Alzheimer’s disease: insights into pathology, molecular mechanisms, and therapy

Protein & Cell, Journal Year: 2024, Volume and Issue: unknown

Published: May 11, 2024

Abstract Alzheimer’s disease (AD), the leading cause of dementia, is characterized by accumulation amyloid plaques and neurofibrillary tangles in brain. This condition casts a significant shadow on global health due to its complex multifactorial nature. In addition genetic predispositions, development AD influenced myriad risk factors, including aging, systemic inflammation, chronic conditions, lifestyle, environmental exposures. Recent advancements understanding pathophysiology are paving way for enhanced diagnostic techniques, improved assessment, potentially effective prevention strategies. These discoveries crucial quest unravel complexities AD, offering beacon hope management treatment options millions affected this debilitating disease.

Language: Английский

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Association of rapid eye movement sleep latency with multimodal biomarkers of Alzheimer's disease

Alzheimer s & Dementia, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 27, 2025

Abstract INTRODUCTION Sleep disturbances are associated with Alzheimer's disease (AD) and related dementias (ADRD), but the relationship between sleep architecture, particularly rapid eye movement (REM) sleep, AD/ADRD biomarkers remains unclear. METHODS We enrolled 128 adults (64 disease, 41 mild cognitive impairment [MCI], 23 normal cognition [NC]), mean age 70.8 ± 9.6 years, 56.9% female, from a tertiary hospital in China. Participants underwent overnight polysomnography (PSG), amyloid β (Aβ) positron emission tomography (PET), plasma biomarker analysis: phosphorylated tau at threonine 181 (p‐tau181), neurofilament light (NfL), brain‐derived neurotrophic factor (BDNF). RESULTS After adjusting for demographics, apolipoprotein E ( APOE ) ε4 status, cognition, comorbidities, highest tertile of REM latency was higher Aβ burden = 0.08, 95% confidence interval [CI]: 0.03 to 0.13, p 0.002), elevated p‐tau181 0.19, CI: 0.02 reduced BDNF levels ‐0.47, –0.68 –0.13, 0.013), compared lowest tertile. DISCUSSION Prolonged may serve as novel marker or risk pathogenesis. Highlights Rapid (REML) be potential (AD/ADRD) REML beta burden, tau‐181 lower (BDNF) levels. Intervention trial is needed determine if targeting can modify risk. Slow‐wave not biomarkers.

Language: Английский

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Combining Glial Fibrillary Acidic Protein and Neurofilament Light Chain for the Diagnosis of Major Depressive Disorder

Analytical Chemistry, Journal Year: 2024, Volume and Issue: 96(4), P. 1693 - 1699

Published: Jan. 17, 2024

Major depressive disorder (MDD) is a prevalent brain affecting more than 2% of the world's population. Due to lack well-specific biomarkers, it difficult distinguish MDD from other diseases with similar clinical symptoms (such as Alzheimer's disease and cerebral thrombosis). In this work, we provided strategy address issue by constructing combinatorial biomarker serum glial fibrillary acidic protein (GFAP) neurofilament light chain (NFL). To achieve convenient sensitive detection two proteins, developed an electrochemical immunosandwich sensor using metal-ion-doped carbon dots (Pb-CDs Cu-CDs) probes for signal output. Each probe contains approximately 300 Pb2+ or 200 Cu2+, providing excellent amplification. This method achieved limits 0.3 pg mL–1 GFAP 0.2 NFL, lower most reported limits. Analysis real samples showed that concentration ratio which associated relative degree inflammation neurodegeneration, suitable not only distinguishing healthy individuals but also specifically thrombosis. The good specificity gives GFAP/NFL broad application prospects in screening, diagnosis, treatment MDD.

Language: Английский

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Plasma p‐tau217 and p‐tau217/Aβ1‐42 are effective biomarkers for identifying CSF‐ and PET imaging‐diagnosed Alzheimer's disease: Insights for research and clinical practice

Alzheimer s & Dementia, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 30, 2025

