Alzheimer's & Dementia最新文献

INTRODUCTION

Sleep–wake disturbances frequently occur at early stages of Alzheimer's disease (AD) and accelerate disease progression, but the underlying neural mechanisms are not fully understood.

METHODS

We examined sleep–wake behavior and locus coeruleus (LC) activity in young 5xFAD mice using electrophysiology and pharmacological approaches targeting adrenergic signaling and potassium channels.

RESULTS

5xFAD mice displayed dark phase–specific hyperarousal and impaired brain state transitions by 2 months of age. LC neurons exhibited increased tonic firing due to impaired Kv4 and Kv7 potassium channel conductance, resulting from soluble amyloid beta (Aβ)-induced disruption of α2A adrenergic receptor regulation. Pharmacological activation of α2A adrenergic receptors restored Kv4/7 function and normalized LC excitability. Local administration of guanfacine (α2A agonist) or retigabine (Kv7 modulator) significantly rescued sleep–wake disturbances.

DISCUSSION

These findings identify LC hyperexcitability as a mechanistic driver of early sleep disruption in AD and implicate α2A receptors and Kv7 channels as promising therapeutic targets for early intervention.

The development of non-pharmacological treatment approaches is supported by evidence that addressing key modifiable risk factors may prevent or delay up to 45% of dementia cases. The Charlie and Harriet Shaffer Cognitive Empowerment Program (CEP) was developed to address current gaps in access to, and evidence for, interventions that reduce lifestyle risk factors and improve quality of life in individuals with mild cognitive impairment (MCI). Co-designed with patients and families, clinicians, researchers, and industry professionals, the CEP is situated in a conceptual framework that guides assessments and interventions/supports to holistically address the experience of living with MCI. CEP comprises four cores (Therapeutic Programs, Technology, Built Environment, and Innovation Accelerator) that map to the conceptual framework. We contend that our approach provides an opportunity to contribute to the evidence base for multidomain lifestyle programs and gain a deeper understanding of MCI and how individuals can be empowered to manage it.

Highlights

INTRODUCTION

Alzheimer's disease (AD) study participants may present with cognitive impairment who do not have brain amyloid deposits (Aβ−). Identifying predictive biomarkers for non-amyloid-related CI may provide better screening tests for trials seeking only CI Aβ+ participants and new therapy targets.

METHODS

Analysis of the Bio-Hermes biomarker database identified subpopulations of clinically normal, CN Aβ− (n = 313), CI Aβ− (n = 296), and CI Aβ+ (n = 258), and CN Aβ+ (n = 84) participants. Comparative analysis of demographics, clinical assessments, biomarkers, cytokines, and proteomics results was conducted.

RESULTS

Subgroup comparison of CI Aβ− versus CN Aβ− found that neurofilament light most clearly differentiated CI Aβ− from CN Aβ− participants. No other biomarker analysis reached a level of differential significance.

DISCUSSION

Analyses showed many novel biomarkers do not differentiate CI Aβ− from CN Aβ−. New biomarkers are needed to best determine the neuropathology of the clinical presentation of AD.

Highlights

INTRODUCTION

The vascular endothelial growth factor (VEGF) signaling family plays a role in neurodegenerative diseases, including Alzheimer's disease (AD). Previous work has shown widespread effects of the members FLT1, FLT4, and VEGFB on AD outcomes. However, these analyses have focused within the non-Hispanic White (NHW) population.

NETHODS

The goal of this study was to analyze the effects of the VEGF family in underrepresented populations, leveraging large and diverse bulk RNA sequencing and tandem mass tag–mass spectrometry (TMT-MS) proteomic data. Outcomes included measures of AD pathology and diagnosis.

RESULTS

Within underrepresented populations, we replicated previously reported effects of FLT1 and FLT4, whereby higher protein abundance was observed in the AD brain and was associated with higher neuropathology burden. In stratified analyses, these associations were largely consistent across race and ethnicity.

DISCUSSION

This multi-omic study on the role of the VEGF family in AD emphasizes the need for more representative studies focused on therapeutic targets for AD.

Highlights

INTRODUCTION

This studyexamined the independent contribution of chronic traumatic encephalopathy (CTE) neuropathology to symptoms.

METHODS

The sample included 614 brain donors with (n = 366) and without (n = 248) autopsy-confirmed CTE. Brain donors with other major neurodegenerative disease diagnoses were excluded. Informants completed cognitive and neuropsychiatric measures. Dementia was determined during diagnostic consensus conferences.

RESULTS

CTE stage IV (of IV) was associated with 4.48 (95% confidence interval [CI] = 1.97–10.90) increased odds of having dementia. CTE stage III had an odds ratio of 2.12 (95% CI = 1.91–3.77). Higher CTE stage was associated with greater informant-reported cognitive symptoms (p < 0.01). There were no associations with mood/behavioral scales.

DISCUSSION

CTE stage III/IV neuropathology was associated with dementia and cognitive symptoms: those with stage IV were 4.5 times more likely to have dementia than those without CTE. It is uncertain if low-stage CTE clinically manifests, and mood/behavioral symptoms likely have multifactorial causes and/or a fluctuating course.

Highlights