Alzheimer's & Dementia最新文献

INTRODUCTION

We systematically characterized plasma protein profiles in cerebral amyloid angiopathy (CAA) using proteomics and identified a hub protein panel for disease diagnosis and risk stratification.

METHODS

A total of 146 patients with probable CAA and 128 community-dwelling controls were prospectively enrolled. Plasma samples underwent proteomic analysis, and the hub proteins were validated in two validation cohorts. Machine learning algorithms were applied to construct and validate the performance of the circulating panel.

RESULTS

We identified 166 differentially expressed proteins in patients with CAA. Six hub proteins were selected to form the circulating panel, demonstrating excellent performance to distinguish patients from controls in all cohorts. Additionally, the risk stratification system derived from the hub protein panel accurately identified patients at high risk for new-onset lobar intracerebral hemorrhage.

DISCUSSION

Our findings revealed distinctive circulating protein signatures in CAA and established a validated hub protein panel aiding in CAA screening and risk stratification.

Highlights

INTRODUCTION

Twitter (X) is widely used to reflect individual perspectives. We wished to study social insight regarding dementia using this digital platform.

METHODS

We conducted a cross-sectional study retrieving tweets containing “dementia” or “#dementia” and their Thai equivalents. English tweets were randomly selected, while all Thai tweets were collected. We identified user types, topics, and sentiments.

RESULTS

Of 10,062 English and 9511 Thai tweets, general users were the most prevalent in both languages. “Dementia” was used accurately in 39.0% of English tweets and as misinformation in 49.2% of Thai tweets. Stigma was significantly more common in English (38.9%) than in Thai (22.6%) tweets (p-value < 0.001), and negative perceptions were expressed in 44.2% and 81.3% of English and Thai tweets, respectively (p-value < 0.001).

DISCUSSION

Different inappropriate uses of “dementia” were observed. To alleviate negative perceptions, reducing stigmatization is urgently needed in English-speaking communities, whereas in Thailand, appropriate dementia education should be undertaken immediately.

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INTRODUCTION

High levels of chronic stress and low social support have been associated with worse cognition among older adults, but the underlying mechanisms remain unclear.

METHODS

We included 2117 older adults (mean age 65.5 years) enrolled in the Health and Aging Brain Study – Health Disparities (HABS-HD). Linear regression models evaluated the associations between social support or chronic stress and Alzheimer's-related blood-based biomarkers (BBMs), including amyloid beta (Aβ) 42/40 ratio, neurofilament light chain (NfL), phosphorylated tau (p-tau)181, and total tau (t-tau). Interactions between chronic stress or social support and gender or race/ethnicity in relation to BBMs were assessed.

RESULTS

Higher chronic stress was associated with higher levels of t-tau. Higher social support was associated with lower levels of NfL. Neither gender nor race/ethnicity modified the associations between chronic stress or social support and BBM levels.

DISCUSSION

Chronic stress and social support are associated with BBMs of neurodegeneration.

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BACKGROUND

Heterogeneity in Alzheimer's disease (AD) progression introduces variability in treatment effect assessments. Using predicted future progression as an AD prognostic covariate (APC) may reduce this variability. This study evaluates this strategy in lecanemab trials and its implications for AD trial design.

METHODS

Two APCs were derived at baseline for each trial participant from published models with historical controls: one with clinical features, the other adding structural MRI features. Their impact on estimating the difference in cognitive decline between the treatment and placebo arms and the time saved from delayed progression (TSDP) was assessed.

RESULTS

Incorporating either APC reduced variance estimates by up to 19.1% across phase II and phase III trials, increased power to 90.2%, and reduced sample size by 27.2%. These APCs improved treatment effect estimates and TSDP, demonstrating broad applicability across endpoints.

DISCUSSION

APCs enhance treatment effect evaluation, improve statistical power, and reduce required sample sizes in Alzheimer's trials.

CLINICAL TRIALS.GOV IDENTIFIERS

NCT01767311 (Lecanemab Study 201), NCT03887455 (Lecanemab Study 301; ClarityAD).

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INTRODUCTION

The association of scam susceptibility with the timing of Alzheimer's disease (AD) dementia onset is unknown.

