Alzheimer's & Dementia最新文献

INTRODUCTION

Proteins interacting with amyloid beta (Aβ) fibrils could be key to plaque formation in Alzheimer's disease (AD) and represent potential biomarkers and therapeutic targets. Previous proteomic studies using microdissected plaques might have captured non-specific components rather than true Aβ interactors.

METHODS

Biotinylated Aβ40 or Aβ42 peptides were induced to form fibrils, with Scrambled peptides as controls, and incubated with protein extracts from AD and control prefrontal cortex tissue. Pull-down assays coupled with label-free proteomics identified fibril interactors. Dysregulation and localization were assessed by Western blot, immunofluorescence, immunocytochemistry, immunohistochemistry, and in silico analyses.

RESULTS

We identified 185 Aβ40- and 874 Aβ42-associated proteins, with 78 shared. Sixteen proteins, including protein kinase C gamma type (PRKCG), displaying altered expression in AD, were validated as actual interactors and plaque components ex vivo. Remarkably, modulation of PRKCG influenced fibril formation.

DISCUSSION

This study expands the Aβ plaque-associated proteome, identifies novel interactors, and highlights PRKCG as a drug-targetable regulator of AD amyloidogenesis.

Highlights

Background

Mild Behavioral Impairment (MBI) involves the late-onset, sustained emergence of neuropsychiatric symptoms (NPS) in predementia populations. Prior studies examining amyloid and tau PET in relation to MBI have shown a link to amyloid burden but not to tau. However, the role of plasma biomarkers in MBI remains uncertain. In this study, we aimed to determine whether MBI is associated with plasma p-tau217 levels in older adults without dementia.

Method

We included 168 older adults (136 cognitively unimpaired [CU] and 32 with mild cognitive impairment [MCI] ) from the TRIAD cohort. Participants had amyloid status assessed by [18F]AZD4694 Aβ-PET. Plasma p-tau217 levels were quantified using the Janssen Simoa Assay. MBI was assessed using the Mild Behavioral Impairment Checklist (MBI-C), global cognition was measured with the Mini-Mental State Examination (MMSE) and the sum of boxes of the Clinical Dementia Rating (CDR-SB). Multivariable linear regression analyses examined associations between plasma p-tau217 and MBI-C total and subdomain scores, adjusting for age, sex, and CDR-SB.

Result

When controlling for age and sex, higher p-tau217 levels were significantly associated with increased MBI-C total (β = 15.97, p = 0.03), emotion dysregulation (β = 5.98, p = 0.017), and impulse dyscontrol (β = 7.92, p = 0.012). However, these associations did not remain significant once CDR-SB was included in the model. Instead, MBI-C total and its subdomains emotion dysregulation, impulse dyscontrol, and motivation were related only to cognitive status.

Conclusion

These findings suggest that p-tau217 could play a role in MBI, particularly in the impulse dyscontrol and emotion dysregulation domains, neuropsychiatric symptoms which have been previously linked to Alzheimer's disease. However, overall cognitive status emerged as the strongest predictor of these behavioral symptoms in older adults. Further research is warranted to clarify how p-tau217 levels and cognitive decline interact to influence the risk and progression of MBI.

INTRODUCTION

The alpha-synuclein seed amplification assay (SAA) has shown excellent performance in the detection of Lewy body pathology in cerebrospinal fluid (CSF). Lewy body pathology is prognostically relevant in patients at risk for dementia. Current assays only provide binary results, so there is a need to quantify the extent of pathology in living patients.

METHODS

In addition to the “standard” SAA, we developed a quantitative SAA (qnSAA) and measured 432 CSF samples (216 baseline–follow-up pairs).

RESULTS

qnSAA results correlated with cognitive performance. Seventy-five percent of participants with fast qnSAA kinetics converted to dementia in the observed interval. Overall, participants with fast qnSAA kinetics accounted for 27.3% of dementia converters in the entire cohort.

