Journal of Alzheimer's Disease最新文献

BackgroundThe choroid plexus (ChP) and glymphatic system are crucial for cerebrospinal fluid (CSF) homeostasis and brain waste clearance. While their individual roles in Alzheimer's disease (AD) are recognized, the mechanisms linking ChP structural changes, glymphatic dysfunction, and CSF dynamics to metabolic and cognitive decline remain unclear.ObjectiveWe aimed to investigate the interrelationships among ChP volume, glymphatic function, CSF volumetric changes, cerebral glucose metabolism, and cognitive status across the AD spectrum.MethodsThis cross-sectional study included 142 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, categorized as cognitively normal (NC, n = 38), early mild cognitive impairment (EMCI, n = 31), late mild cognitive impairment (LMCI, n = 31), and AD (n = 42). We analyzed multimodal neuroimaging data, including normalized ChP volume (nChP), CSF sub-volumes, the diffusion tensor imaging along the perivascular space (DTI-ALPS) index, and [18F]-FDG-PET standardized uptake value ratios. Partial correlation and mediation analyses were performed, adjusting for covariates.ResultsIncreased nChP correlated with larger CSF (nTotal-CSF: r = 0.324, FDR-p = 0.004), lower DTI-ALPS, and reduced FDG. nChP drove cognitive decline via two paths: "nChP→nTotal-CSF→ Mini-Mental State Examination (MMSE)" (44.1% total effect) and "nChP→DTI-ALPS→FDG→MMSE" (9.9%, p < 0.001). CSF showed spatial mediation: nCSF-LV (66.20% on metabolism) outperformed external CSF (38.90%); DTI-ALPS negatively correlated with nCSF-LV (r = -0.406, FDR-p < 0.01).ConclusionsOur findings demonstrate that ChP enlargement is linked to cognitive impairment through pathways involving CSF dynamics and glymphatic function, with cerebral hypometabolism as a key downstream effector. This study posits a "CSF dynamics imbalance" cascade in AD, highlighting the potential of targeting Choroid Plexus-CSF-glymphatic axis for early diagnosis and intervention.

TAR DNA-binding protein 43 (TDP-43) is a multifunctional DNA/RNA-binding protein whose abnormal phosphorylation and aggregation are central to the pathogenesis of several neurodegenerative diseases. TDP-43 proteinopathy, characterized by hyperphosphorylation and cytoplasmic accumulation, is a defining pathological feature of amyotrophic lateral sclerosis and frontotemporal lobar degeneration, and is frequently observed in Alzheimer's disease. The phosphorylation state of TDP-43 is dynamically regulated by a network of protein kinases-including CK1, GSK3β, CDC7, and PKA-and counterbalanced by phosphatases such as PP2A and PP1; however, the precise molecular mechanisms governing this equilibrium in disease remain incompletely understood. Notably, phosphorylated TDP-43 acquires prion-like properties, enabling self-templated aggregation and cell-to-cell propagation, which amplifies pathology and drives disease progression. These insights have catalyzed the development of therapeutic strategies aimed at modulating TDP-43 phosphorylation, with kinase inhibitors and phosphatase enhancers emerging as promising candidates for targeting TDP-43 proteinopathies. This review integrates current knowledge on the regulatory networks controlling TDP-43 phosphorylation, examines its role in prion-like spread, and evaluates emerging therapeutic approaches aimed at mitigating TDP-43-mediated neurodegeneration.

