Journal of Alzheimer's Disease最新文献

Amyloid-β (Aβ) can deposit in or near the microvascular basement membrane (BM) in Alzheimer's disease (AD). We examined the effect of the Aβ binding antibody, lecanemab, on BM collagen IV (Col-IV) using viable brain microvessels (MV) isolated from human postmortem brain tissue with high AD neuropathologic change (ADNC=3, 16 females (mean 86 years), 11 males (mean 81 years)). MVs were exposed to lecanemab or isotype for 4 days and examined for Col-IV related outcomes: western blotting, capillary electrophoresis, RT-PCR, and degraded Col-IV. We find a subset of MV from some donors demonstrate Col-IV changes that could cause microvascular injury when exposed to lecanemab.

BackgroundEye movement abnormalities have emerged as promising non-invasive candidate biomarkers for the early detection, progression monitoring, and differential diagnosis of Alzheimer's disease (AD), with preliminary clinical evidence supporting their translational potential. Current AD diagnostic methods are limited by subjectivity, high cost, and complexity-making non-invasive biomarkers critical, especially for mild cognitive impairment (MCI). The tight functional link between the eye and brain underscores eye movement abnormalities as a window into AD-related pathology.ObjectiveThis systematic review summarizes AD-associated multi-modal eye movement dysfunctions (focusing on saccades, fixation, and smooth pursuit), clarifies their pathological mechanisms, clinical value, and translational feasibility, providing a basis for constructing an AD biomarker system.MethodsLiterature searches were conducted in PubMed, Web of Science, and Google Scholar using ("Alzheimer's disease" OR "mild cognitive impairment" AND "eye movements" OR "saccades" OR "smooth pursuit" OR "fixation") with a search cutoff date of September 30, 2025. Studies deemed irrelevant or lacking sufficient data were excluded.ResultsAD/MCI patients exhibit eye movement abnormalities: prolonged saccadic latency, increased antisaccade errors, reduced fixation stability, and attenuated smooth pursuit gain, which are closely linked to core AD pathologies, detectable in AD/MCI stages, and can, to a certain extent, distinguish AD from Parkinson's disease and frontotemporal dementia, and have value for MCI-to-AD conversion prediction.ConclusionsEye movement abnormalities hold promise as non-invasive biomarkers for AD, with potential for preclinical screening and differential diagnosis. To advance translation, future research should prioritize AI-driven multi-modal integration, standardized detection protocols, portable device development, and preclinical longitudinal validation.

BackgroundChronic hypoxia has been acknowledged as a significant risk factor for Alzheimer's disease (AD), yet the impact of high-altitude hypoxia on AD pathogenesis remains poorly understood.ObjectiveThis study aims to investigate the effects of chronic high-altitude hypoxia on cognitive function and AD-related pathology.MethodsA cross-sectional cohort comprising 186 high-altitude migrants (HAM) and 378 high-altitude natives (HAN) was recruited for a preliminary assessment. We further conducted 101 HAM, 135 HAN, and 66 low-altitude controls (LA) for plasma biomarkers research. Plasma Aβ₄₀, Aβ₄₂, and T-tau levels were quantified by SIMOA. In parallel, APP/PS1 mice were exposed to hypobaric hypoxia (simulated at 5,500 m) or normoxia for 30 days, followed by behavioral tests, brain immunohistochemistry, and transcriptomic/proteomic analyses.ResultsHAM subjects exhibited significant deficits in Montreal Cognitive Assessment scores and delayed recall subscores compared to LA controls, with both measures showing a positive correlation with peripheral oxygen saturation (SpO₂). Notably, HAN showed preserved memory despite lower overall cognitive scores. Plasma levels of amyloid-β (Aβ)₄₀, Aβ₄₂, and Aβ₄₂/Aβ₄₀ ratio were significantly lower in both HAM and HAN groups compared to the LA group. In mice, chronic hypoxia exacerbated hippocampal Aβ deposition and induced spatial memory decline. Multi-omics analyses revealed the upregulation of oxidative stress and neuroinflammatory pathways and identified S100A8/A9 as a potential key mediator in hypoxia-accelerated AD pathology.ConclusionsOur findings demonstrate that chronic high-altitude hypoxia contributes to cognitive decline and AD-related pathological changes, likely mediated by Aβ burden and oxidative stress. High-altitude hypoxia might be an important environmental risk factor for AD.

