics, analysis of variance and correlation analysis were performed on the data, and Mplus8.3 was used to construct a moderated mediation model.ResultsSPA is positively correlated with depression, with physical function playing a mediating role between SPA and depression, accounting for 16.2% of the total effect. The results of the interaction term between SPA and MCR were significant (β = -0.089, p = 0.009), indicating that MCR moderates the relationship between SPA and physical function.ConclusionsThis study reveals the mediating role of physical function and the moderating role of MCR. It suggests that attention should be paid to the physical and mental management of community-dwelling older adults with negative self-perceptions of aging, reduce the risk of MCR, to prevent and alleviate the depressive symptoms.

BackgroundJuxtacortical perivascular spaces (jPVS) were observed in cerebral amyloid angiopathy (CAA), yet the diagnostic relevance between jPVS and CAA remains unclear.ObjectiveTo explore the association between in-vivo jPVS burden and clinical diagnosis of CAA, as well as established CAA imaging markers.MethodsWe retrospectively enrolled patients with probable CAA or arteriolosclerosis who underwent ultrahigh-field 5.0 T MRI. A visual rating scale was used to quantify jPVS burden. Established CAA markers were evaluated, including centrum semiovale perivascular spaces (CSO-PVS), lobar intracerebral hemorrhage (ICH), lobar cerebral microbleeds (CMBs), and cortical superficial siderosis (cSS). Multivariable logistic regression, receiver operating characteristic analyses, and generalized linear models were applied.ResultsAmong 117 participants (48 probable CAA and 69 arteriolosclerosis, mean age 65.6 ± 9.8 years, 63.2% males), jPVS burden was significantly higher in CAA (p < 0.001). The jPVS burden was independently associated with clinically diagnosed CAA (odds ratio for the highest tertile of total jPVS: 14.93; 95% confidence interval: 4.59-48.53; p < 0.001, compared with the lowest tertile), after adjusting for age, sex, hypertension, diabetes, and hyperlipidemia. Total jPVS count demonstrated good discrimination for CAA (area under the curve 0.799, 95% confidence interval: 0.717-0.882, p < 0.001) and was independently correlated with CSO-PVS, lobar ICH, lobar CMBs, and cSS (all p < 0.05).ConclusionsThe jPVS burden is independently associated with the clinical diagnosis of CAA and established CAA imaging markers. These findings may contribute to advancing the current understanding of CAA imaging and support jPVS as a complementary marker with potential clinical utility.

BackgroundDeep cervical lymphatic venous anastomosis (dcLVA) is a novel surgical approach for patients with Alzheimer's disease (AD). Its theoretical basis lies in the promotion of the clearance of large biomolecular metabolites in the central nervous system by unblocking the deep cervical lymphatic system. Currently, there is a lack of systematic and comprehensive research on biomarkers for monitoring disease progression and therapeutic efficacy in patients with AD after treatment. Single-molecule technology is applied widely in the field of medicine to detect trace amounts of proteins, especially for detecting the biomarkers related to neurodegenerative diseases such as AD.ObjectiveThis study presents the data of 30 AD patients who underwent dcLVA surgery and the results of analyzing AD biomarkers, exploring the efficacy of dcLVA treatment, and explores whether peripheral blood biomarkers could be used to monitor the treatment effects.MethodsUsing single-molecule technology to detect dynamic changes in blood biomarkers, combined with cognitive scores and Clinician's Interview-Based Impression of Change Plus (CIBIC-plus) data, a prognostic prediction model is constructed.ResultsThe results show that dcLVA surgery elevates peripheral blood amyloid-β (Aβ)₄₂ levels which correlate significantly with the CIBIC plus score. The combination of Aβ₄₂ and Aβ_42/40 achieved the highest AUC (0.737) at 180 days post-surgery, showing good diagnostic performance and potential as a prognostic biomarker for dcLVA surgery.ConclusionsBy leveraging the dynamic changes of blood biomarkers, it is helpful to adjust the treatment plan in a timely manner, thereby achieving personalized treatment and improving the treatment effectiveness.

