Alzheimer's Research & Therapy最新文献

Transcranial alternating current stimulation (tACS) in the theta frequency range has been shown to enhance working memory (WM) performance. However, no studies have directly compared the effects of theta tACS between cognitively healthy elderly (HE) subjects and subjects with non-amnestic mild cognitive impairment (MCI). Our proof-of-concept study investigated the effects of monofocal (frontal) and bifocal (frontoparietal) theta tACS on WM in two cognitive loads in HE subjects and in subjects with MCI. In this sham-controlled, single-blinded, repeated-measures study with counterbalanced stimulation order across subjects (n = 55), theta tACS (4.51 Hz, 1.5 mA, 20 min) was applied either over the frontal site alone or simultaneously over frontal and parietal sites. WM 2-back and 3-back tasks were performed during and after each stimulation session. In the HE group, both frontal and frontoparietal stimulations improved performance, albeit with load-dependent differences. Frontal stimulation was particularly effective in the higher cognitive load, enhancing accuracy (β = -3.87; p = .033) and reaction times (β = - .042; p = .002) in the 3-back task. Frontoparietal stimulation improved accuracy (β = -3.74; p = .027) but not reaction time (p > .22) in the 2-back task in the HE group. Frontoparietal stimulation enhanced accuracy in the 3-back task across all participants (β = 1.91; p = .043). In the MCI group, frontal stimulation led to faster reaction times in the 3-back task, although the effects were not robust. Lastly, a marginally significant improvement in reaction times was observed in a letter 2-back transfer task following frontal stimulation (β = - .034; p < .092) across all participants. Our findings indicate that theta tACS over the frontal and frontoparietal areas elicits benefits in WM performance, driven mainly by enhancements in HE subjects. The effects of stimulation varied with cognitive load and montage, suggesting that optimal stimulation parameters may differ depending on task demands. The non-amnestic MCI group did not exhibit greater improvements despite their lower baseline performance, possibly due to higher variability in pathology and compensation. Multiple sessions or alternative stimulation parameters may be needed to achieve robust effects in subjects with MCI. The study was retrospectively registered on ClinicalTrials.gov (NCT06563453).

Background: Mitochondrial dysfunction and dysregulated calcium homeostasis contribute to Alzheimer's disease (AD) pathogenesis. The extrasynaptic N-methyl-D-aspartic acid (NMDA) receptor (eNMDAR) plays a crucial role in calcium influx and subsequent signaling cascades. In individuals with AD, the reduced expression and function of glutamate transporter-1 (GLT-1) result in glutamate spillover from the synaptic clefts to the extrasynaptic region, thereby activating eNMDAR and inducing mitochondrial damage. Ceftriaxone (Cef) has been reported to ameliorate cognitive deficits in APPswe/PS1dE9 (APP/PS1) mice by upregulating GLT-1. This study aimed to explore whether Cef alleviates mitochondrial dysfunction to improve cognitive impairment and the roles of GLT-1 and eNMDAR, particularly the participation of eNMDAR-induced intracellular calcium signaling in this process.

Methods: C57BL/6J, APP/PS1, and GLT-1-knockdown APP/PS1 mice were used. NMDA (1 mM, 2 µL per ventricle) was injected cerebroventricularly into APP/PS1 mice once to activate eNMDAR. Cef (200 mg/kg) was intraperitoneally administered for 14 days. Cognitive function was evaluated by novel object recognition, novel location recognition and Morris water maze tests. Hippocampal mitochondrial ultrastructure was observed using transmission electron microscopy. Hippocampal mitochondrial membrane potential (MMP) was detected using JC-1 staining. The expression of eNMDAR and proteins related to mitochondrial biogenesis and dynamics was evaluated by western blot. A neuron‒astrocyte coculture derived from the cerebral cortex of embryonic mice was used to evaluate the effects of Cef on eNMDAR-induced neuronal calcium influx, mitochondrial calcium accumulation and MMP loss using live-cell imaging.