Abstract INTRODUCTION With the advancement of disease‐modifying therapies for Alzheimer's disease (AD), validating plasma biomarkers against cerebrospinal fluid (CSF) and positron emission tomography (PET) standards is crucial in both research real‐world settings. METHODS We measured phosphorylated tau (p‐tau)217, p‐tau181, amyloid beta (Aβ)1‐40, Aβ1‐42, neurofilament light chain cohorts. Participants were categorized by brain status using US Food Drug Administration/European Medicines Agency–approved CSF or PET methods. RESULTS Plasma p‐tau217 p‐tau217/Aβ1‐42 demonstrated superior accuracy detecting pathologies, with area under curve from 0.94 to 0.97 all Specificity was lower cohort but improved significantly integrating demographic clinical factors, aligning performance Additionally, exhibited strong correlations their counterparts standardized uptake value ratios, significant associations amyloid‐positive participants. DISCUSSION are effective diagnostic tools. However, patient demographics, apolipoprotein E ε4 status, cognitive condition must be considered improve specificity practice. Highlights (p‐tau)217 p‐tau217/amyloid (Aβ)1‐42 exceptional (area curve: 0.94–0.97) pathologies across (Southern China Aging Brain Initiative [SCABI]‐1, SCABI‐2) practice (RCP) Incorporating patient‐specific factors (sex, age, ε4, status) RCP cohort, its that biomarkers, particularly showed robust underscoring as non‐invasive alternatives. proved highly diagnosing burden, offering a practical solution bridge advancements

Language: Английский

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CSF proteomics identifies early changes in autosomal dominant Alzheimer’s disease

Cell, Journal Year: 2024, Volume and Issue: 187(22), P. 6309 - 6326.e15

Published: Sept. 26, 2024

In this high-throughput proteomic study of autosomal dominant Alzheimer's disease (ADAD), we sought to identify early biomarkers in cerebrospinal fluid (CSF) for monitoring and treatment strategies. We examined CSF proteins 286 mutation carriers (MCs) 177 non-carriers (NCs). The developed multi-layer regression model distinguished with different pseudo-trajectories between these groups. validated our findings independent ADAD as well sporadic AD datasets employed machine learning develop validate predictive models. Our identified 137 distinct trajectories MCs NCs, including eight that changed before traditional biomarkers. These are grouped into three stages: stage (stress response, glutamate metabolism, neuron mitochondrial damage), middle (neuronal death, apoptosis), late presymptomatic (microglial changes, cell communication). revealed a six-protein subset more effectively differentiated from compared conventional

Language: Английский

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Systematic proteomics in Autosomal dominant Alzheimer’s disease reveals decades-early changes of CSF proteins in neuronal death, and immune pathways

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 13, 2024

To date, there is no high throughput proteomic study in the context of Autosomal Dominant Alzheimer's disease (ADAD). Here, we aimed to characterize early CSF proteome changes ADAD and leverage them as potential biomarkers for monitoring therapeutic strategies. We utilized Somascan® 7K assay quantify protein levels from 291 mutation carriers (MCs) 185 non-carriers (NCs). employed a multi-layer regression model identify proteins with different pseudo-trajectories between MCs NCs. replicated results using publicly available datasets well data sporadic (sAD). biologically contextualize results, performed network pathway enrichment analyses. Machine learning was applied create validate predictive models. identified 125 significantly Twelve showed even before traditional AD (Aβ42, tau, ptau). These belong three modules that are associated age at onset: 1) stage module stress response, glutamate metabolism, mitochondria damage; 2) middle module, enriched neuronal death apoptosis; 3) presymptomatic characterized by microglia, cell-to-cell communication processes, indicating an attempt rebuilding establishing new connections maintain functionality. subset nine can differentiate NCs better than (AUC>0.89). Our findings comprehensively described captured specific biological processes happen phases disease, fifteen five years clinical onset. small potentials become therapy-monitoring MCs. Proteomic generation supported NIH: RF1AG044546.

Language: Английский

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Multi-Omic Blood Biomarkers as Dynamic Risk Predictors in Late-Onset Alzheimer’s Disease

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(2), P. 1231 - 1231

Published: Jan. 19, 2024

Late-onset Alzheimer’s disease is the leading cause of dementia worldwide, accounting for a growing burden morbidity and mortality. Diagnosing before symptoms are established clinically challenging, but would provide therapeutic windows disease-modifying interventions. Blood biomarkers, including genetics, proteins metabolites, emerging as powerful predictors at various timepoints within course, preclinical stage. In this review, we discuss recent advances in such blood biomarkers determining risk. We highlight how leveraging polygenic risk scores, based on genome-wide association studies, can help stratify individuals along their profile. summarize studies analyzing protein well report proteomic- metabolomic-based prediction models. Finally, combination multi-omic potentially be used memory clinics diagnosis to assess dynamic an individual has developing dementia.