BackgroundSeveral monoclonal antibodies designed to slow cognitive and functional decline in individuals with early Alzheimer's disease (AD) have been recently approved. However, a comprehensive evaluation of the cost-effectiveness of all FDA-approved neurotherapeutic agents for AD remains lacking.ObjectiveThis study aimed to systematically review and analyze the incremental costs and effectiveness of currently available FDA-approved neurotherapeutic agents for AD to provide consolidated evidence on their economic value.MethodsA systematic review was conducted across PubMed, Embase, Cochrane CENTRAL, and Web of Science, adhering to the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) and PRISMA guidelines.ResultsTwenty-three articles were included. Most studies (74%) used a Markov model. Nearly half (48%) of studies were analyzed from both healthcare system and societal perspectives. Industry-funded studies made up 43%, while 39% were funded by non-profits, and 17% received no funding. Quality-adjusted life year (QALY) was the most common effectiveness measure (91%). At a willingness-to-pay (WTP) threshold of $100,000/QALY, all studies found memantine cost-effective, and more than half reported cost-effectiveness for donepezil, rivastigmine, and galantamine. Aducanumab, lecanemab, and donanemab were not cost-effective in any study. Under the WTP threshold of $150,000/QALY, value-based prices for aducanumab, lecanemab, and donanemab were estimated below $5,960, $15,700, and $33,700, respectively.ConclusionsTraditional symptom-targeting drugs were consistently cost-effective, whereas anti-amyloid therapies were not. Future independent cost-effectiveness analyses would benefit from head-to-head comparisons using real-world data and greater attention to disparities in dementia research.

BackgroundVascular cognitive impairment (VCI) is the second most common dementia etiology after Alzheimer's disease. However, plasma biomarkers of VCI remain insufficiently validated.ObjectiveWe aimed to identify plasma biomarker candidates for VCI by using integrated multi-omics analyses.MethodsWe prospectively recruited VCI patients and healthy controls (HCs), performed proteomic and metabolomic analyses with ELISA validation, and conducted plasma protein quantitative trait loci (pQTL)-based Mendelian randomization (MR) with VCI-related imaging phenotypes.ResultsProteomics identified 871 differentially upregulated proteins, in 8 VCI patients compared to 6 HCs. Proteins containing YWHAZ, CLDN5, VCL, TPM4, TLN1, CAP1, ITGB3, GP1BB, and ROCK2 were further investigated. ELISA validation conducted on another 8 VCI patients and 8 HCs showed levels of CAP1 (257.1 ± 51.48 versus 204.7 ± 27.47 ng/L, 95% CI: 8.19-96.68, p = 0.0235) and ROCK2 (10.10 ± 2.417 versus 7.555 ± 1.835 ng/mL, 95% CI: 0.24-4.84, p = 0.0328) were significantly higher in the VCI group. CAP1 expression demonstrated a significant association with glycolysis-related metabolites, particularly lactate and the complex glycolysis score, based on adjusted rank correlation analysis (panel-wise FDR < 0.05). MR analysis utilizing plasma pQTL data and vascular dementia and its imaging-derived phenotypes suggested no evidence for a causal effect in either direction.ConclusionsPlasma CAP1 and ROCK2 levels were observed elevated in individuals with VCI, with CAP1 showing metabolomic consistency in relation to glycolytic pathways. These findings provide preliminary exploratory signals suggesting that CAP1 and ROCK2 may merit further investigation in the context of VCI.

