Journal of Alzheimer's Disease最新文献

BackgroundAlzheimer's disease (AD) accounts for the majority of dementia-related disorders among aging populations. Given the irreversible nature of AD, early detection of cognitive impairment is critical for improving prognosis and facilitating timely interventions before individuals meet the clinical criteria for AD.ObjectiveThe objective of this review is to provide a comprehensive summary of recent advances in task-based electroencephalography (EEG), such as using attention and inhibitory control tasks, which has recently emerged as a promising non-invasive biomarker for assessing neurophysiological alterations associated with AD and mild cognitive impairment (MCI).MethodsThis systematic review evaluates the efficacy of task-based EEG biomarkers in distinguishing cognitively impaired individuals from those without impairment. A comprehensive literature search was conducted across PubMed, Semantic Scholar, and SpringerLink databases for studies published between 2017 and 2024.ResultsFindings indicate consistent neurophysiological alterations in MCI and AD, particularly reductions in event-related potential amplitudes and prolonged latencies, with P3 abnormalities observed in about half of the studies assessing selective attention and inhibitory control. Similarly, a comparable number of studies using working memory tasks report disrupted functional connectivity patterns, increased low-frequency oscillations (delta and theta activity), and reduced fast oscillations (alpha and beta activity).ConclusionsThese EEG-based indices demonstrate potential as objective biomarkers for detecting neural alterations associated with cognitive decline in both AD and preclinical dementia stages. Further research is needed to standardize EEG protocols and validate their clinical utility for early diagnosis and disease progression monitoring.

BackgroundEarly detection of mild cognitive impairment (MCI) is essential for initiating timely intervention and delaying progression to dementia. However, current diagnostic approaches often lack scalability and efficiency, limiting their utility in primary care and community settings.ObjectiveThis study developed and validated the Integrated Cognitive Screening Platform (ICSP), a self-administered, tablet-based tool designed for rapid, multidomain screening of MCI.MethodsICSP comprises five cognitive tasks involving immediate and delayed memory, attention, sensory perception, and executive function. Both accuracy scores and reaction times (RTs) were recorded and processed within five minutes. A total of 126 participants (76 with MCI, 50 cognitively normal controls) completed standard neuropsychological assessments and the ICSP battery. A multivariate logistic regression model was developed using 60% of the data as a training set and evaluated on the remaining 40% as a validation set.ResultsRTs and accuracy scores in sensory perception and executive function tasks, along with educational attainment, were identified as significant predictors of MCI. The model achieved high classification performance (AUC: 0.915; p < 0.001), with robust validation performance (AUC: 0.821; p < 0.001).ConclusionsICSP is an accurate and scalable digital screening tool capable of identifying MCI with high specificity. Its multimodal design and automated analysis make it well-suited for clinical and community-level early detection of cognitive impairments.Trial registrationThis study was registered with the Chinese Clinical Trial Registry (Registration No. ChiCTR2400082429) on March 28, 2024.

BackgroundAlzheimer's disease (AD) is an incurable neurodegenerative disease with poorly understood pathogenesis. Understanding changes in protein sequences due to amino acid substitutions (AASs) may be important for uncovering molecular mechanisms of this disease.ObjectiveThe study aimed at developing a bioinformatic pipeline for searching AASs in proteomic data and revealing the AD-specific ones, highlighting potential biomarkers and/or therapeutic targets.MethodsThe developed pipeline integrates peptide de novo sequencing approach, database searches, and retention time prediction. It was applied to a large collection of AD proteomic data from global consortium studies obtained for post-mortem brain tissue samples.ResultsProteins with identified AASs were clustered by functionality. Proteins heavily enriched with AASs were the ones associated with ion transport activity, ATP binding, and G-protein signaling, aligning with known AD mechanisms. Further we classified the identified AASs by their origin (tRNA misacylation, post-translational modifications, single nucleotide polymorphisms) and by Braak stage and sex. Pathogenicity analysis, cross-referenced with clinical information, identified pathogenic mutations in HBD (W38S), GFAP (N77D), and NEFL (N98D).ConclusionsThe developed pipeline successfully maps disease-relevant protein variants by uncovering novel molecular features of a disease with biomarker and therapeutic potential. AASs identified in the work for AD samples reveal specific pathogenic mutations and implicate important biological processes.

