Alzheimer's & Dementia最新文献

INTRODUCTION

This study longitudinally examined 154 magnetic resonance imaging (MRI) biomarkers in cognitively normal (CN) individuals to identify structural brain changes most strongly associated with subsequent cognitive impairment (SI).

METHODS

We analyzed 509 Baltimore Longitudinal Study of Aging participants (age ≥ 50, CN at baseline) with longitudinal cognitive and 3T MRI (T1/T2-weighted scans and diffusion tensor imaging) data. MRI biomarker associations with SI status were analyzed, adjusting for confounders and stratifying by sex and amyloid beta (Aβ) status.

RESULTS

Participants who developed SI over 4.6 years’ follow-up showed greater longitudinal changes in white matter (WM) integrity, particularly in the corpus callosum, cingulum bundle, and inferior fronto-occipital fasciculus, compared to CN-stable. To a lesser degree, we also observed temporal thinning and atrophy linked to SI. These associations were amplified among males and amyloid-positive individuals.

DISCUSSION

Longitudinal alterations in WM microstructural integrity were most strongly associated with future impairment, highlighting the importance of early WM changes in the development of MCI and dementia.

INTRODUCTION

This study evaluated the efficacy of deep cervical lymphatic–venous anastomosis (dcLVA) for severe Alzheimer's disease (AD).

METHODS

A total of 139 severe AD patients undergoing dcLVA were enrolled, and changes in cognitive function and biomarkers were evaluated by comparing preoperative measures with postoperative outcomes over a 6-month follow-up period.

RESULTS

Patients undergoing dcLVA showed modestly elevated Mini-Mental State Examination (MMSE) scores from 48 hour postoperatively to 6-month follow-up. At 6-month, observable changes across functional status and neuropsychiatric symptoms were documented, as demonstrated by reductions in scores on the Activities of Daily Living (ADL) scale, Neuropsychiatric Inventory (NPI), Neuropsychiatric Inventory-Caregiver Distress (NPI-D), and Sleep Disorders Inventory (SDI). Biomarker analyses revealed decreased cerebrospinal fluid (CSF) β-amyloid (Aβ) 42, Aβ40, and p-Tau levels postoperatively, along with increased plasma concentrations of these markers. No deaths or serious procedure-related adverse events occurred during 6-month follow-up.

DISCUSSION

These findings suggest that dcLVA may confer multifaceted clinical benefits in severe AD patients, including attenuation of certain neuropsychiatric dysfunctions and a potential slowing of symptom progression.

INTRODUCTION

Although it has become clear that alterations in lipid metabolism are associated with Alzheimer's disease (AD), it is unclear how they contribute to both cognitive decline and the pathophysiology of AD.

METHODS

Lipidomics and activity-based protein profiling (ABPP) were performed in the frontal cortex of control, AD and resilient donors, that is, individuals with AD pathology without cognitive decline.

RESULTS

The most pronounced alterations in lipids were in ω6-derived oxylipins, which were particularly increased in AD. Triacylglycerols (TAGs) and lipid droplets (LDs) were more abundant in the AD donors compared to the resilient donors. Multi-omics factor analysis (MOFA) showed that increased ω6-derived oxylipins and the loss of inhibitory neurons were associated with amyloid beta (Aβ) plaque load.

DISCUSSION

Our multi-omics data show a molecular response associated with Aβ load shared among AD and resilient donors, but reduced LDs in resilient donors compared to AD.

Highlights

INTRODUCTION

Amyloid beta peptide (Aβ) accumulation in the brain is an Alzheimer´s disease (AD) hallmark. Sleep disturbances hamper Aβ production and clearance, thereby exacerbating the Aβ burden. The mechanisms involved remain unclear. We reported that amyloid precursor protein (APP), the Aβ source, possesses intracellular signaling that attenuates Aβ production and prevents cognitive decline in AD mice. Our follow-up study assessed whether enhancing APP-mediated signaling affected sleep.

METHODS

We expressed a membrane-tethered APP intracellular domain (mAICD) and a variant lacking the Gα_S-interacting site in AD mouse brains. Sleep patterns, cognitive behaviors, blood–brain barrier (BBB) integrity, and gliosis were examined.

RESULTS

Sleep, BBB integrity, and memory were strongly correlated. mAICD expression rescued sleep and cognitive function impairments, prevented BBB leakage, and promoted astrocyte redistribution surrounding the neurovascular units in AD mice. Gα_S interaction with mAICD was critical.

DISCUSSION

APP-mediated signaling plays a key role in regulating sleep, maintaining BBB integrity, and preserving memory in AD.

INTRODUCTION

While higher physical activity (PA) levels are linked to lower Alzheimer's disease (AD) risk, traditional PA measures overlook temporal activity patterns.

METHODS

We developed the activity complexity measure in 164 older adults (mean age = 65.3 years) who completed wrist-worn accelerometry and neuropsychological tests. PA complexity was derived using multiscale entropy (MSE) and averaged across days. Day-to-day variability was also computed. Plasma biomarkers (Aβ42, Aβ40, p-tau181, p-tau217, p-tau231) were measured.

RESULTS

Participants with subjective cognitive decline and impaired scores without complaints showed lower PA complexity than cognitively unimpaired participants, but not those with mild cognitive impairment or AD. Low PA complexity was associated with poorer cognitive function (p < 0.03). Greater day-to-day variability in PA complexity was associated with higher plasma p-tau levels.