DISCUSSION

Findings demonstrate promising properties of qnSAA measurements in a cohort of patients at risk for dementia. qnSAA results showed improved prognostic relevance and have potential to measure target engagement of therapies against Lewy body pathology.

INTRODUCTION

Epigenetic clocks associate with neuropathology and Alzheimer's disease (AD) clinical risk, but findings are mixed regarding whether clocks associate with blood-based biomarkers and in non-European populations.

METHODS

We calculated biological age and age acceleration from blood methylation data in 704 older Hispanic adults and tested associations with clinical diagnosis and antemortem biomarker levels.

RESULTS

Age acceleration was significantly associated with sex, clinical diagnosis, and levels of eight plasma biomarkers, including P-tau217 levels. Additionally, biomarker associations trended more significantly among APOE-ε4 non-carriers. We also identified that methylation levels in CD4 and CD8 T-cell types are associated with age acceleration.

DISCUSSION

We demonstrated that biological age acceleration, measured in blood, in a Hispanic cohort enriched for preclinical individuals, can stratify clinical AD risk and is associated with plasma AD biomarker levels.

Highlights

Background

The Alzheimer's disease (AD) Braak staging is a key framework for classifying tau pathology progression in AD based on histopathological post-mortem brain examinations. However, adapting it to PET imaging can be challenging due to differences in tracer uptake patterns and binding properties, which affect sensitivity, specificity, and regional staging. This study compares Braak staging across four tau PET tracers: Flortaucipir, MK6240, PI2620, and RO948.

Methods

We assessed 90 participants across the AD spectrum (46 CU, 31 MCI, 13 dementia; mean age 66.1 ± 7.8) using Aβ PET and four tau PET tracers: (Flortaucipir, MK6240, PI2620, and RO948). Braak positivity was defined based on Aβ− CU individuals (mean +2.5 SD, SUVR). To evaluate systematic bias and agreement between tracers, we computed pairwise differences at corresponding Braak stage estimates and applied the Bland-Altman method to assess mean bias and limits of agreement. Additionally, Tau PET Braak region trajectories were modeled as functions of Aβ burden (Centiloid scale) using the Lowess method.

Results

Braak stage trajectories as a function of Aβ differ depending on the tracer and the sequential order of abnormality is highly variable. For instance, while for MK6240, RO948 and PI2620, Braak I is the first region to became abnormal, for Flortaucipir the earliest region to became abnormal is Braak IV (Figure 1). This variable pattern of abnormality impacts in the concordance of Braak staging between tracers with the highest Braak staging agreement resulting in concordance levels of approximately 70%. The highest levels of agreement between tracers usually happen at Braak 0 or Braak IV-V, with intermediate stages showing very low concordance (Figure 2). The Bland-Altman analysis identified wide limits of agreement, suggesting high variability and high tracer-specific differences (Figure 3). On the other hand, it also identified that mean differences between tracers were small, indicating minimal systematic bias.

Conclusion

These preliminary findings reveal discrepancies in Braak staging when comparing Flortaucipir, MK6240, PI2620 and RO948. These findings suggest that while the tracers provide comparable stages on average, they may not be fully interchangeable in individual cases.

INTRODUCTION

Relatively low rates of Latino participation in Alzheimer's disease and related dementias (ADRD) research makes it difficult to determine whether identified disease mechanisms, risk factors, or novel treatments generalize to this population.

METHODS

We introduced ADRD research opportunities through a model cognitive screening program in primary care and neurology specialty care clinics in areas with high proportions of Latino residents.

RESULTS

Out of 523 Latino adults (mean age = 72.1 years, mean education = 6.8 years, 62.1% female, 88.1% tested in Spanish), 520 allowed the use of screening data for research, and high percentages agreed to a research registry with contact about ADRD research opportunities (primary care: 91.9%, neurology: 86.6%). Registrants supported 368 referrals to 45 studies (21% successfully recruited). Thirty-one individuals participated in ≥1 study, producing 79 enrollments across 15 ADRD studies.

DISCUSSION

Results demonstrate that combining a needed clinical service with recruitment efforts can enhance participation of older Latino adults in ADRD research.