Language: Английский

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Alzheimer’s Disease: Exploring the Landscape of Cognitive Decline

ACS Chemical Neuroscience, Journal Year: 2024, Volume and Issue: 15(21), P. 3800 - 3827

Published: Oct. 11, 2024

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and impaired daily functioning. The pathology of AD marked the accumulation amyloid beta plaques tau protein tangles in brain, along with neuroinflammation synaptic dysfunction. Genetic factors, such as mutations APP, PSEN1, PSEN2 genes, well APOE ε4 allele, contribute to increased risk acquiring AD. Currently available treatments provide symptomatic relief but do not halt progression. Research efforts are focused on developing disease-modifying therapies that target underlying pathological mechanisms Advances identification validation reliable biomarkers for hold great promise enhancing early diagnosis, monitoring progression, assessing treatment response clinical practice effort alleviate burden this devastating disease. In paper, we analyze data from CAS Content Collection summarize research progress We examine publication landscape insights into current knowledge advances developments. also review most discussed emerging concepts assess strategies combat explore genetic pharmacological targets, comorbid diseases. Finally, inspect applications products against their development pipelines drug repurposing. objective broad overview evolving regarding AD, outline challenges, evaluate growth opportunities further combating

Language: Английский

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Advances in Blood Biomarkers for Alzheimer’s Disease: Ultra-Sensitive Detection Technologies and Impact on Clinical Diagnosis

Degenerative Neurological and Neuromuscular Disease, Journal Year: 2024, Volume and Issue: Volume 14, P. 85 - 102

Published: July 1, 2024

Abstract: Alzheimer's disease has escalated into a critical public health concern, marked by its neurodegenerative nature that progressively diminishes cognitive abilities. Recognized as continuously advancing and presently incurable condition, AD underscores the necessity for early-stage diagnosis interventions aimed at delaying decline in mental function. Despite proven efficacy of cerebrospinal fluid positron emission tomography diagnosing AD, their broader utility is constrained significant costs invasive these procedures. Consequently, innovation blood biomarkers such Amyloid-beta, phosphorylated-tau, total-tau et al, distinguished high sensitivity, minimal invasiveness, accessibility, cost-efficiency, emerges promising avenue diagnosis. The advent ultra-sensitive detection methodologies, including single-molecule enzyme-linked immunosorbent assay immunoprecipitation-mass spectrometry, revolutionized plasma biomarkers, supplanting previous low-sensitivity techniques. This rapid advancement technology facilitates more accurate quantification pathological brain proteins AD-associated bloodstream. manuscript meticulously reviews landscape current research on immunological markers anchored National Institute Aging—Alzheimer's Association AT(N) framework. It highlights selection forefront technologies now integral to assessing markers. Additionally, this review examines crucial pre-analytical processing steps samples significantly impact outcomes addresses practical challenges faced during clinical testing. These discussions are enhancing our comprehension refining diagnostic precision using blood-based biomarkers. aims shed light potential avenues improvement techniques employed detecting investigating thereby contributing field research. Keywords: disease, blood, technologies,

Language: Английский

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Blood-derived mitochondrial DNA copy number is associated with Alzheimer disease, Alzheimer-related biomarkers and serum metabolites

Alzheimer s Research & Therapy, Journal Year: 2024, Volume and Issue: 16(1)

Published: Oct. 23, 2024

Blood-derived mitochondrial DNA copy number (mtDNA-CN) is a proxy measurement of function in the peripheral and central systems. Abnormal mtDNA-CN not only indicates impaired mtDNA replication transcription machinery but also dysregulated biological processes such as energy lipid metabolism. However, relationship between Alzheimer disease (AD) unclear. We performed two-sample Mendelian randomization (MR) using publicly available summary statistics from GWAS for AD to investigate causal AD. estimated whole-genome sequence data blood brain samples 13,799 individuals Alzheimer's Disease Sequencing Project. Linear Cox proportional hazards models adjusting age, sex, study phase were used assess association with The biomarkers serum metabolites was evaluated Neuroimaging Initiative linear regression. conducted mediation analysis test natural indirect effects change on risk through significantly associated metabolites. MR suggested decreased blood-derived increased (OR = 0.68; P 0.013). Survival showed that higher conversion mild cognitive impairment (HR 0.80; 0.002). identified significant associations FDG-PET (β 0.103; 0.022), amyloid-PET 0.117; 0.034), CSF amyloid-β (Aβ) 42/40 (β=-0.124; 0.017), t-Tau 0.128; 0.015), p-Tau 0.140; 0.008), plasma NFL 0.004) females. Several species, amino acids, biogenic amines mtDNA-CN. Causal analyses about third effect mediated by (P 0.009), this more females < 0.005). Our measured predictive including particularly Further, we illustrate possibly increases dysregulation metabolism inflammation.

Language: Английский

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