DISCUSSION

Lower PA complexity and greater instability across days were associated with poorer cognition and AD pathology. Longitudinal studies should examine whether low PA complexity serves as digital biomarkers of preclinical AD.

Highlights

INTRODUCTION

Sleep disruption, particularly loss of slow-wave sleep (SWS), is common in Alzheimer's disease (AD), but its neurobiological underpinnings remain unclear. We investigated whether locus coeruleus (LC) integrity relates to SWS across the AD continuum and whether sex and perivascular spaces (PVSs) modify these associations.

METHODS

In a cohort (11 controls, 30 mild cognitive impairment, 17 AD dementia) we combined overnight polysomnography with LC-sensitive magnetic resonance imaging of the LC, basal ganglia and centrum semiovale PVS ratings, and cerebrospinal fluid noradrenaline. Multivariable linear regression adjusted for demographics, disease stage, and medication use.

RESULTS

Higher LC integrity was associated with greater slow-wave activity and slow oscillation power, with stronger effects in females. Basal ganglia PVS burden was related to lower SWS spectral power, whereas noradrenaline levels were not associated with sleep.

DISCUSSION

LC integrity, sex, and PVS burden show associations with SWS alterations in aging and AD, supporting restorative sleep as a potential therapeutic target.

INTRODUCTION

Alzheimer's disease (AD) involves β-amyloid (Aβ) accumulation, tau pathology, and neuroinflammation, driving cognitive decline. Despite extensive research, disease-modifying therapies remain elusive. We integrated single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, and in vitro validation to identify repurposable drugs for AD¹.

METHODS

Computational drug repurposing was performed using cell-type-specific analysis of scRNA-seq datasets from AD cortical regions. Trichostatin-A (TSA) effects were validated in human induced pluripotent stem cells (iPSC) -derived cortical neurons exposed to Aβ oligomers. Cross-dataset integration identified convergent therapeutic targets.

RESULTS

TSA emerged as the top candidate, protecting neurons from Aβ toxicity and preserving synaptic integrity. DISC1 (Disrupted-In-Schizophrenia 1) was uniquely upregulated across TSA-treated neurons, AD-associated neuronal subpopulations, and protective microglial subtypes.

DISCUSSION

DISC1 represents a convergent therapeutic target for AD, mediating TSA's neuroprotective effects through pathways regulating GSK3β, mitochondrial transport, and synaptic plasticity, providing a mechanistic framework for developing AD therapeutics.

INTRODUCTION

Metabolic disorders are risk factors for Alzheimer's disease (AD), although underlying mechanisms remain unclear. We investigated the relationship between peripheral metabolic markers – adiponectin, fibroblast growth factor 21 (FGF-21), and insulin-like growth factor binding protein 2 (IGFBP-2) – and AD.

METHODS

Participants with subjective cognitive decline (SCD), mild cognitive impairment (MCI), AD, and cognitively healthy (CH) controls were from the Consortium for the Early Identification of Alzheimer's Disease–Quebec cohort (n = 287). Serum adiponectin, FGF-21, and IGFBP-2 concentrations were measured, compared between groups, and assessed for associations with clinical, cognitive, biochemical, and magnetic resonance imaging (MRI) data.

RESULTS

Metabolic dysfunction was linked to lower adiponectin and IGFBP-2, but higher FGF-21. Both FGF-21 and IGFBP-2 increased with age and were inversely associated with cognitive performance. IGFBP-2 was elevated at SCD stage and correlated with plasma tau phosphorylated at threonine 181 and amygdala atrophy. Adiponectin was unrelated to cognition.

DISCUSSION

These findings suggest that IGFBP-2 and, to a lesser extent, FGF-21 may serve as early biomarkers of cognitive impairment, reflecting intricate links between peripheral dysmetabolism and AD.

INTRODUCTION

We estimated the lifetime risk of incident dementia and mild cognitive impairment (MCI) from ages 55–105 and examined differences by sex and race.

METHODS

Data were drawn from five harmonized longitudinal cohort studies at the Rush Alzheimer's Disease Center, including 4611 participants for dementia and 3915 for MCI. Diagnoses were based on annual clinical evaluations. Lifetime risk was estimated using nonparametric cumulative incidence curves by age conditional on being alive and event-free at the index age, accounting for competing mortality and delayed study entry, stratified by sex and race.

RESULTS

Lifetime risk from age 55 was 43% (95% confidence interval [CI]: 38%–47%) for dementia and 62% (95% CI: 57%–67%) for MCI. Female participants had higher risks than male participants, and racial differences were modest.

DISCUSSION

These findings extend lifetime risk estimation beyond age 90 among diverse older adults and provide MCI estimates, emphasizing equity-focused prevention and public health strategies to reduce cognitive impairment.

Highlights

Lifetime risk (cumulative incidence) of dementia and mild cognitive impairment (MCI) was estimated from ages 55 to 105 using nonparametric cumulative incidence models accounting for competing risk of death and left truncation.

The estimated lifetime risk was 43% for incident dementia and 62% for MCI, with risk rising steeply after age 75 and appearing to level off at the oldest ages.

Women and Black participants showed higher lifetime risks, partly reflecting mortality and selective survival dynamics.

Exploratory analyses suggested elevated risks among Latino participants and those with a history of stroke.

These findings extend lifetime risk estimation beyond age 90 and highlight the need for equitable, culturally informed dementia prevention and monitoring strategies.