BackgroundRetinal imaging offers a noninvasive window into neurodegenerative changes, yet its relationship with established cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) remains poorly understood. This study addresses a critical gap by examining whether retinal structural findings on optical coherence tomography (OCT) correlate with CSF biomarkers of AD pathology and neurodegeneration.ObjectiveTo determine if CSF biomarkers correlate with retinal OCT imaging findings in individuals with AD.MethodsIn this cross-sectional study, subjects underwent lumbar puncture for CSF collection and were imaged using the Zeiss Cirrus HD-5000 with AngioPlex.ResultsForty participants (73 eyes) were included in this study. Twenty-one had normal cognition and negative CSF AD biomarkers, 12 had normal cognition and positive CSF AD biomarkers, and seven had mild cognitive impairment. Central subfield thickness (CST), retinal nerve fiber layer (RNFL), and ganglion cell inner plexiform layer (GCIPL) thicknesses were associated with CSF amyloid-β 42/40 ratio (Aβ_42/40), phosphorylated tau at threonine 181 (pTau181)/Aβ₄₀ ratio, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) using multivariable generalized estimating equations. There were no statistically significant associations between CSF pTau181/Aβ₄₀ ratio, NfL, or GFAP and CST, GCIPL thickness, or RNFL thickness (p > 0.05 for all). Aβ_42/40 ratio was positively associated with GCIPL thickness (p = 0.02), but not with CST or RNFL thickness (p = 0.31 and p = 0.82, respectively).ConclusionsDecreased CSF Aβ_42/40 ratio, a biomarker of amyloid plaque pathology, is associated with decreased GCIPL thickness. GCIPL thinning may correspond with CSF abnormalities consistent with amyloid pathology that is present even prior to cognitive decline.

BackgroundAlzheimer's disease is common in later life and affects the person with dementia as well as their family. As the disease progresses, declining functions of activities of daily living increase dependence on relatives for support, who can become caregivers.ObjectiveTo summarize the current state of knowledge regarding caregivers' views on Alzheimer's disease and other types of dementia, and to identify overarching themes.MethodsWe conducted a scoping review using PRISMA guidelines. Inclusion criteria were: a) qualitative studies or qualitative sections of mixed-methods studies about views on dementia among informal caregivers, b) publication between 2013 and 2023, c) publication in a peer-reviewed journal, d) English or German language. The search was carried out in five scientific databases (MEDLINE, PsycInfo, PSYNDEX, CINHAL, Web of Science). Information on authors, years, settings, participants, aims, methods, type of analysis, and results were extracted. Using reflexive thematic analysis, themes of views on dementia reported in the given articles were summarized.ResultsWe identified 42 relevant studies reporting views on dementia in informal caregivers and constructed seven themes: "Dementia as natural cognitive decline", "Dementia as caregiver burden", "Dementia as stigmatized experience", "Dementia as transition in relationship dynamics", "Dementia as uncertainty", "Dementia as enriching experience" and "Dementia as self-inflicted vs. externally determined".ConclusionsViews on dementia among informal caregivers encompass complex, multi-dimensional attitudes and perceptions warranting a nuanced dementia discourse and offering various starting points for interventions. "Dementia as transition in relationships dynamics" emerged as an especially important topic requiring more attention in dementia research.

BackgroundAlzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β plaques, neurofibrillary tangles, and synaptic dysfunction. Dysregulation of ionotropic glutamate receptors (iGluRs), including NMDA, AMPA, and kainate receptors, contributes to excitotoxicity, synaptic impairment, and cognitive decline, underscoring their therapeutic potential.ObjectiveThis study aimed to conduct a comprehensive bibliometric analysis of iGluR research in AD from January 1, 1986 to August 23, 2025.MethodsWe systematically searched and analyzed the publications related to iGluRs in AD from PubMed, Web of Science, and Scopus using CiteSpace, VOSviewer, and Bibliometrix. Metrics included publication volume, citation impact, international collaborations, keyword co-occurrence, and burst detection.ResultsA total of 4810 papers were identified for analysis. The most prolific country, institution, journal, and author were the United States, Harvard University system, Journal of Neurochemistry, and Lipton SA, respectively. Research has evolved from NMDAR dysfunction and Aβ toxicity to clinical applications, such as memantine therapy, with recent trends focusing on AMPAR modulation and neuroprotection. Emerging researchers from China have demonstrated rapid growth. Keyword analysis reflected a sustained interest in molecular mechanisms and an increasing emphasis on clinical translation.ConclusionsThis study delineates the evolution of iGluR research in AD from mechanistic insights to therapeutic innovation. While NMDARs remain central, future efforts should prioritize understudied targets like AMPARs and KARs, and leverage emerging technologies, such as cryo-electron microscopy, single-cell sequencing, and artificial intelligence, to refine therapeutic strategies and facilitate personalized medicine. It highlights targeted iGluR modulation as a promising therapeutic avenue for combating AD.