BackgroundNormal aging is accompanied by cognitive decline and structural changes in the brain, most notably within the hippocampus and amygdala. However, distinguishing these age-related alterations from the earliest signs of neurodegenerative disorders remains challenging.ObjectiveThis study aims to investigate and compare the alteration patterns of hippocampus and amygdala during normal aging and in cases of mild cognitive impairment (MCI) and Alzheimer's disease (AD), which will provide insights into their distinct structural profiles.MethodsA total of 2195 participants aged 20-90 from three public cohorts (1364 cognitively normal controls, 623 MCI, and 208 AD) were grouped by decade to examine age- and disease-related differences in surface-based morphometry of hippocampus and amygdala. Radial distance, tensor-based morphometry, and multivariate tensor-based morphometry were calculated and combined to generate the Multivariate Morphometry Statistics, which capture both radial and tangential deformations at each vertex. Statistical and deformation analyses were further performed to identify the alteration patterns across 15000 surface vertices between age groups.ResultsIn healthy adults, significant intergroup differences were observed in the hippocampal CA1 and subiculum, as well as in the lateral, basolateral, and accessory basal nuclei of the amygdala. In MCI and AD, additional significant differences were detected in the hippocampal CA2-3 subfield and the central, medial, and cortical nuclei of the amygdala.ConclusionsWe provide a surface-based morphometry map of the hippocampus and amygdala across age groups in normal and pathological aging, revealing distinct morphological patterns that enhance understanding of aging and neurodegeneration.

Reports highlight new Alzheimer's disease treatments using anti-amyloid-β immunotherapy, but we see major concerns. The trials supporting lecanemab and donanemab approvals have methodological flaws, and the benefits may be smaller than the minimal clinically important difference-or absent-since patients with poor tolerance were excluded from efficacy analyses. Moreover, treatment increases amyloid-related imaging abnormalities, suggesting local tissue damage, and is linked to brain volume loss. These issues raise doubts about whether regulators are adequately balancing risks and benefits compared to academic critics.

BackgroundYoung-onset dementia (YOD) causes major life disruptions and emotional strain for both persons living with YOD and their informal caregivers. Non-pharmaceutical interventions may help to improve quality of life and reduce stress.ObjectiveWe aimed at investigating the effects of non-pharmaceutical interventions for persons living with YOD and their informal caregivers and to explore the intervention characteristics.MethodsWe conducted a systematic review including randomized and non-randomized controlled trials (PROSPERO: CRD42025645744). We searched major bibliographic databases and performed citation and web searches. Two reviewers independently screened titles, abstracts, and full texts. For data extraction, we used Elicit, an artificial intelligent research assistant; with extractions confirmed by a human reviewer. The methodological quality was assessed using the Mixed Methods Appraisal Tool (MMAT). We performed a narrative synthesis based on a harvest plot. When appropriate, we performed meta-analyses.ResultsWe found 9 trials assessing interventions on education and information or skills building interventions that were published between 1990 and 2024 (median sample size: 58). Meta-analyses revealed no statistically significant impact on behavioral outcomes, activities of daily living, and quality of life of persons living with YOD and no statistically significant impact on burden, depression and anxiety, and quality of life of informal caregivers.ConclusionsEvidence on the effectiveness of non-pharmaceutical interventions for persons living with YOD and their informal caregivers is limited and inconsistent. Further, larger, and multiple randomized controlled trials assessing the impact of non-pharmaceutical interventions with comparable outcomes, standardized measurements, and longer follow-ups are needed.

