Alzheimer's & Dementia最新文献

BACKGROUND

Obstructive sleep apnea (OSA) is associated with Alzheimer's disease (AD) risk. Racial-, ethnic-, and sex-specific mechanisms of OSA and AD risk were examined.

METHODS

We analyzed data from 3978 polysomnography patients without cognitive decline aged ≥ 60 including 663 OSA+ patients (284 non-Hispanic White, 207 Black, 172 Hispanic) matched to OSA– cohorts (1:1, n = 663; 1:4, n = 2652) and followed for AD through 2013.

RESULTS

During the 8.5 (standard deviation 1.4) year period, 358 patients developed AD. AD risk was higher for Black (adjusted hazard ratio [aHR] 2.24 [1.24–2.71]), Hispanic (aHR 1.73, [1.38–3.51]), White (aHR 1.83, [1.21–3.37]), male (aHR 2.38, [1.31–3.47]), and female (aHR 1.37, [1.14–2.41]) patients. Hypoxia, sleep fragmentation, and sleep duration (p < 0.01) were associated with increased risk. Black and Hispanic, and female patients showed stronger effects for hypoxia and duration, and fragmentation, respectively.

DISCUSSION

Hypoxia, fragmentation, and duration may underlie racial-, ethnic-, and sex-specific effects of AD risk.

INTRODUCTION

Reversion to normal cognition in mild cognitive impairment (MCI) is relatively common. This study tested whether total sleep time (TST) and sleep efficiency (SE) on the night before cognitive testing predicts MCI reversion.

METHODS

Fifty-eight community-dwelling older adults with MCI (mean age = 75 years) participated. MCI was defined as cognitive performance ≥ 1.5 standard deviation below norms in at least one domain, with preserved daily functioning. Participants completed cognitive testing at baseline and 1-year follow-up, and sleep was objectively measured using actigraphy at baseline. Logistic regression assessed whether prior-night TST and SE predicts reversion, adjusting for age and sex.

RESULTS

Sixteen participants (27.6%) reverted. Shorter prior-night TST was associated with higher odds of reversion, whereas SE showed no significant association. Random night or chronic sleep measures showed no associations.

DISCUSSION

Acute sleep disruption may transiently impair cognition and contribute to MCI misclassification. Sleep screening before testing may improve diagnostic reliability.

Highlights

INTRODUCTION

We examined how neurovascular and astrocytic response alter cognition in Alzheimer's disease (AD).

METHODS

Cognitive scores, biomarkers of AD and astrocytic activation, vascular factors, and brain structure data from 693 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants were analyzed using analysis of covariance (ANCOVA), multiple linear and cox regression, mediation and mixed models.

RESULTS

Cerebrospinal fluid (CSF) vascular endothelial growth factor (VEGF)-C levels varied significantly across cognitive stages (normal cognition [CN], mild cognitive impairment [MCI], and AD). Vascular factors showed stage-specific patterns with amyloid beta (Aβ) and tau pathology. Higher CSF VEGF-C and angiotensin-converting enzyme (ACE) correlated with better cognition and milder brain atrophy. CSF ACE was also associated with slower decline and lower AD risk. The effect of Aβ pathology on cognition was mitigated by CSF VEGF-C, whereas tau pathology and neurodegeneration were mitigated by CSF ACE. Independently, these CSF factors mediated the association between CSF glial fibrillary acidic protein (GFAP) and cognition. Astrocytic biomarkers mediated AD pathology–vascular links.

DISCUSSION

Dynamic astrocyte–vascular interplay in AD pathology could influence cognition, considered as a potential therapeutic target.

INTRODUCTION

Understanding neuroinflammation across the Alzheimer's disease (AD) spectrum is essential to elucidate disease mechanisms and individualize therapy.

METHODS

Human microglial translocator protein (TSPO) expression under inflammatory stimuli was assessed by immunoblot experiments. Ninety-six participants were enrolled across four groups: cognitively unimpaired amyloid (CU A) + and −, mild cognitive impaired (MCI) A+, and Alzheimer's disease dementia (ADD) A+. Neuroinflammation using ¹¹C-ER176 TSPO positron emission tomography (PET) was compared to amyloid and tau PET. Correlations between neuroinflammation, amyloid, and tau pathology were examined across disease stages.

RESULTS

TSPO was upregulated in human microglia under AD-like inflammatory conditions. Neuroinflammation, defined by PET TSPO, increased in CU A+ participants and became more widespread with increasing disease severity, aligning with worsening amyloid and tau pathology. Associations with tau were particularly extensive in temporal and parietal regions.

DISCUSSION

These findings suggest probable amyloid association with early microglial activation, while tau pathology is closely tied to wider distribution of neuroinflammation.

Highlights

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.