Results: Cef treatment attenuated hippocampal mitochondrial dysfunction, including ultrastructural damage, reduced aspect ratio, dysregulation of MMP, impaired biogenesis and dynamics, and cognitive deficits, and prevented the upregulation of eNMDAR expression in APP/PS1 mice in a GLT-1-dependent manner. These protective effects on hippocampal mitochondrial dysfunction and cognitive deficits were counteracted by eNMDAR activation. Furthermore, Cef incubation inhibited eNMDAR-mediated calcium influx in a GLT-1-dependent way and reduced MMP in primary cortical neurons. Notably, Cef incubation significantly suppressed mitochondrial calcium overload, which was mechanistically linked to the observed decline in MMP.

Conclusions: Cef treatment prevented the upregulation of eNMDAR expression and the subsequent extracellular calcium influx in a GLT-1-dependent manner, thereby reducing mitochondrial calcium loading and ultimately mitigating mitochondrial damage and cognitive deficits in APP/PS1 mice.

Background: More than 300 mutations in presenilin 1 (PSEN1) lead to autosomal dominant Alzheimer's disease (ADAD). PSEN1, as the catalytic subunit of γ-secretase, generates amyloid-β (Aβ) peptides through a sequential proteolysis of the amyloid precursor protein (APP). While ADAD typically presents with progressive cognitive decline, ~ 25% of PSEN1 mutation carriers develop spastic paraparesis (SP), a debilitating motor condition. The molecular basis of this phenotypic heterogeneity remains unknown. This study examines Aβ profiles generated by PSEN1 variants associated with different clinical presentations with the aim of exploring potential associations between different Aβ profiles and clinical heterogeneity.

Methods: We analysed reported Aβ peptide profiles generated in vitro by 160 PSEN1 variants, categorized by their associated AD or AD + SP phenotype. We employed an integrated analytical approach combining univariate comparisons of Aβ profiles with machine learning classification.

Results: AD + SP-linked mutations showed significantly higher Aβ43 levels and more severe impairments in γ-secretase processivity compared to pure dementia associated variants. Machine learning consistently identified Aβ43 as the most important feature allowing for the phenotypic classification. Unlike processivity impairments, total Aβ production was comparable between groups, suggesting specific rather than global alterations in γ-secretase function.

Conclusions: Our analysis reveals a robust association between elevated Aβ43 levels and SP development in PSEN1 mutation carriers. While this correlation does not establish causation, the distinct impact of SP-associated mutations on γ-secretase function, resulting in elevated Aβ43 production, suggests that mutation-specific mechanisms may underlie clinical heterogeneity in ADAD, with potential implications for biomarker and translational research.

Introduction: Previous studies on serum lipid levels and cognitive outcomes have shown inconsistent results, partly due to differences in timing of lipid assessment, cognitive status, and lack of longitudinal data. This study aimed to examine both baseline and longitudinal changes in lipid profiles in relation to dementia onset and cognitive progression across different stages of cognitive impairment.

Methods: A retrospective cohort study was conducted using data from the History-Based Artificial Intelligent Clinical Dementia Diagnostic System (HAICDDS), a multicenter memory clinic registry in Taiwan. Among 2,452 adults aged ≥ 60 years, lipid levels (total cholesterol, low-density lipoprotein cholesterol [LDL-c], high-density lipoprotein cholesterol [HDL-c], and triglycerides [TG]) were assessed at baseline and follow-up. Participants were stratified into subjective cognitive decline, mild cognitive impairment, or dementia. Cox proportional hazards models were used to evaluate associations with incident dementia or cognitive progression.

Results: U-shaped associations were observed between lipid levels and cognitive outcomes. After adjusting for demographic and vascular risk factors, both low baseline values and extreme reductions-particularly in HDL-c and TG-were significantly associated with increased risk of dementia onset or progression.

Conclusion: Lipid instability, especially in HDL-c and TG, may serve as a marker of cognitive vulnerability. These findings suggest that longitudinal changes in serum cholesterol should be carefully monitored in older adults at risk of cognitive decline.

Background: Lecanemab was recently approved for the treatment of patients with early Alzheimer's disease (AD) and demonstrated reduced senile amyloid plaque and less decline on the measures of cognition and function in clinical trials. However, the real-world data on its efficacy and safety remain limited. We aimed to evaluate the effectiveness and tolerance of lecanemab treatment and determine biomarkers at baseline that could predict cognitive deterioration and the occurrence of amyloid-related imaging abnormaities (ARIA) in real-world clinical practice.

