Journal of Alzheimer's Disease最新文献

BackgroundEpileptic seizures and subclinical epileptiform activity are increasingly recognized as comorbidities in Alzheimer's disease (AD) and have been associated with accelerated cognitive decline. Whether antiseizure medication (ASM) therapy favorably influences cognitive trajectories in AD remains unclear.ObjectiveTo assess the effects of ASM therapy on cognitive trajectories in patients with AD with comorbid epilepsy, and to identify patient subgroups most likely to benefit.MethodsWe retrospectively studied 538 patients (403 AD only; 135 AD with comorbid epilepsy) treated with newer-generation ASMs between 2020 and 2025. Cognitive change over 24 months was assessed using the Mini-Mental State Examination (MMSE). Analyses included linear mixed-effects modeling, sliding window interaction analysis across baseline MMSE scores (11-29), and 1:1 propensity score matching stratified by baseline MMSE (≤21, 22-26, and ≥27).ResultsAfter propensity score matching, baseline MMSE scores were well balanced between the groups. The sliding window analysis suggested a subgroup-specific interaction between group and time in the MMSE (range 22-26), peaking at MMSE 25. In the 22-26 stratum, MMSE at 12 months was higher in the AD with comorbid epilepsy group than in the AD-only group (23.23 ± 0.46 versus 20.33 ± 0.52, p < 0.001). The 24-month difference (22.92 ± 1.37 versus 19.36 ± 0.99, p = 0.047) was borderline and considered exploratory.ConclusionsAntiseizure therapy was associated with favorable cognitive trajectories in patients with AD and comorbid epilepsy, particularly with baseline MMSE 22-26. These exploratory findings suggest a potential therapeutic window that warrants confirmation in prospective studies.

BackgroundSocial engagement has been connected to better psychological well-being, improved QoL, and resilience to neuropathological changes. Yet, little is known about the details of social engagement in dementia, which could inform effective interventions.ObjectiveWith this study, we aimed at providing information on social engagement of people with dementia (PWD), given by proxies and PWD.Methods501 people actively involved in dementia care in Germany (86% female; mean age 53.5 years) provided answers to a structured, quantitative survey via online/paper questionnaire, or interview on (i) the types of social activities that PWD engage in, (ii) PWDs' motivation for social engagement, (iii) the support PWD get to engage, (iv) barriers to engage in activities, and (v) ways to increase social engagement. Descriptive analyses as well as overall and pairwise comparisons were performed.ResultsPWD often attend therapies (M = 3.6, SD = 1.0) and sometimes meet-ups with friends (M = 3.0, SD = 1.0), and they remain interested in social engagement (M = 3.5, SD = 1.7). Support was perceived to come mainly from family members (88.9%), partners/spouses (85.9%), and friends/acquaintances (59.9%). Most participants perceived activities not being dementia-friendly (16.1%) and the lack of support (25.6%) as a major barrier to social engagement. To increase the engagement of PWD, participants suggested that social activities need to be adapted to their abilities (83.1%), that the community needs to provide inclusive activities (75.0%), and that specialized care services need to be expanded (41.4%).ConclusionsTo facilitate and increase social engagement of PWD, support from social contacts and inclusive community behavior could be valuable steps.

BackgroundSocial isolation is a key modifiable risk factor for cognitive decline, yet its mediating mechanisms are not fully understood.ObjectiveThis study examines depression and systemic inflammation (neutrophil-to-lymphocyte ratio, NLR) as mediators between social isolation and domain-specific cognitive impairments.MethodsUsing cross-sectional data from 1272 adults aged ≥60 (NHANES 2011-2014), we constructed a social isolation index (0-4) incorporating marital status, living arrangements, functional limitations, and social participation barriers. Cognition was assessed via Alzheimer's Disease Word Learning Test (CERAD-WL) (verbal memory), Animal Fluency (executive function), Digit Symbol Substitution Test (processing speed), and composite Z-scores. Mediation analyses with PHQ-9 depression scores and NLR controlled for sociodemographic, lifestyle, and clinical factors.ResultsSevere social isolation (score = 3) showed dose-response associations with cognitive impairment, particularly in processing speed (DSST β = -11.66, p < 0.01) and global cognition (Z-score β = -0.59, p < 0.01). Depression accounted for about 14.5-20.3% of the association with executive function and processing speed, and NLR explained 25.4% of verbal memory problems. Significant direct effects persisted post-mediation (e.g., CERAD-WL β = -0.519; DSST β = -2.374, p < 0.001), suggesting unmeasured pathways.ConclusionsSocial isolation was associated with cognition through tripartite mechanisms: depression-linked processing speed/executive dysfunction, inflammation-mediated verbal memory decline, and direct neurobiological effects. Integrated interventions targeting social connectivity and depression are clinically prioritized over anti-inflammatory strategies. Findings emphasize domain-specific vulnerabilities requiring precision approaches for isolated older adults.