Alzheimer's disease (AD) is projected to become the highest-burden neurological disorder globally. Mounting evidence implicates the gut microbiome in AD pathogenesis. This scoping review of gut microbiomes in mild cognitive impairment (MCI) and AD included dietary and probiotic interventions. We included original research and systematic reviews/meta-analyses. Animal and non-English studies were excluded. We searched PubMed, Scopus, and Cochrane Library through February 2023. Using Arksey and O'Malley's framework and the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA)-Extension for Scoping Reviews (ScR) checklist, we screened 4751 articles, with 58 meeting predefined inclusion criteria. Our results demonstrated that gut dysbiosis was frequently reported in MCI and AD, including increased Pseudomonadota and Actinomycetota in AD and reduced diversity in some cases. Probiotic and dietary interventions showed promise in modulating cognition and microbiota, inconsistently. Emerging evidence links dysbiosis to cognitive decline; however, methodological heterogeneity and limited follow-up impede causal inference. Research should prioritize standardized protocols, functional microbiome analysis, and longitudinal human studies to clarify therapeutic potential.

Highlights

Background

There has been a recent focus within Alzheimer's Disease (AD) research on potential CSF biomarkers as diagnostic tools. PET imaging and CSF biomarkers have been used to determine the amyloid status of individuals when characterising AD. While these measures have largely correlated with each other, it is also suggested that there could be patients who can have discordant results. However, it is still unclear what proportion of AD subjects demonstrate the discordance. Additionally, whether these changes are associated with different pathological and clinical characteristics of the patients. Here, we investigated the discordance between CSF Aβ42:40 and amyloid status and evaluated whether there are any significant changes in their levels of tau aggregation.

Method

313 participants’ data were selected from the ADNI database. The cutoff for Aβ42:40 was then calculated using the Youden Index resulting from receiver operating characteristic (ROC) curve. The formula used was J = maxc {Se (c) + Sp (c) − 1}, resulting in a maximum cutoff of J = 0.057 for Aβ42:40. This cutoff produced a discordance rate of 10.5%, with n = 33 of 313 patients being discordant. We then performed t-tests to investigate the potential clinical differences between concordant and discordant patients.

Result

Independent samples t-tests indicated that levels of pTau181 and total Tau significantly differed between the concordant and discordant groups. pTau181 was significantly lower in the discordant group (t(71.2)=-3.166, p = .002), as was Tau (t(53.9)=-2.046, p = .046). Further data is found in Figure 1.

Conclusion

Demonstration of different levels of tau deposition in the discordant groups implies there may be other pathological processes influencing neurodegeneration in these subjects. A discordance of 10% between CSF amyloid and PET amyloid implies that we should evaluate these subjects in greater detail before enrolling them in intervention studies.

References

1. Hansson, O. et al. (2019). https://doi.org/10.1186/s13195-019-0485-0

2. Pyun, JM. et al. (2024) https://doi.org/10.1038/s41398-024-02766-6

INTRODUCTION

Data sharing among investigators of Alzheimer's disease and related dementias (ADRD) allows for representative datasets, supports reproducibility, and increases rigor. Yet limited evidence on investigators’ practices and experiences precludes solutions that promote optimal practices.

METHODS

A cross-sectional survey of US-based ADRD investigators with National Institutes of Health awards funded between 2016 and 2019.

RESULTS

Among 585 respondents (response rate of 64.5%), 62.9% were engaged in data sharing in the previous 5 years. Among data requesters, 61.8% reported that all requests were fulfilled within 6 months. Among those who received requests, 85.1% reported fulfilling all requests. Reasons for declining requests included existing data use agreement requirements, Institutional Review Board standards, and resource limitations. Respondents who shared data reported positive consequences (e.g., developing collaborations) more often than negative (e.g., being “scooped”).

DISCUSSION

Data sharing behaviors among ADRD researchers are encouraging. Nevertheless, addressing remaining barriers could help avoid the negative consequences of data requests not being fulfilled.

Highlights