BackgroundAbnormal tau aggregation is implicated in the development of neurodegenerative diseases such as Alzheimer's disease (AD). The presence of tau in the extracellular space and the spread of tau between nerve cells is associated with its toxicity. At present, researchers are trying to treat AD by limiting, blocking or removing extracellular tau.ObjectiveTo investigate the molecular mechanism underlying the cytotoxicity of extracellular tau oligomers.MethodsThe morphology of tau oligomers was observed by transmission electron microscopy. The neurocytotoxicity of tau oligomers was examined using CCK-8 assay. The localization of tau oligomers in cells was observed by laser confocal microscopy. The influence of tau oligomers on apoptosis was detected by Hoechst 33342/PI double-staining, Annexin V/PI double-staining and flow cytometry. JC-1 staining, DCFH-DA staining and Fluo-4 AM staining were used to evaluate the effect of tau oligomers on mitochondria. Western blot analysis was used to investigate the mechanism underlying the effects of tau oligomers on apoptosis and autophagy.ResultsAfter treatment with tau oligomers, the viability of SH-SY5Y cells decreased, and a typical apoptotic morphology was observed. Tau oligomers can enter cells, decrease the mitochondrial membrane potential, increase reactive oxygen species levels and drive calcium levels up to disrupt calcium homeostasis. The cytotoxicity of tau oligomers is closely related to the induction of mitochondrial apoptosis and blockade of mitophagy.ConclusionsThis study provides a molecular mechanism for understanding the cytotoxicity of extracellular tau oligomers and provides a therapeutic target for the development of effective treatment strategies for tau-related diseases.

BackgroundSubjective cognitive complaints are common in older populations and may signpost incident Alzheimer's disease and related dementias.ObjectiveTo determine the frequency and predictors of cognitive impairment and dementia among Yoruba-speaking community dwelling older persons (65 years and above) from 2 communities in Oyo State, Southwest Nigeria who have Subjective cognitive complaints.MethodsThis was a cross-sectional, observational study conducted within two urban communities in Oyo State, South West Nigeria and involving 150 consenting and voluntarily participating elderly participants aged 65 years and above who had subjective cognitive complaints. Demographic and clinical data were obtained using a pro forma. Participants also had cognitive screening and a focused clinical examination by a physician. Categorization following consensus diagnosis was according to International Classification of Diseases version 11 (ICD-11) namely dementia, mild cognitive impairment and no cognitive impairment.ResultsThere were no statistically significant differences in the socio-demographic and cognitive performance scores on neuropsychological testing across sites. At final diagnosis, 4 participants had dementia (2.7%) while 15 participants (10%) had mild cognitive impairment. On logistic regression, only moderate-severe decline on the Clinical Dementia Rating Scale was significantly associated with higher odds of cognitive decline in this sample.ConclusionsAbout 1 in 7 older persons in this study already had objective cognitive decline. Subjective cognitive complaints in older Yoruba Africans should prompt early screening. Prospective studies to identify the consistent predictors of cognitive decline in this population are needed.

BackgroundClinically, phosphorylation of Tau protein at threonine 181 (p-Tau181) acts as a crucial biomarker for AD detection. However, the mechanisms through which Tau phosphorylation at threonine (Thr)181 site leads to Tau aggregation and corresponding neuropathological changes remain unclear.ObjectiveTo investigate the effect of the phosphorylated tau peptide at Thr181 on tau aggregation, synaptic and cognitive impairments.MethodsWe synthesized the phosphorylated tau peptide Tau-pT181 and the non-phosphorylated tau peptide Tau-nT181, and verified their effects on the aggregation of the Tau repeat domain R3 fragment peptide and Tau pathology.ResultsThioflavin S assay showed that Tau-pT181 significantly promoted the aggregation of R3, whereas Tau-nT181 did not induce R3 aggregation. Moreover, Tau-pT181 not Tau-nT181 led to the aggregation of Tau protein in 293/tau cells and decreased synapse-associated proteins in primary hippocampal neurons. One month after injecting Tau-pT181 and Tau-nT181 respectively into the rat CA1 hippocampal region, we found that exclusively the phosphorylated peptide Tau-pT181 induced endogenous Tau aggregation, synaptic damage, neuronal loss, while Tau-pT181 group exhibited significant cognitive impairment compared with the normal saline rats. Transcriptome analysis of neurons differentiated from iPSCs treated with Tau-pT181/Tau-nT181 suggest that phosphorylated peptides had a greater impact on axonogenesis, neuronal development, and Wnt signaling pathway.ConclusionsThe present study offers the first direct evidence that Tau phosphorylation at Thr181 induces Tau aggregation, and Tau-pT181 directly leads to neuropathological alterations and cognitive impairments, and establishes a new theoretical foundation for Tau Thr181 phosphorylation site as a core diagnostic marker and therapeutic target for AD.

