Journal of Alzheimer's Disease最新文献

BackgroundBenzo[a]pyrene (BaP), a common environmental neurotoxicant, has been linked to neurodegenerative diseases, yet its role in Alzheimer's disease (AD) remains unclear.ObjectiveThis study integrated network toxicology, machine learning, single-cell transcriptomics, and bibliometric analysis to explore BaP's mechanistic role in AD.MethodsA total of 253 BaP-AD common targets were identified and analyzed via GO/KEGG enrichment and PPI network construction. Key genes were screened using GEO-based AD differential expression data and machine learning (LASSO and SVM). Molecular docking assessed BaP-target interactions. Cell-type-specific expression was analyzed using single-cell RNA-seq (GSE157827). ROC curves evaluated diagnostic value, and bibliometrics explored research trends.ResultsTargets were enriched in oxidative stress and MAPK/PI3K-Akt pathways. EGFR and HSP90AB1 were identified as core targets, with strong BaP binding affinities (-8.4 and -11.7 kcal/mol, respectively). EGFR was highly expressed in astrocytes and OPCs; HSP90AB1 in astrocytes and neurons. EGFR had better diagnostic performance (AUC = 0.781). Bibliometric analysis showed increasing attention on EGFR's role in AD.ConclusionsBaP may promote AD by targeting EGFR and HSP90AB1, affecting inflammation, proteostasis, and survival pathways. Notably, EGFR may serve emerge a promising biomarker for early diagnosis and therapeutic intervention in AD. This study revealed the underlying molecular mechanisms linking environmental toxicants to AD pathogenesis.

BackgroundSubjective cognitive complaints (SCC) have been identified as potentially prodromal to dementia and Alzheimer's disease but research in Latin American populations is lacking.ObjectiveTo analyze sociodemographic and clinical factors associated with incidence of SCC and cognitive decline in Chile.MethodsA prospective population-based study in a central-south county of Chile: the MAUCO cohort. We included adults (38-74 years) with a SCC questionnaire and Mini-Mental State Examination (MMSE) test at baseline and follow-up, and normal baseline cognitive assessments. Multivariate Cox regression was used to assess associations between sociodemographic, clinical factors and incidence of SCC and cognitive decline.Results2136 participants had cognitive assessments at baseline and follow-up. Average age was 56 years (SD 9.13), 76% female, 25% had <6 years of education. Mean follow-up was 5.0 (SD 0.64) years. Among 1504 participants without baseline SCC, 254 (16.8%) reported SCC at follow-up. Older age (HR 1.02; 95% CI 1.01-1.03), use of benzodiazepines (HR 2.14; 95% CI 1.27-3.61), antidepressants (HR 1.88; 95% CI 1.07-3.30) or depressive symptoms (HR 1.60; 95% CI 1.19-2.15) were associated to SCC incidence. Of 1646 with a normal baseline MMSE, 208 (12.6%) developed cognitive decline. The number of medications (HR 1.11; 95% CI 1.03-1.20), and baseline SCC (HR 1.40; 95% CI 1.05-1.88) were associated with cognitive decline.ConclusionsUse of benzodiazepines and antidepressants were the main factors associated with SCC, while SCC and MMSE score were the strongest predictors of cognitive decline. Both should be used to target preventive interventions.

Hearing loss is a risk factor for dementia, but dementia subtypes underlying this association and effect modifiers are unknown. Using data collected from 2000 Framingham Heart Study participants we found that hearing loss increases risk for Alzheimer's disease and vascular dementia in participants aged 60-70 years ("young-old") at time of hearing assessment (Alzheimer's disease: HR 1.46[CI 1.07-2.0] p = 0.017; vascular dementia: HR 2.08[CI 1.22-3.56] p = 0.007). Longer duration of hearing loss determines increased risk for Alzheimer's disease and vascular dementia, and screening and intervention for hearing loss from mid-life may help reduce dementia.

BackgroundAdverse childhood experiences have a lasting negative effect on both mental and physical health and likely increase the risk of dementia.ObjectiveOur study aims to investigate the association between adverse childhood experiences (ACEs) and dementia in Chinese older adults, and to explore whether sociodemographic variables and health status influence this association.MethodsThis study utilized data from the China Health and Retirement Longitudinal Study (CHARLS) and included 5092 participants. Logistic regression models were employed to evaluate the association between ACEs and dementia. Stratified and interaction analyses were conducted to examine the influence of demographic and lifestyle characteristics on this association. Two sensitivity analyses were further performed.ResultsCompared to individuals without ACE exposure, those who experienced three (OR: 1.292, 95% CI: 1.025-1.627) or four or more ACEs (OR: 1.363, 95% CI: 1.070-1.737) had a significantly higher risk of dementia, demonstrating a clear dose-response relationship. Subgroup analyses revealed that ACEs were significantly associated with dementia among adults aged 60-79 years, females, rural residents, highly educated, married, and reported lifetime history of drinking, no lifetime history of smoking, or short sleep duration. No significant interaction was observed between subgroup variables and ACEs in the interaction analysis.ConclusionsOur findings demonstrated that Chinese older adults experiencing ACEs were at higher risk of developing dementia compared to those without. Preventing and mitigating ACEs will enhance neurocognitive health and promote successful aging.

