Alzheimer's Research & Therapy最新文献

Background: Socio-cognitive assessment in neurocognitive disorders (NCDs) is rare in clinical practice and no consensus exists as to a uniform operationalization of socio-cognitive measures for NCDs in memory clinics. The SIGNATURE initiative aims to optimize the use of socio-cognitive measures in memory clinics, defining expert recommendations. We report consortium guidelines for the use of socio-cognitive measures in NCDs based on available evidence from the literature and the current state of practices in memory clinics.

Methods: Using a Delphi consensus method supported by a literature review and the results of an international survey, 22 specialists defined recommendations for the context of use, relevance in NCD diagnosis, priorities for future research and facilitators/obstacles of socio-cognitive assessment in major and mild NCDs.

Results: Overall, panelists recommended social cognition testing in routine diagnostic assessment to evaluate both socio-cognitive and socio-behavioral alterations. A set of clinical, methodological, implementation and external factors facilitating or hampering the use of socio-cognitive tasks was identified.

Conclusions: This is the first focused endeavor to favor the implementation of socio-cognitive assessment, which is required by DSM-5 but seldom performed despite clear evidence of its clinical relevance for diagnosis and care. Our results provide an initial set of recommendations, refinable through the future actions of the SIGNATURE initiative. Future collaborative clinical research projects should overcome current limitations and foster the use of ecological and cross-culturally validated measures in clinics.

Background: The development of effective disease-modifying therapies for Alzheimer's disease (AD) remains a critical unmet need. While Mendelian randomization (MR) has been leveraged to identify genetic variants to accelerate AD target discovery, previous studies have been limited by narrow phenotypic coverage, insufficient multiomics validation, and inadequate mechanistic exploration. This study aims to overcome these limitations via comprehensive MR to identify robust therapeutic targets.

Methods: We performed an integrative multiomics MR analysis leveraging over 50 genome-wide association study (GWAS) datasets spanning AD, cerebrospinal fluid (CSF) biomarkers (Aβ42, p-tau), neuroimaging endophenotypes, cognitive traits, and risk factors. Blood/CSF/brain protein quantitative trait loci (pQTLs) from large-scale proteomics studies were analyzed to identify druggable targets. A rigorous validation cascade was subsequently performed: Bayesian colocalization was performed to assess whether the same variants are associated with the protein and other traits; summary-data-based MR was performed to distinguish pleiotropy from linkage; mediation analysis was performed to quantify biomarker-driven causal pathways; integrated analysis of multiomics (single-cell RNA-seq and proteome) data was performed to resolve cellular specificity, and (PPI) interaction networks were generated; phenome-wide MR (Phe-MR) was performed across 679 traits to evaluate on-target side effects; and structure-based druggability screening was conducted.

Results: Proteome-wide MR analysis revealed 15 potential drug targets for AD; six of these targets (PILRA, GRN, ACE, TIMD3, TREM2) were validated as Tier 1 (highest-confidence targets with external validation and causal consistency). Mediation analysis revealed that IDUA reduced the risk of AD through Aβ42 and p-tau in the CSF, whereas Siglec-7/9 increased the risk of AD through p-tau in the CSF. Additional targets revealed associations with AD biomarkers, neuroimaging, and cognitive function. Single-cell analysis highlighted the enrichment of key microglial and astrocyte targets. PPI network analysis revealed interaction pathways between seven drug targets and four AD therapeutics, and druggability assessment revealed seven potential therapeutics.

Conclusions: This study established a comprehensive AD target atlas, revealing mechanism-anchored targets that were validated across multiomics analyses and a clinically actionable framework integrating efficacy, biology, and safety profiling. Overall, these results advance AD drug discovery by revealing prioritized targets with causal biological support and providing a validated development roadmap.

