Journal of Alzheimer's Disease最新文献

BackgroundThe role of histone deacetylase 6 (HDAC6) in neurodegenerative diseases, particularly Alzheimer's disease (AD), has attracted significant research interest. Peroxiredoxin 2 (Prx2), a key antioxidant enzyme and HDAC6 substrate, plays a neuroprotective role against oxidative stress-mediated apoptosis.ObjectiveThis study systematically investigates the neuroprotective mechanism of the HDAC6-Prx2 axis in both cellular and transgenic AD models.MethodsAn AD model was established by bilateral hippocampal microinjection of Aβ_1-42 oligomers in mice. The assessments of mice or their brain samples were included behavioral tests, immunofluorescence, western blot, NADP+/NADPH ratio, and oxidative stress assays. HDAC6-mediated acetylation of Prx2 was confirmed via co-immunoprecipitation, and the specific site was identified.ResultsThe disruption of the HDAC6-Prx2 interaction can significantly alleviate the apoptosis of hippocampal neurons in AD mice and salvage learning/memory deficits. Inhibiting HDAC6 can increase the acetylation level of Prx2 K196, thereby enhancing its antioxidant activity. Acetylated Prx2 inhibits the excessive production of reactive oxygen species (ROS), which is mechanically linked to HDAC6-dependent neuronal apoptosis This pathway mechanistically links HDAC6 activity to oxidative stress-induced apoptosis. HDAC6-mediated deacetylation of Prx2 K196 was shown to exacerbate oxidative damage and cognitive decline.ConclusionsThe study identifies a novel pathway where HDAC6 inhibition elevates Prx2 K196 acetylation, breaking the vicious cycle of ROS and apoptosis. Dual targeting of HDAC6 activity and Prx2 acetylation status represents a promising therapeutic strategy for AD.

BackgroundAccumulating evidence indicates that helicobacter pylori (HP) is related to Alzheimer's disease (AD).ObjectiveTo investigate the roles of HP on the pathogenesis of AD involving gut-brain axis dysfunction and blood-brain barrier (BBB) disruption.MethodsTotal 62 AD patients were categorized into AD with HP (AD-HP) and AD with no (AD-nHP) groups. Demographic and cognitive data were collected, and HP infection was confirmed by ¹³C-urea breath test. The levels of BBB variables, neuroinflammatory factors, and AD biomarkers in cerebrospinal fluid (CSF) were measured using enzyme-linked immunosorbent assay. Gut microbiota and metabolites were profiled by 16S ribosomal ribonucleic acid gene sequencing and gas chromatography-mass spectrometry. Correlations and linear regression among above variables were analyzed.ResultsAD-HP group exhibited impaired overall cognition and cognitive domains of immediate and short-term memory and language, and elevated CSF levels of matrix metallopeptidase (MMP) 9, vascular endothelial growth factor (VEGF), interferon-γ, and phosphorylated tau (P-tau) 181. Overall cognitive score was positively correlated with amyloid-β₄₂ and negatively with P-tau181 levels in CSF. Positive correlations were observed between P-tau181 and soluble triggering receptor expressed on myeloid cells 2, between P-tau231 and chitinase-3-like protein, and between P-tau231 and BBB variables (receptor for advanced glycation endproducts, MMP9, zsonula occludens-1, and claudin-5). In AD-HP group, there was a unique dysbiosis pattern of gut microbiota and metabolites, and HP was particularly associated with the reduced gut 23-nordeoxycholic acid methyl ester and elevated CSF VEGF level (all p < 0.05).ConclusionsHP infection exacerbates gut dysbiosis, promotes BBB disruption, intensifies neuroinflammation, accelerates AD pathology, and aggravates cognitive decline.

For years, the understanding of Alzheimer's disease (AD) has been shaped by the amyloid hypothesis, which suggests that pathological markers like amyloid-β (Aβ) and phosphorylated tau are the primary drivers of the disease. This hypothesis has guided the development of major treatment strategies, including monoclonal antibodies targeting Aβ. However, most of these treatments have failed to produce clinically significant results, highlighting the urgent need for a new therapeutic approach. It is now evident that AD is a complex, multifactorial disease that develops over decades, ultimately leading to Aβ and tau accumulation. Therefore, addressing the underlying causes of these depositions is crucial. One well-supported yet underrecognized theory is the infection hypothesis, which links infections to AD pathology. Despite substantial scientific evidence, this perspective has faced significant resistance. In this review, we describe how chronic infections contribute to AD by triggering neuroinflammation and Aβ accumulation. We also explore the barriers to accepting the infection hypothesis and the steps necessary for its integration into drug development and early-stage treatment strategies. Persisting with an amyloid-centric approach will only exacerbate the societal burden. Embracing the infection hypothesis could transform AD research, diagnosis, and treatment, bringing new hope to millions.

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.

BackgroundSedentary behavior is common in older adulthood and is associated with poor health outcomes. Less is known about how sedentary behavior relates to cognition in older adulthood and how it relates to increased risk for cognitive decline associated with Alzheimer's disease (AD).ObjectiveWe sought to examine these associations in a large, population-based cohort of community-dwelling older adults residing in a Rust Belt region of the United States.MethodsA subset of the population-based Monongahela-Youghiogheny Healthy Aging Team (MYHAT) participants (n = 193) completed 7 days of wrist-accelerometry following comprehensive neuropsychological assessment. Cross-sectional linear regression models related sedentary time to domains of cognition. Models were adjusted by age, sex, education, and APOE4 carrier status and moderate to vigorous physical activity (MVPA). The interaction between sedentary behavior and APOE4 genotype on cognition was also examined.ResultsGreater sedentary behavior was associated with worse executive function (β = -0.06, p = 0.01) and memory (β = -0.06, p = 0.05) performance. These results were attenuated when adjusting for MVPA. No significant interactions between sedentary time and APOE4 carrier status were observed, although estimation results applying the delta method on regression coefficients suggested the associations were stronger in APOE4 non-carriers when compared to APOE4 carriers.ConclusionsHigher levels of sedentary behavior were associated with worse performance in cognitive domains implicated in AD. Public health initiatives and precision-based medicine approaches to reduce sedentary behavior in a population-based cohort of older adults may be important AD prevention measures. Results support the importance of reducing sedentary time.

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.