BackgroundAgitation in Alzheimer's disease significantly impacts patient outcomes and caregiver burden. Brexpiprazole has emerged as a promising treatment option, but optimal dosing remains unclear.ObjectiveTo evaluate the comparative efficacy and safety of different brexpiprazole doses in treating agitation associated with Alzheimer's disease through a systematic review and network meta-analysis (NMA).MethodsFollowing PRISMA guidelines, we searched PubMed, Embase, Web of Science, and Scopus through January 2025. Four randomized controlled trials (N = 1451) comparing various brexpiprazole doses (0.5-3 mg/day) with placebo were included. Primary outcomes included changes in the Cohen-Mansfield Agitation Inventory (CMAI), the Clinical Global Impression-Severity Scale (CGI-S), and the Neuropsychiatric Inventory-Nursing Home Version (NPI-NH) scores, alongside safety measures.ResultsBrexpiprazole 2 mg demonstrated significant improvement in CMAI scores versus placebo (mean difference [MD]: -5.88; 95% CI: -8.13 to -3.63) and CGI-S scores (MD: -0.48; 95% CI: -0.95 to -0.01). Multiple doses showed significant NPI-NH improvements, with 2-3 mg showing the strongest effect (MD: -4.60; 95% CI: -7.54 to -1.66). Higher doses (2-3 mg) increased treatment-emergent adverse events (risk ratio [RR]: 1.20-1.33) but showed no significant difference in serious adverse events compared to placebo.ConclusionsBrexpiprazole 2 mg provides optimal therapeutic benefit while maintaining a favorable safety profile. The findings support initiating treatment at lower doses with careful titration to 2 mg based on individual response and tolerability. Future research should focus on long-term outcomes and real-world effectiveness.

BackgroundTwo epidemiological studies demonstrated an association between essential tremor (ET) and prevalent dementia as well as substantially elevated risks of incident dementia among ET cases. At this early point, the underlying pathophysiology of ET-dementia is not known. In vivo biomarkers of Alzheimer's disease (AD) and neurodegeneration could help bridge the gap between the pathophysiological processes that present in the context of ET-dementia.ObjectiveExamine blood concentrations of t-tau, p-tau181, p-tau217, Aβ_42/40, neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) in ET with a range of cognitive diagnoses.Methods40 ET cases (mean age = 81.5 ± 7.3; including 20 normal cognition (NC), 12 cognitively normal with some weaknesses, 4 mild cognitive impairment, and 4 dementia) were enrolled in a study of cognitive performance in ET, during which phlebotomy was performed.ResultsGreater cognitive difficulty was associated with higher blood concentrations of p-tau217, p-tau181, GFAP, and NfL, and a lower Aβ_42/40 ratio (p tests for trend < 0.05). Cases with dementia had marginally higher concentrations of p-tau217 (p = 0.06) and higher concentrations of GFAP and NfL (p < 0.05) than cases with NC. Furthermore, higher concentrations of p-tau217, GFAP, and NfL were associated with lower cognitive test scores across multiple cognitive domains (p < 0.05).ConclusionsAlbeit based on a small sample of cases, our findings suggest a potential role of blood-based biomarkers as markers for cognitive function in ET patients. Cognitive decline in ET may be due to underlying neurodegenerative processes involving tau and perhaps Aβ pathology.

BackgroundAmyloid-related imaging abnormalities (ARIA) are a recognized complication of anti-amyloid monoclonal antibodies for Alzheimer's disease (AD). While typically asymptomatic, a subset of patients develops severe clinical symptoms and radiological findings requiring intensive management. Data on their presentation, treatment, and outcomes remain limited.ObjectiveWe report two cases and analyze the clinical features of all published cases of severe symptomatic ARIA, with a focus on associated risk factors, therapeutic approaches, and patient outcomes.MethodsWe report two cases of severe symptomatic ARIA in patients treated with gantenerumab. A systematic review was conducted following PRISMA guidelines using MEDLINE, Web of Science, and manual reference screening. We included case reports and series providing individual-level data on symptomatic ARIA episodes classified as severe by clinical criteria. Demographic, genetic, clinical, radiological, therapeutic, and outcome data were extracted.ResultsThirty-six cases were included (2 new and 34 from 21 publications). Fifteen cases were associated with lecanemab, 10 with gantenerumab, 6 with donanemab, and 5 with other antibodies. APOE ε4 was present in 62.5%, including 10 ε4/ε4 homozygotes. Baseline MRI showed hemorrhagic markers in 10 cases, including superficial siderosis in 2 of the 5 patients with isolated macrohemorrhages. Most episodes occurred within 6 months of treatment. Symptoms included altered consciousness (75%), focal deficits (66.7%), seizures (38.9%), and headache (36.1%). ARIA-E resolved in all non-fatal cases. Corticosteroids were used in 72%. Among the patients whose outcome data were available, 15 patients recovered completely, 10 had persistent deficits, and 10 died.ConclusionsSevere symptomatic ARIA is a rare but serious adverse effect of anti-amyloid therapy. Standardized diagnostic and therapeutic guidelines are needed to minimize ARIA-related morbidity and mortality.PROSPERO registration no. CRD420251055067.