Introduction: Sleep and circadian rhythm disturbances have been related to cognitive decline and increased risk of Alzheimer's disease (AD). These disruptions are also closely associated with biological ageing processes. Telomere shortening, a key marker of cellular ageing, has been implicated in various age-related diseases, including AD. Although sleep disturbances have been linked to shorter telomere length (TL), the effects of sleep, its variability, and circadian rhythms on telomere dynamics (over 18 months) remain unknown. Furthermore, the interplay between these factors and AD risk has yet to be investigated in healthy older adults. Therefore, the objective of this study was to explore how sleep, sleep variability, and circadian rhythms affect telomere dynamics in healthy older adults and the influence of AD risk on these relationships.

Methods: Data from 124 healthy older adults (mean age ± SD: 69.27 ± 3.73y) from the Age-Well interventional trial (NCT02977819) were analyzed. Blood samples were collected to determine three TL metrics (50th and 20th percentile TL, and percentage of critically short telomeres (%CST) at baseline and after 18-month follow-up). Sleep and its variability were assessed using the Somno-Art^® device over 5 nights (n = 77), and circadian rhythms using actigraphy for 1 week (n = 123). Multiple linear regressions examined whether baseline sleep and circadian rhythm measures predicted TL changes over time. Interaction analyses assessed the modulatory effects of amyloid (Aβ) status, assessed using Forbetapir-PET imaging, and APOE4 status on these relationships. Age, sex, education, BMI, and intervention group were included as covariates.

Results: Poor sleep quality (characterized by lower sleep efficiency and higher wake after sleep onset) and greater variability in sleep efficiency predicted an increase in %CST. Greater regularity in sleep/wake patterns was associated with a decrease in 50th and 20th percentile TL and an increase in %CST. In Aβ-positive individuals, longer latency of rapid eye movement sleep predicted a reduction in 20th percentile TL and an increase in %CST.

Conclusions: This study suggests that poor sleep quality, sleep variability and circadian rhythm disturbances may accelerate cellular ageing through telomere shortening in older adults. Our results highlight the potential value of sleep interventions in mitigating biological ageing and reducing vulnerability to age-related diseases.

Background: Current antidementia drugs can temporarily slow cognitive decline in Alzheimer's disease but are underused. Regional and socioeconomic disparities, including limited specialist access in rural or deprived areas, may exacerbate inequities and challenge the rollout of emerging disease-modifying therapies. This study aimed to evaluate associations between regional contextual factors and antidementia drug prescription (AD-Rx) among newly diagnosed people living with Alzheimer's disease (PlwAD) in Germany and to identify spatial clustering of prescribing patterns.

Methods: This study analyzed anonymized claims data from three statutory health insurers for 53,753 PlwAD who received their first diagnosis between January 2020 and December 2022. Regions, defined by three-digit postal codes (ZIP3, n = 576), were categorized by the German Index of Socioeconomic Deprivation (GISD) quintiles and Degree of Urbanization (urban, suburban, rural). Multilevel logistic regression with random intercepts for ZIP3 was used to assess associations between receiving AD-Rx (dichotomous) and urbanization and deprivation, adjusting for age, sex, the Charlson Comorbidity Index, the long-term care level and the year of diagnosis. Global Moran's I was used to evaluate large-scale spatial clustering, and regional Moran's I was calculated to detect regional hotspots and coldspots.

Results: Overall, 64% of PlwAD received at least one AD-Rx. Rural residency was associated with slightly lower odds of receiving AD-Rx compared to urban areas (OR 0.92; 95%CI 0.87-0.98; p = 0.010), whereas deprivation was not. Interaction models demonstrated that an increased deprivation further reduced AD-Rx odds in rural areas (OR per GISD unit = 0.98; 95% CI 0.96-0.99; p = 0.024). Global Moran's I revealed no significant large-scale clustering (I = 0.011; p = 0.613), but regional analysis identified several regional hotspots (high-high clusters) predominantly in moderately deprived urban areas and coldspots (low-low clusters) in highly deprived or rural areas.

Conclusion: Alzheimer's patients in rural and high-deprivation regions face limited access to recommended antidementia medications. Targeted interventions, such as teleconsultations, expanding specialist outreach, and collaborative care models in underserved areas, as well as regional dementia networks and national registries, could promote the equitable delivery of current and future Alzheimer's antibody therapies. However, further qualitative and quantitative research is needed to identify the underlying regional causes of these treatment disparities.