BackgroundApolipoprotein E (APOE) polymorphisms, particularly the APOE4 genotype, are established genetic risk factors for Alzheimer's disease (AD). However, the clinical utility of combining APOE genotypes with serum lipids and blood-based AD biomarkers remains incompletely defined.ObjectiveTo investigate the association between APOE gene polymorphisms, serological indicators, and the occurrence of AD.MethodsBlood samples of 109 patients with AD and 85 non-AD participants were used to detect APOE genotypes. Serum levels of total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), amyloid-β 1-42 (Aβ_1-42), and p-tau-181 were measured. Receiver operating characteristic analysis was performed in an independent validation set of 82 cases.ResultsThe frequency of the APOE4 genotype was significantly higher in the AD group compared with the non-AD group, whereas APOE2 and APOE3 genotypes showed no significant differences. TC, HDL-C, and LDL-C levels were significantly elevated in the AD group compared with the non-AD group, while TG, Aβ_1-42, and p-tau-181 levels did not differ significantly. Among patients with AD carrying the APOE4 genotype, TC and LDL-C levels were significantly higher than those in non-AD APOE4 carriers. Further, within the AD group, APOE4 carriers had a significantly higher proportion of elevated TC and LDL-C levels than non-APOE4 carriers. Validation experiments revealed that the combination of APOE4 genotype with elevated TC and LDL-C demonstrated greater diagnostic efficacy for AD.ConclusionsAPOE4 genotype combined with elevated TC and LDL-C levels strongly correlate with AD onset and may be valuable auxiliary biomarkers for AD diagnosis and treatment.

BackgroundCognitive impairment is increasingly prevalent in younger populations. The interplay between environmental exposures like noise and genetic susceptibility in dementia etiology remains unclear. This study investigated the combined effects of work-related cumulative noise exposure (WCNE) and genetic polymorphisms on cognitive performance.ObjectiveTo examine the relationships among WCNE, genetic factors (APOE rs429358/rs7412 and PS-1 rs165932), and lower cognitive performance (LCP), and to analyze the potential interaction.MethodsThis study included 523 workers from a health surveillance cohort in western China. WCNE was assessed for each participant. Genotyping was performed for APOE (rs429358/rs7412) and PS-1 (rs165932) polymorphisms. Cognitive function was evaluated via Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). The individual and combined effects of WCNE and genetic factors on LCP were analyzed.ResultsAPOE rs429358/rs7412 were not significantly associated with LCP. The PS-1 rs165932T allele (PS-1T) was associated with LCP (p < 0.05). The adjusted odds ratios (aORs) for LCP (evaluated by MMSE and MoCA) in the PS-1T group were 2.443 (95% CI: 1.149-5.195) and 2.065 (95% CI: 1.091-3.906), respectively. Age and WCNE had an interaction effect on the LCP for both MMSE and MoCA (p < 0.05), while PS-1T had an effect modification on the relationship between WCNE and LCP (p < 0.05).ConclusionsThese findings highlight the urgent need to identify and mitigate noise exposure risks in vulnerable populations. These findings also provide evidence for further mechanistic studies exploring how noise, aging, and genetic susceptibility contribute to cognitive impairment through underlying biological mechanisms.

BackgroundThe retrosplenial cortex (RSC) is a cortical area that functions as a key component of the core network of brain regions involved in cognitive functions such as episodic memory, navigation, and planning. The RSC is capable of theta rhythm generation and, like the hippocampus, could be compromised in neurological diseases such as Alzheimer's disease (AD). Importantly, detecting early changes in RSC of transgenic animals could be translated into non-invasive biomarkers that can detect preclinical stages of AD and related dementias.ObjectiveOur aim in the present study was to evaluate molecular and functional alterations in the RSC of very young 3xTg-AD mice (1-month-old).MethodsImmunohistochemistry, anterograde viral tracer using an adeno-associated virus, western blotting, and electrophysiology were all carried out.ResultsOur results show significant accumulation of intracellular amyloid-β (Aβ) and hyperphosphorylated tau (pTau) in principal neurons from 1-month-old 3xTg-AD mice, which correlates with GSK3β activation and tau phosphorylation at serine 396. Coincidentally, oscillatory activity from the RSC is altered in the young 3xTg-AD mice. Specifically, we found that theta frequency is significantly higher in the transgenic animals.ConclusionsIn summary, our results suggest that the early accumulation of intracellular Aβ may affect the excitability of the RSC network, possibly due to changes in pTau resulting from GSK3β activation.