Methods: To determine the indication for lecanemab, the patients were evaluated through neurological examinations, cognitive assessments, blood test, head magnetic resonance imaging (MRI), amyloid positron emission tomography, lumbar puncture, genetic testing, and clinical conferences. The Mini-Mental State Examination (MMSE) was used to assess cognition, and the MRI scans were used for safety monitoring of ARIA.

Results: Between January 2024 and October 2025, 234 patients were screened, 100 initiated lecanemab treatment. The mean age was 72.7 years, and 68 (68.0%) patients were female. Among the 71 patients surveyed via MRI prior to the 14th infusion, 12 (16.9%) had ARIA detected. Compared with those of patients without ARIA, the baseline cerebrospinal fluid (CSF)-ptau181 levels of patients with ARIA significantly increased. When the patients were divided into high and low CSF-ptau181 groups according to the cutoff value (78.6 pg/ml) which derived from ROC analysis for ARIA prediction, the MMSE scores of the high ptau group were significantly declined compared to that of the low ptau group at 6 and 12 months after baseline. The infusion-reactions occurred only in 6.0% of patients. The longitudinal observation revealed that the plasma thrombomodulin levels significantly decreased after 6 months of lecanemab treatment.

Conclusion: Lecanemab was generally well tolerated by most patients with early AD and treatment appeared to be more effective and safer in patients with low CSF-ptau181 levels.　Our results suggest an association between lecanemab treatment and reduced markers of vascular endothelial injury.

Background: Neuroinflammation plays a key role in Alzheimer's disease (AD) pathophysiology, but it is not clear how neuroinflammation contributes to disease progression. We aim to investigate the role of neuroinflammation on longitudinal cognition and survival in a unique cohort with PET imaging of translocator protein (TSPO) binding tracer [¹¹C]PK11195 and long-term follow-up. We hypothesized that higher [¹¹C]PK11195 binding would be associated with faster cognitive decline and higher mortality.

Methods: 19 participants with AD dementia, 9 participants with MCI due to AD, and 21 healthy controls (HC) with historical dynamic [¹¹C]PK11195 PET data were included. Principal component analysis was performed to identify relevant [¹¹C]PK11195 patterns. An additional AD ROI consisting of temporal and parietal regions was investigated. [¹¹C]PK11195 scores in the principal components (PCs) and AD ROI were compared between groups using ANOVA. Longitudinal MMSE covering a period up to 11 years was used to measure cognitive decline. We used linear mixed models with random subject-specific intercepts and slopes corrected for age, sex and syndrome diagnosis to investigate the association of neuroinflammation with cognition in MCI and AD. Survival data were available for all MCI and AD participants, up to 15.7 years after PET. To examine the influence of neuroinflammation on survival time, we used age, sex, and syndrome diagnosis adjusted cox proportional-hazards models.

Results: Two PCs were retained. PC1 explained 55.4% of the variance and was most explained by [¹¹C]PK11195 binding in the thalamus and entorhinal cortex. PC2 explained 15.3% of the variance and constituted of mostly the entorhinal cortex. There was no difference in [¹¹C]PK11195 PET between AD, MCI and HCs (range F(2) = 0.157-1.231, P > 0.3). [¹¹C]PK11195 did not predict longitudinal MMSE (PC1: β = 0.02, P = 0.73; PC2: β = 0.1, P = 0.44; AD ROI: β = 1.3, P = 0.57) or survival (PC1: HR = 0.90[95%CI: 0.80, 1.03], P = 0.13; PC2: HR = 0.96[0.75, 1.23], P = 0.72; AD ROI: HR = 0.02[0.00, 1.33], P = 0.06).

Conclusions: Contrary to our hypothesis, we did not find evidence for [¹¹C]PK11195 PET predicting long-term cognitive decline or survival. This may indicate that the level of [¹¹C]PK11195 PET binding earlier in the disease trajectory is not directly linked to the long-term outcome.