BackgroundHealthy lifestyles may reduce dementia risk by helping build cognitive reserve across the life course and promoting resilience and better cognitive outcomes in late-life. Whether self-reported lifestyle changes are informative for assessing brain health remains unclear.ObjectiveTo determine whether self-reported lifestyle changes (determinants) are associated with cognition, resilience, and Alzheimer's disease and related dementias (ADRD) biomarkers (outcomes), and whether these associations vary by sociodemographic characteristics and cognitive impairment status.MethodsData was obtained from 260 adults (age-range: 50-92). Self-reported change (increase/no change, decrease) in diet and physical, cognitive, and social activity from age 25 to present was evaluated in relation to cognition, resilience, and biomarkers within a cross-sectional design. ANCOVA models adjusted for age, sex, race, ethnicity, and education were used to examine associations between lifestyle change and outcomes. Effect modification by sex, race, ethnicity, and cognitive impairment status was also tested.ResultsSelf-reported increases in physical activity and diet were associated with better cognition and higher resilience, while increases in social activity with higher resilience and larger amygdala volume. Associations were stronger when increases occurred in multiple lifestyle domains. Associations differed by cognitive impairment status; no variation by sex and race was observed.ConclusionsIncreases in lifestyle behaviors relative to age 25 were associated with better cognitive and brain health outcomes, especially when increases occurred across multiple domains. These findings align with longitudinal evidence linking lifestyle engagement to cognitive aging and suggest that cross-sectional self-report of change may provide a useful proxy for estimating long-term lifestyle patterns.

A recent case study reported a PSEN2 mutation carrier with high amyloid burden but unexpectedly restricted tau pathology and preserved cognition. While genetic and proteomic factors were explored, the patient's lifelong occupational heat exposure may represent an overlooked contributor to resilience. We highlight evidence from preclinical, clinical, and epidemiological studies suggesting that elevated body temperature promotes tau clearance via enhanced proteostasis. This observation invites deeper investigation into thermoregulation as a modifiable factor in tau homeostasis and Alzheimer's disease vulnerability, with implications for both biomarker interpretation and therapeutic strategies targeting tau-mediated neurodegeneration.

Mild cognitive impairment (MCI) is a critical transitional stage between normal aging and dementia that remains challenging to detect. Many traditional neuropsychological assessments designed for early detection of MCI are time-consuming, require specialized training and/or demonstrate limited validity, making them impractical for widespread use in primary care settings. This article is divided into two phases. The first phase provides a rapid review of the current landscape of cognitive screening tools, while the second presents a novel, fully automated, digital screener based on two tasks from the Creyos cognitive assessment platform. This novel screener has been designed, using machine learning, for rapid administration without clinical supervision. The preliminary findings demonstrate that our two-task screener effectively differentiates between cognitively normal individuals and those at risk of progression along the Alzheimer's disease continuum. Furthermore, validation analyses showed that the screener has high sensitivity and specificity, outperforming many conventional assessments. By offering a brief, accessible, and reliable alternative to standard screening tools, our screener has the potential to enhance early detection efforts and facilitate timely intervention, ultimately improving patient outcomes, reducing the burden on clinicians, and optimizing healthcare resources.

BackgroundCyclin-dependent kinase 5 (CDK5) plays a critical role in neuronal development, synaptic plasticity, and cytoskeletal regulation. Its dysregulation has been implicated in Alzheimer's disease (AD); however, supporting genetic evidence remains limited in Middle Eastern populations.ObjectiveThis study aimed to identify CDK5 genetic variants in a Saudi cohort with AD and evaluate their association with disease susceptibility, without addressing downstream functional mechanisms.MethodsPeripheral blood samples were obtained from 52 Saudi patients with AD and 60 age- and sex-matched healthy controls. Genomic DNA was extracted and quantified using a NanoDrop One spectrophotometer. CDK5 exons 1, 2, 6, 7, and 12 were amplified and sequenced by Sanger methodology on an ABI 3500 Genetic Analyzer. Variant screening and frequency comparisons were performed between dementia and control groups.ResultsEight CDK5 variants were identified in exonic (2, 12) and intronic (1-2, 7-8, 11-12) regions, including three novel variants (c.105delG, c.858C > T, and one intronic variant). No variants were detected in exons 1, 6, or 7. Frameshift variants c.103del and c.105delG were significantly more frequent in AD cases (38%) than controls (5%) (p < 0.001). Conversely, the synonymous c.855C > T variant (Exon 12) was more common in controls (23%) than cases (5%) (p < 0.01), indicating a significant association between specific CDK5 variants and AD.ConclusionsIdentification of novel CDK5 variants associated with AD in a Saudi cohort highlights population-specific genetic susceptibility. Further functional and biomarker studies are needed to clarify their biological relevance.