BackgroundPeople with dementia often spend most of the day without care, without encounters, and usually without activity. There is a knowledge gap on how people with dementia experience these periods of time.ObjectiveWe aimed to map studies on times without care and encounters of people with dementia, including Alzheimer's disease, in the institutional or domestic long-term care setting.MethodsWe performed a living evidence map with four search cycles (each May and November from 2023 to 2024) and considered PubMed, CINAHL, PsycInfo, Web of Science Core Collection, citation searching, and web searching. We included studies from the institutional or domestic long-term care setting, published as journal article with no restriction on the study design or publication year. Key characteristics and results were narratively summarized.ResultsWe included 28 studies. Sixteen studies (57%) were conducted in the UK or Ireland. Twenty-one studies (75%) had a cohort design and 7 (25%) were qualitative studies. Twenty-five studies (89%) used observations as the primary data collection method. Between two and 78% of the observed time, people with dementia experienced times without care and encounters. Only eight studies (29%) explored their experiences during these times. However, none of the studies were specifically focused on that.ConclusionsOur results demonstrate that the duration of times without care and encounters is highly variable. The findings highlight the need for primary studies exploring times without care and encounters from the perspectives of people with dementia.

BackgroundPeople living with Alzheimer's disease and related dementias experience barriers to accessing routine primary eyecare, increasing risk of preventable sight loss. One barrier is a negative experience with previous eye tests (defined as a comprehensive eye examination involving multiple tests to assess visual function and eye health). We explored eye test experiences for people with dementia and identified improvements. Supporting people with dementia to keep up regular eye tests may reduce risk of preventable sight loss, thereby supporting wellbeing and independence.ObjectiveFrom the perspectives of people living with dementia, family carers and optometrists: 1) Identify ways to improve experiences of having an eye test, and self-managing eye problems at home; and 2) Determine if/how optometrists change their testing and management approach to accommodate dementia.MethodsSemi-structured interviews were conducted with people living with dementia at home, past/current family carers and practicing optometrists. Framework analysis produced an integrated perspective. People with dementia and carers guided the research.ResultsIdentified themes were: 1) Good eyesight matters to people with dementia; 2) Varied impacts of dementia upon the eye test and following eyecare advice at home; 3) Adapting the eye test and eyecare advice to accommodate dementia; 4) What makes a good eye test experience for people living with dementia; and 5) Unmet training and education needs in dementia-friendly eyecare.ConclusionsDementia education/training to support optometrists to accommodate dementia, and encouraging people with dementia and carers to declare a dementia diagnosis before the eye test, could help break down barriers to accessing dementia-friendly eyecare.