METHODS

One thousand ninety-two older adults without dementia underwent assessments of scam susceptibility and annual clinical evaluations to document incident AD dementia. Accelerated failure time models examined the relation of scam susceptibility with dementia onset.

RESULTS

During a mean of 5 years of follow-up (standard deviation = 3.1), 188 individuals (17%) were diagnosed with incident AD dementia. A higher level of scam susceptibility was associated with a considerably earlier dementia onset ($�\beta$ = −0.039; 95% confidence interval: −0.061, −0.017); those with a high level of susceptibility developed AD dementia at a mean age of 90.9 years compared to 98.2 for those with a low level. Results persisted after controlling for global cognition, sex, and education.

DISCUSSION

Scam susceptibility is associated with a markedly earlier onset of AD dementia. Assessment of susceptibility may facilitate early identification of individuals at risk of developing dementia.

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INTRODUCTION

We evaluated the independent associations between high-density lipoprotein cholesterol (HDL-C) and triglyceride (TG) levels with Alzheimer's disease and related dementias (ADRD).

METHODS

Among 177,680 members of Kaiser Permanente Northern California who completed a survey on health risks, we residualized TGs and HDL-C conditional on age, sex, and body mass index. We included these residuals individually and concurrently in Cox models predicting ADRD incidence.

RESULTS

Low (hazard ratio [HR] 1.06, 95% confidence interval [CI] 1.02–1.10) and high quintiles (HR 1.07, 95% CI 1.03–1.12) of HDL-C residuals were associated with an increased risk of ADRD compared to the middle quintile. Additional adjustment for TGs attenuated the association with high HDL-C (HR 1.03, 95% CI 0.99–1.08). Low TG residuals were associated with an increased ADRD risk (HR 1.10, 95% CI 1.06–1.15); high TG residuals were protective (HR 0.92, 95% CI 0.88–0.96). These estimates were unaffected by HDL-C adjustment.

DISCUSSION

Low HDL-C and TG levels are independently associated with increased ADRD risk. The correlation with low TG level explains the association of high HDL-C with ADRD.

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INTRODUCTION

MicroRNA (miRNA) activity is increasingly appreciated as a key regulator of pathophysiologic pathways in Alzheimer's disease (AD). However, the role of miRNAs during the progression of AD, including resilience and prodromal syndromes such as mild cognitive impairment (MCI), remains underexplored.

METHODS

We performed miRNA-sequencing on samples of posterior cingulate cortex (PCC) obtained post mortem from Rush Religious Orders Study participants diagnosed ante mortem with no cognitive impairment (NCI), MCI, or AD. NCI subjects were subdivided as low pathology (Braak stage I/II) or high pathology (Braak stage III/IV), suggestive of resilience. Bioinformatics approaches included differential expression, messenger RNA (mRNA) target prediction, interactome modeling, functional enrichment, and AD risk modeling.

RESULTS

We identified specific miRNA groups, mRNA targets, and signaling pathways distinguishing AD, MCI, resilience, ante mortem neuropsychological test performance, post mortem neuropathological burden, and AD risk.

DISCUSSION

These findings highlight the potential of harnessing miRNA activity to manipulate disease-modifying pathways in AD, with implications for precision medicine.

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INTRODUCTION

Genome-wide association studies (GWAS) studies in Alzheimer's disease (AD) demonstrate ancestry-specific loci. Previous studies in the regulatory architecture have only been conducted in Europeans (EUs), thus studies in additional ancestries are needed. Given the prevalence of AD genes expressed in microglia, we initiated our studies in induced pluripotent stem cell (iPSC) -derived microglia.

METHODS

We created iPSC-derived microglia from 13 individuals of either high Amerindian (AI), African (AF), or EU global ancestry, including both AD and controls. RNA-seq, ATAC-seq, and pathway analyses were compared between ancestries in both AD and non-AD genes.

RESULTS

Twelve AD genes were differentially expressed genes (DEGs) and/or accessible between ancestries, including ABI3, CTSB, and MS4A6A. A total of 5% of all genes had differential ancestral expression, but differences in accessibility were less than 1%. The DEGs were enriched in known AD pathways.

DISCUSSION

This resource will be valuable in evaluating AD in admixed populations and other neurological disorders and understanding the AD risk differences between populations.

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