BackgroundThe levels of soluble amyloid-β (Aβ)₄₂ oligomers in the brains of patients with Alzheimer's disease (AD) are well-known to correlate with the extent of synaptic loss. However, the abnormal role of these oligomers in disrupting the balance of the endo-lysosomal pathways for substance degradation in AD brains and cellular models remains unclear.ObjectiveWe aimed to investigate whether extracellular Aβ₄₂ oligomers alter the composition, distribution, and identity of vesicular components and impact the processing of substances involved in the endo-lysosomal pathways of protein degradation.MethodsWe overexpressed Rab7, Lamp-1, and β-1,4-galactosyltransferase-1 proteins in nondifferentiated SH-SY5Y cells. We then incubated these cells with extracellular Aβ₄₂ oligomers, and evaluated the effects on the morphology, composition, and distribution of vesicular components in the endo-lysosomal pathway using super-resolution confocal microscopy. Additionally, we assessed the effects of Aβ₄₂ oligomers incubation on the degradation and processing of endocytosed fluorescent transferrin in vivo.ResultsOur findings revealed that Aβ₄₂ oligomers alter the distribution and identity of Rab7- and Lamp-1-coated vesicles, as well as the Golgi apparatus. This alteration resulted in the formation of disorganized vesicles carrying distinct surface markers of the endo-lysosomal pathway, without evident changes to the cytoskeleton. In vivo evaluation showed a delayed degradation of endocytosed fluorescent transferrin after incubation with Aβ₄₂ oligomers.ConclusionsAβ₄₂ oligomers may contribute to neuronal toxicity by inducing changes in the identity, distribution and balance of vesicular components associated with the endo-lysosomal pathway. This disruption impacts the processing and degradation of various materials that accumulate in the cytoplasm.

BackgroundPostoperative delirium (POD) affects up to a third of older surgical patients, leading to significant morbidity, mortality, and potential progression to Alzheimer's disease (AD). Polygenic risk scores (PRS) capture inherited susceptibility to complex diseases, but their relevance to POD is unclear.ObjectiveWe examined whether higher AD-PRS predict increased POD risk in patients without dementia and whether sleep burden modifies this relationship.MethodsThis study included 345 414 UK Biobank participants (mean [SD] age: 70.1 [7.9], range: 40.4-87.6 years; 54.0% women) to identify new-onset POD, using the International Classification of Disease-10 coding within three days of surgery. Participants with mild cognitive impairment, dementia, or dementia diagnosed within one year of POD were excluded. AD-PRS was calculated as a weighted sum of genetic variants, with scores divided into quartiles due to the absence of standardized thresholds. Covariates included demographics, comorbidities, and lifestyle factors. Cox proportional hazard models were used to evaluate the relationship between AD-PRS and POD risk.ResultsA total of 1610 POD cases were identified. Compared to Q1, individuals in Q3 (HR = 1.23, 95% CI [1.07-1.42], p < 0.01) and Q4 (1.35, [1.18-1.56], p < 0.001) had progressively higher POD risk. Findings were consistent across alternate POD definitions and subgroups defined by sleep burden, sex, age, cardiovascular risk, and inflammatory markers.ConclusionsHigher AD-PRS is independently associated with greater POD risk in adults without dementia. AD genetic susceptibility may help identify high-risk surgical patients and warrants validation in prospective perioperative cohorts.

This article synthesizes key themes emerging from the CTAD 2025 meeting, highlighting significant advances in Alzheimer's disease (AD) research and clinical practice. New disease-modifying approaches-ranging from next-generation anti-amyloid-β and anti-tau antibodies to small-molecule aggregation inhibitors and gene-based strategies-underscore a growing shift toward multi-target therapeutic frameworks. Blood-based biomarkers, such as p-tau217, p-tau181, glial fibrillary acidic protein, and neurofilament light, are nearing clinical readiness, while digital biomarkers and wearable technologies are enabling remote, continuous assessment of cognitive and physiological functions. Clinical trial design is increasingly oriented toward earlier disease stages and genetically or biomarker-defined high-risk groups, incorporating adaptive methodologies and real-world data to enhance efficiency and generalizability. Collectively, these developments signal an impending transition over the next two to three years from a centralized, cognitive scale-driven model of AD care to a more decentralized, biomarker-guided precision paradigm. CTAD 2025 thus marks a pivotal inflection point in the evolving structure of AD diagnosis and treatment.