BackgroundDementia is a major global public health challenge, and gaps in public knowledge and stigma impede timely diagnosis and inclusive care. The Dementia Friends program is a brief community intervention to improve dementia knowledge and attitudes, but its effectiveness outside the UK, including Israel, is under-evaluated.ObjectiveThis study examined whether participation in the Israeli Dementia Friends program was associated with changes in dementia-related knowledge and stigma. In addition, we assessed whether perceived susceptibility, familiarity with dementia, and self-perception as a change agent were linked to these changes.MethodsA pre-post research design included 820 participants at baseline (Time 1) and 205 at a three-month follow-up (Time 2). Participants completed questionnaires on subjective and objective dementia knowledge, stigma (emotional reactions and discriminatory behavior), perceived susceptibility, and perceiving oneself as a change agent. Data was analyzed using t-tests, analyses of variance (ANOVA), and regression analyses.ResultsSignificant increases were found in subjective (p = 0.005) and objective (p = 0.019) dementia knowledge, with improved positive emotional reactions (p = 0.012). Negative emotional reactions decreased (p = 0.05), but discriminatory behavior showed no significant change (p = 0.75). Higher education was most strongly associated with increases in knowledge, and reductions in perceived susceptibility were associated with decreases in negative emotional reactions and discriminatory behavior.ConclusionsProgram participation was associated with higher dementia knowledge and more positive emotional responses, though discriminatory behaviors persisted. More comprehensive strategies beyond education are needed to fully address stigma.

BackgroundAlzheimer's disease (AD) is an incurable neurodegenerative disease with poorly understood pathogenesis. Understanding changes in protein sequences due to amino acid substitutions (AASs) may be important for uncovering molecular mechanisms of this disease.ObjectiveThe study aimed at developing a bioinformatic pipeline for searching AASs in proteomic data and revealing the AD-specific ones, highlighting potential biomarkers and/or therapeutic targets.MethodsThe developed pipeline integrates peptide de novo sequencing approach, database searches, and retention time prediction. It was applied to a large collection of AD proteomic data from global consortium studies obtained for post-mortem brain tissue samples.ResultsProteins with identified AASs were clustered by functionality. Proteins heavily enriched with AASs were the ones associated with ion transport activity, ATP binding, and G-protein signaling, aligning with known AD mechanisms. Further we classified the identified AASs by their origin (tRNA misacylation, post-translational modifications, single nucleotide polymorphisms) and by Braak stage and sex. Pathogenicity analysis, cross-referenced with clinical information, identified pathogenic mutations in HBD (W38S), GFAP (N77D), and NEFL (N98D).ConclusionsThe developed pipeline successfully maps disease-relevant protein variants by uncovering novel molecular features of a disease with biomarker and therapeutic potential. AASs identified in the work for AD samples reveal specific pathogenic mutations and implicate important biological processes.

BackgroundMild cognitive impairment (MCI) is a heterogenous condition which places individuals at higher risk for Alzheimer's disease, yet it is not well understood. Studies of primarily prevalent MCI have identified different subtypes characterized by different neuropsychological profiles, while a recent incident MCI study empirically identified four neuropsychological subtypes (amnestic, dysexecutive, dysnomic, and subtle cognitive impairment (SCI) subtypes).ObjectiveWe aimed to identify whether four distinct neuropsychological subtypes could be empirically derived in a sample of a) incident MCI and b) DSM5 mild neurocognitive disorder (mNCD).MethodsWe used data from the Personality and Total Health Through Life study. Participants were aged 72-78, with a diagnosis of incident MCI (n = 117), and/or mNCD (n = 161). We undertook a cross-sectional cluster analysis on neuropsychological data from participants from four domains: executive, memory, language, and visuospatial.ResultsFor incident MCI, cluster analysis derived four subtypes, (dysexecutive, SCI, mixed dysnomic/visuospatial and mixed dysexecutive/visuospatial). For mNCD, the resulting four cluster solution included dysexecutive, SCI-amnestic/dysnomic, SCI-dysexecutive and mixed/global impairment. Discriminant function analysis revealed that 94% and 91% of MCI and mNCD participants respectively were correctly classified based on the cognitive domain scores, and further analysis confirmed the SCI groups showed reduced cognitive performance compared with matched cognitively unimpaired participants.ConclusionsNeuropsychological subtypes were empirically derived in both incident MCI and mild NCD samples, with both SCI and dysexecutive clusters most reliably detected and consistent with previous studies. The early identification of these MCI/mNCD subtypes may help to identify patient groups for targeted early intervention in clinical settings.