BackgroundArgyrophilic grain disease (AGD) is a common yet underrecognized tauopathy that often mimics Alzheimer's disease (AD) in clinical and imaging presentations. While regional atrophy in AGD has been reported on magnetic resonance imaging (MRI), network-level structural changes remain poorly understood.ObjectiveWe aimed to explore a gray matter volume network related to AGD.MethodsStructural MRI data were collected from 12 patients with pathologically confirmed AGD (age at MRI, 87.7 ± 5.5 years; male, 4), 12 patients with pathologically confirmed AD (83.4 ± 10.0 years; male, 4), and 9 healthy controls (HCs; 82.4 ± 1.9 years; male, 2) at Fukushimura Hospital in Japan. Scaled Subprofile Model with principal component analysis was applied to preprocessed gray matter volume data of AGD and HCs to identify an AGD-related network.ResultsAn AGD-related network involving relative reduction in the ambient gyrus, entorhinal cortex, hippocampus, amygdala, and thalamus was identified. Represented by principal components 1, 2, and 3, this network showed significantly higher expression in patients with AGD than HCs (p < 0.0001, permutation test). The expression of the network was also higher in patients with AD than HCs (p < 0.0001, t-test).ConclusionsThis exploratory study identified a gray matter volume network related to AGD, providing a basis for future research of network-based imaging approaches.

BackgroundCognitive decline and incident dementia in ageing populations have been linked to brain parenchymal injury and the ALPS index (ALPS-I).ObjectiveThis investigation aimed to elucidate whether the baseline ALPS-I could predict incident dementia and cognitive decline in this population.MethodsIn total, 973 dementia-free participants from the Shunyi Study (mean age, 57 years; 37% male) received MRI between 2013 and 2016 to quantify the ALPS-I. The longitudinal relationships between the ALPS-I and cognitive deterioration in various cognitive areas were evaluated via linear mixed models. Cox proportional hazard models were utilized to explore the link between the index and incident dementia. Mediation assessments were carried out to identify the potential mediating effects of brain parenchymal injury on the link between the ALPS-I and cognition.ResultsThe baseline ALPS-I predicted longitudinal changes in global cognition (Montreal Cognitive Assessment), language (verbal fluency test), visuospatial perception (block design subtest of Wechsler intelligence scale), and executive function (Trail Making Test). A lower score was markedly associated with a higher incident dementia risk. Mediation analysis revealed that fractional anisotropy mediated the associations between the ALPS-I and executive function (mediation effect: 21.9%) and visuospatial perception (mediation effect: 68.8%). The white matter hyperintensity fraction was found to mediate the link between the ALPS-I and global cognition (mediation effect: 55.0%).ConclusionsThis longitudinal evidence supports a link between the ALPS-I and cognitive degeneration. Furthermore, the link is mediated by subcortical parenchymal injury.

BackgroundEpigenetic mechanisms, particularly histone modifications at gene promoters, are crucial for controlling gene transcription.ObjectiveWe aim to find out epigenomic aberrations during the progression of neurodegenerative disorders.MethodsWe employed a multifaceted approach to investigate how the two key histone methylation marks, H3K4me3 (linked to gene activation) and H3K27me3 (linked to gene suppression), are altered in postmortem prefrontal cortex of humans with mild cognitive impairment (MCI) or Alzheimer's disease (AD).ResultsCompared to controls, MCI and AD exhibited pronounced losses of permissive H3K4me3 peaks at promoters of genes enriched in synaptic plasticity and neurotransmission, and significant gains of H3K4me3 peaks at promoters of genes enriched in transcriptional regulation. AD displayed more substantial H3K4me3 losses on synaptic genes than MCI. Conversely, significant gains of repressive H3K27me3 peaks were observed at synaptic gene promoters in both disease groups, with MCI exhibiting more pronounced H3K27me3 gains on synaptic genes than AD. Weighted Gene Correlation Network Analysis (WGCNA) revealed multiple modules characterizing distinct patterns of gains and losses of H3K4me3 and H3K27me3 during the transition from MCI to AD. Integrative analysis of epigenomic and transcriptomic data indicated that these histone mark alterations were well correlated with the downregulation of synaptic genes and upregulation of transcriptional regulators in AD.ConclusionsThis comprehensive profiling uncovers a stage-dependent reorganization of histone modifications at critical gene loci, implicating these events in the molecular cascade of AD pathogenesis. Targeting dysregulated chromatin states may offer novel therapeutic avenues for early intervention of AD.

BackgroundAntidepressant and anxiolytic medication use in people with dementia (PwD) may contribute to potentially inappropriate prescribing and be associated with mortality.ObjectiveTo investigate trends in prescribing of these medications and their association with mortality risk among PwD.MethodsA nested case-control study was conducted in Northern Ireland (NI) using linkage of five administrative population-based data sources within a cohort of dementia patients (identified if a medication indicated for dementia was prescribed). Dementia patients who died were matched to one control who lived at least as long as their matched case after dementia diagnosis (matched on age, sex and year of dementia). Exposure to antidepressant and anxiolytic medications was assessed from two years prior to study entry. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression after adjusting for demographic factors and comorbidities.ResultsThe study included 14,420 dementia cases. Antidepressants were prescribed to 59.2% of cases and 54.7% of controls while 44.8% of cases and 36.0% of controls were prescribed anxiolytics. There was evidence of a weak increased risk of mortality in PwD prescribed antidepressants (fully adjusted OR = 1.08; 95% CI 1.02-1.14) and a strong increased risk in those prescribed anxiolytics (fully adjusted OR =1.26; 95% CI 1.19-1.33) compared to nonusers.ConclusionsIn this large NI population-based cohort of PwD, elevated levels of antidepressant and anxiolytic prescribing were observed. The use of anxiolytic medications was strongly associated with mortality in PwD.