BackgroundEarly diagnosis of Lewy body dementia (LBD) is challenging, largely due to clinical heterogeneity and features overlapping with Alzheimer's disease (AD). Clinical differentiation is particularly challenging in females, who are more likely to have a mis- and delayed diagnosis than males with LBD.ObjectiveTo investigate whether there are sex differences in the prodromal symptoms and rate of change preceding dementia in people with Lewy body (LB) and pure AD pathologies.MethodsWe used data from National Alzheimer's Coordinating Center for people with dementia and LB (n = 196; 89 females, 107 males; including mostly people with AD co-pathology) or pure AD pathology (n = 308, 167 females, 141 males, without LB co-pathology). Prevalence of cognitive, behavioral, and parkinsonism symptoms were assessed annually starting with two-years prior to dementia. Changes over time for prevalences were compared between pathology groups and sexes.ResultsCognitive fluctuation prevalence was higher for males with LB than other groups. Compared to males with LB, females with LB had faster increase in judgment, language, visuospatial deficit prevalence and dementia severity. Relative to females with AD, affective symptom prevalence increased slower for females with LB. Relative to males with AD, males with LB had higher prevalence of parkinsonism and attention deficit, with slower increase in attention deficit prevalence.ConclusionsCognition can decline faster for females than males during prodromal LBD. Presence of parkinsonism and cognitive fluctuation can help differentiate LB from AD pathology for males. Such prominent differences may not occur for females, suggesting the need for sex-specific diagnostic approaches.

BackgroundAlzheimer's disease (AD) and cognitive decline are major global health challenges. The impact of dietary nutrient density, particularly in the context of ultra-processed, fortified foods, on cognitive function remains uncertain.ObjectiveTo examine associations between dietary nutrient density patterns and cognitive performance in U.S. older adults and to evaluate effect modification by key subgroups.MethodsWe analyzed data from 2991 adults aged ≥60 years in NHANES 2011-2014. Nutrient density patterns were derived by latent class analysis of 24-h dietary recalls. Cognitive function was assessed with the CERAD Word Learning, Animal Fluency, and Digit Symbol Substitution Tests. Multivariable linear regression estimated associations between nutrient density patterns and cognitive scores, adjusting for sociodemographic, lifestyle, and clinical factors; stratified analyses assessed effect modification.ResultsFour distinct nutrient density patterns were identified. A High-Nutrient, Ultra-Processed pattern, characterized by high intake of processed foods and relatively lower plant-based nutrients, was associated with poorer cognitive performance, particularly on memory tasks (β = -0.43, p = 0.018), and these associations persisted after full adjustment. Associations were stronger among participants with hypertension or diabetes.ConclusionsDietary nutrient density patterns are independently associated with cognitive function in older adults, with ultra-processed, fortified dietary profiles linked to worse performance, especially in those with cardiometabolic conditions. Targeted dietary strategies that emphasize nutrient-dense, minimally processed foods may help preserve cognitive health in vulnerable subgroups.

BackgroundMotoric cognitive risk (MCR) syndrome is characterized by subjective cognitive complaints and slow gait and confers a higher risk of dementia. Cerebral small vessel disease (CSVD) is associated with poor cognitive, functional, and survival outcomes in aging. Markers of CSVD seen on magnetic resonance imaging (MRI) include white matter hyperintensities (WMHs) and lacunes.ObjectiveTo examine associations between imaging markers of CSVD and the MCR syndrome.MethodsCross-sectional data from 4 cohorts in 4 countries were examined. WMHs and lacunes were quantified from brain MRIs manually, using a standardized grading scale. Regression models examined the associations between WMH and lacunes and MCR, gait speed, slow gait, and cognitive complaints. We also compared the prevalence of the outcomes of interest between participants with "confluent or diffuse" or "no or mild" WMH. Statistical models were adjusted for age, sex, study site, and vascular risk factors.ResultsData from 1772 participants (M Age = 71.1 years, 49.9% female) was analyzed. Higher global WMH scores were associated with MCR (aOR = 1.07, p = 0.015). Frontal and basal ganglia WMH scores were associated with MCR (aOR = 1.23, p = 0.007, aOR = 1.31, p = 0.023, respectively). Participants with "confluent-diffuse" WMH had significantly higher prevalence of MCR (30.2% versus 19.2%, p = 0.003). Basal ganglia lacunes were associated with MCR (aOR = 1.57, p = 0.018).ConclusionsIn this multi-cohort study of older adults without cognitive impairment, we show that WMH and lacunes independently predict increased risk of MCR, after adjusting for key confounders. Our findings, based on a large multi-ethnic cohort, reveal region-specific CSVD patterns linked to MCR and related outcomes.