Trial registration: DRKS00031944.

Background: We aimed to develop individualized predictions for risk of developing any-cause dementia and Alzheimer's disease (AD) dementia, in individuals with subjective cognitive decline (SCD) or mild cognitive impairment (MCI), using plasma phosphorylated-tau-181 (pTau181), phosphorylated-tau-217 (pTau217; in a subset), amyloid beta1-42/1-40 (Aβ42/40), glial fibrillary acidic protein (GFAP) and/or neurofilament light (NfL).

Methods: From the Amsterdam Dementia Cohort we included 314 individuals with SCD (age 61 ± 9 years, n = 184 (59%) male, MMSE 29 ± 1) and 253 individuals with MCI (age 65 ± 7 years, n = 165 (65%) male, MMSE 27 ± 2), who had annual follow-up (median duration 2.4 years). Cox proportional hazards regression models were used to calculate probabilities for progression to dementia and were externally validated in MEMENTO and AIBL cohorts.

Results: During follow-up 20 SCD and 99 MCI patients developed dementia. For MCI patients who progressed to any form of dementia, plasma GFAP contributed on top of age, sex, and MMSE score in the parsimonious individualized prognostic model (C-index = 0.69 [95%CI = 0.63; 0.76]). With AD-dementia as the outcome, GFAP and pTau181 were selected in the parsimonious model on top of the demographic variables (C-index = 0.71 [95%CI = 0.65; 0.76]). In the subset of 197 MCI individuals with pTau217 measurements, pTau217 was selected in the parsimonious model on top of the demographic variables (C-index = 0.75 [95%CI = 0.69; 0.79]). External validation demonstrated that the models are robust in a memory clinic setting.

Conclusions: Our prediction models have utility for clinical practice to calculate progression probabilities for development of dementia in individual patients living with MCI over a 1-, 3- and 5-year time period.

Background: Primary central nervous system lymphoma (PCNSL) often manifests with cognitive impairment or nonspecific symptoms, which can delay diagnosis and worsen prognosis. However, the mechanisms underlying these neurological manifestations remain poorly understood. Previous studies have shown that polyglutamylation, a posttranslational modification, is associated with better responses to methotrexate-based chemotherapy in patients with PCNSL. Moreover, excessive polyglutamylation in neurons has been implicated in neurodegeneration via phosphorylated tau accumulation. This study aimed to elucidate the relationship between polyglutamylation, phosphorylated tau, and cognitive impairment in PCNSL.

Methods: We retrospectively analyzed 140 patients with histologically confirmed PCNSL treated at our institution between 2001 and 2022. Cognitive status at hospital admission was assessed using the Clinical Dementia Rating (CDR) scale. Immunohistochemical analysis of tumor specimens was performed to quantify the polyglutamylation and phosphorylated tau levels. Furthermore, in vitro studies with PCNSL cell lines were conducted to investigate whether the pharmacological upregulation of polyglutamylation by a histone deacetylase inhibitor promotes tau phosphorylation. Statistical analyses examined associations among polyglutamylation status, cognitive impairment, tau phosphorylation, and clinical outcomes.

Results: High polyglutamylation levels were observed in 59% of tumor samples, and this factor was independently associated with cognitive impairment at diagnosis (odds ratio: 3.83, 95% confidence interval 1.19-12.3, p = 0.024). Immunohistochemical analysis demonstrated that tumors with elevated polyglutamylation showed significantly higher phosphorylated tau levels. In vitro experiments confirmed that increased polyglutamylation levels in PCNSL cells led to enhanced tau phosphorylation in PCNSL cell lines.

Conclusions: High polyglutamylation levels in PCNSL were associated with cognitive impairment and increased tau phosphorylation at diagnosis. These findings suggest that polyglutamylation may contribute to neurocognitive symptoms by promoting tau pathology. Elucidating this mechanism may provide novel insights into PCNSL pathophysiology and may inform future studies on disease mechanisms and potential treatment targets.