BackgroundWomen with Alzheimer's disease (AD) have higher prevalence and more severe dementia syndrome than men with AD, and the brain regions are also affected differently. However, the underlying mechanisms are poorly understood.ObjectiveTo characterize the sex-dependent and region-specific gene expression in AD brain.MethodsA previously published large scale bulk tissue gene expression dataset from postmortem brain samples across 19 cortical regions of normal control and individuals diagnosed with dementia and neuropathology of AD was used for differential gene expression analysis. Functional enrichment analysis was used to identify enriched biological functions or pathways related to selected genes. Protein expression level of a selected gene was validated by western blot.ResultsWe identified 113 dysregulated genes in 11 AD brain regions (9 in men, 7 in women, and 5 shared between men and women). Notably, more dysregulated genes were found in women AD brain (77 genes) than in men (49 genes), and 13 dysregulated genes across these 11 brain regions were shared between women and men. Functional analysis further revealed the distinctive enrichment in categories of cellular component, biological process, and/or molecular function in these dysregulated genes. GPR34 gene expression was upregulated in the men AD brain across three different regions and a significant elevation of GPR34 protein level was confirmed in men AD brain.ConclusionsThese findings provide insight into sex- and brain region-specific gene expression dysregulation, which may indicate novel mechanisms underlying AD pathogenesis and will facilitate the development of personalized diagnosis and treatment strategies for AD.

BackgroundAlzheimer's disease (AD) is a neurodegenerative disease affecting millions globally, with particular severity in low- and middle-income countries due to barriers in timely diagnosis and treatment. To date, two monoclonal anti-amyloids have shown positive results in phase III clinical trials. However, their administration is complex, requiring specialized infrastructure, highly trained professionals, and regular follow-ups, posing major challenges for healthcare systems.ObjectiveThis study explores Peruvian neurologists' perceptions of changes needed to implement monoclonal antibodies in line with clinical guidelines.MethodsA cross-sectional study was conducted in Peru using the key informant (KI) methodology. KI were neurologists from multiple regions across the country. A comprehensive list of tertiary-level hospitals (public healthcare system, social security, and police and armed forces) was compiled, and at least one neurologist from each institution was contacted. The instrument used was adapted from a study conducted in Spain, which included questions focusing on changes in diagnosis, patient care, diagnostic and therapeutic techniques, public and family impact, neurology resources, and dementia research. Data analysis was employed using Stata18, using descriptive statistics and frequency distributions.ResultsTwenty-eight neurologists completed the survey. There was consensus on the significant impact monoclonal antibodies would have on neurology services. Over 85% agreed that more neurologists and nurses would be needed. Additionally, 93% supported using brief diagnostic scales in primary care and increasing follow-up visit frequency.ConclusionsThe introduction of monoclonal antibodies for AD in Peru requires modifications to healthcare institutions, highlighting the urgent need for strategic healthcare planning.

BackgroundThe Lieber Institute for Brain Development (LIBD) has one of the largest postmortem human brain banks for the study of neuropsychiatric disorders in the world. The postmortem evaluation involves neuropathological assessment for age-related protein accumulations, specifically phosphorylated tau (p-tau) and amyloid-β (Aβ).ObjectivePresent the LIBD semiquantitative assessment methodology for p-tau and Aβ by comparing proteinopathy by age and by apolipoprotein E (APOE) genotype.MethodsPostmortem brain tissue samples were from 1509 people aged 50 or greater (median age at death = 63 years; range = 50-102). Seven brain regions (four neocortical areas, hippocampal formation, midbrain, and cerebellum) were examined by routine histopathology, p-tau immunohistochemistry (AT8; hippocampus and four neocortical samples), and Aβ immunohistochemistry (BAM01; four neocortical samples). APOE genotyping was performed in a subgroup. Semiquantitative assessments include modified CERAD (Consortium to Establish a Registry for Alzheimer's Disease) and modified Braak approaches.ResultsThere were 63.8% rated as B1 (modified Braak I or II), 30.4% rated as B2 (modified Braak III or IV), and 5.8% rated as B3 (modified Braak V or VI). For those in their early 70 s, half had modified Braak stage III-IV ratings. For decedents in their 80 s, approximately 1 in 4 had modified Braak stage V-VI ratings. Aβ was present in 48.8% (C0 = 51.2%, C1 = 17.2%, C2 = 24.5%, and C3 = 7.1%). Age and APOE genotype were significant predictors of Aβ plaques.ConclusionsThe LIBD protocol assessing p-tau and Aβ burden identified significant associations with age and APOE genotype. More research is needed to understand the spectrum of age-related proteinopathy versus neurodegenerative disease neuropathology.