Current Alzheimer research最新文献

{"title":"Association between Obesity and Cognitive Function in Chinese Older Adults: The Mediating Effects of Sleep Quality and Blood Pressure.","authors":"Shiyi Li, Chan Yong, Yingchao Xiong, Nanyan Li, Zhaowei Yue, Wennuo Liu, Qianqian Liu, Xianlan Li, Qin Ye, Yufei Wang, Junmin Zhou","doi":"10.2174/0115672050381084250528160239","DOIUrl":"https://doi.org/10.2174/0115672050381084250528160239","url":null,"abstract":"<p><strong>Introduction: </strong>The mechanisms underlying the relationship between obesity and cognitive function remain unclear, particularly among older adults, where reliable evidence is limited. This study aimed to explore whether the relationship between obesity and cognitive function is mediated by sleep quality and blood pressure (BP) in older Chinese adults.</p><p><strong>Methods: </strong>We conducted an observational study using data from a cluster randomized controlled trial (RCT) with 5 follow-up periods involving older adults in rural China. The trial took place in Sichuan, China, from May 2021 to May 2023. Telephone Interview for Cognitive Status (TICS- 10) was used to assess the participants' cognitive function. Additionally, linear mixed-effects models and mediation analyses were performed.</p><p><strong>Results: </strong>The mean age of participants was 70.89, and 225 out of 506 participants were males. Weight, waist circumference (WC), and hip circumference (HC) were positively associated with cognitive function, while compared to normal/underweight participants, participants with overweight had a significant association with cognitive function. Sleep quality mediated the association between weight and cognitive function (β = 0.01, [95% CI: 0.00 to 0.01], P < 0.001), accounting for a mediating effect proportion of 4.04% [95% CI: 2.19% to 8.00%]. Diastolic blood pressure (DBP) mediated the association between overweight (β = 0.02, [95% CI: 0.00 to 0.05], P < 0.001), HC (β = 0.01, [95% CI: 0.00 to 0.01], P = 0.02), and WC (β = 0.01, [95% CI: 0.00, 0.01], P <0.001) and cognitive function, explaining approximately 4.46% (95% CI: 0.41% to 12.00%), 7.16% (95% CI: 0.36%, 17.00%), and 9.60% (95% CI: 1.11%, 25.00%) mediating proportion of the total effect, respectively.</p><p><strong>Discussion: </strong>Our study highlights the potential mediating roles of sleep quality and DBP in the relationship between obesity and cognitive function. The findings contribute to understanding the obesity-cognition link in older adults, particularly in rural settings. However, limitations, such as self-reported sleep measures and unmeasured confounders, warrant caution. Further research is needed to clarify the underlying mechanisms and inform targeted interventions.</p><p><strong>Conclusion: </strong>Our study demonstrates a significant positive association between weight, body mass index (BMI), HC, and WC and cognitive function in older adults. These findings suggest that maintaining a moderately high level of adiposity may be protective against cognitive decline in this population. Additionally, the study also provides insights into optimizing cognitive function through factors, such as sleep and BP management.</p>","PeriodicalId":94309,"journal":{"name":"Current Alzheimer research","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144201260","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic Advances in Alzheimer's Disease: Integrating Natural, Semi-Synthetic, and Synthetic Drug Strategies.","authors":"Brijesh Singh Chauhan, Yash Pal Singh, Burkhard Poeggeler, Sandeep Kumar Singh","doi":"10.2174/0115672050366727250513061730","DOIUrl":"https://doi.org/10.2174/0115672050366727250513061730","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a neurodegenerative disorder associated with age, marked by progressive memory loss linked to the decline of cholinergic neurons, accumulation of amyloid plaques, and the presence of Neurofibrillary Tangles (NFTs). Neuropil threads in the brain contribute to amyloidosis and dementia. Despite extensive research, AD's etiology remains unclear, and currently, no promising therapy exists. This review examines the role of natural, semi-synthetic, and synthetic drugs in AD treatment. Natural drugs demonstrate safety and efficacy with minimal adverse effects, while most agents, whether natural or synthetic, target multiple steps or directly counteract amyloidogenesis, tau protein pathology, oxidative stress, NMDA receptor activity, inflammation, acetylcholine (AChE) function, or α, β, γ secretase activity. In pursuit of improved treatment outcomes, we explore the effectiveness and challenges of various therapeutic interventions. Our hypothesis underscores the importance of an integrated approach combining these drug types for tailored symptom relief, suggesting combined therapies may offer greater therapeutic benefits compared to single-drug approaches. The drugs discussed show potential in regulating AD, thereby presenting viable options for its management. However, to obtain more favorable results, additional studies are needed by combining these drugs.</p>","PeriodicalId":94309,"journal":{"name":"Current Alzheimer research","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144201261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anthocyanidins Intake is Associated with Alzheimer's Disease Risk in Americans over 60 Years of Age: Data from NHANES 2007-2008, 2009-2010, and 2017-2018.","authors":"Yan Chen, Jingyi Zhao, Chen Li, Yinhui Yao, Yazhen Shang","doi":"10.2174/0115672050372100250512054404","DOIUrl":"https://doi.org/10.2174/0115672050372100250512054404","url":null,"abstract":"<p><strong>Objective: </strong>At present, there is limited research on the association between dietary intake of anthocyanidins and Alzheimer's disease (AD). More epidemiological studies are needed to better understand this relationship.</p><p><strong>Methods: </strong>We explored the relationship between dietary Anthocyanidins intake and AD among 3806 American adults in the National Health and Nutrition Examination Survey (NHANES) and the United States Department of Agriculture's Food and Nutrient Database for Dietary Studies (FNDDS) from 2007 to 2010, and 2017 to 2018. We use weighted logistic regression model, restricted cubic spline (RCS) and weighted quantile sum (WQS) regression analysis to analyze the relationship between anthocyanidins monomer and AD.</p><p><strong>Results: </strong>The weighted logistic regression model showed that the total intake of anthocyanidins was the fourth (OR:0.979; 95% CI: 0.966-0.992) quantile (relative to the lowest quantile) is related to the reduction of AD risk. RCS analysis showed that the total intake of anthocyanidins was negatively linearly correlated with AD (nonlinear P value was 0.002). The WQS regression analysis shows that cyanidin and malvidin are the main contributors to the comprehensive effects of six anthocyanidins.</p><p><strong>Conclusion: </strong>Our results show that a higher dietary intake of anthocyanidins is associated with a lower risk of AD.</p>","PeriodicalId":94309,"journal":{"name":"Current Alzheimer research","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144201259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluating the Therapeutic Effects of Oxytocin on Animal Model of Alzheimer's Disease: A Systematic Review.","authors":"Ensieh Shafigh, Giti Sadeghi, Negar Abbasi Jamat, Fatemeh Hassanpour, Moslem Solhirad, Leila Karimi-Zandi","doi":"10.2174/0115672050386593250521064527","DOIUrl":"https://doi.org/10.2174/0115672050386593250521064527","url":null,"abstract":"<p><strong>Introduction: </strong>Alzheimer's Disease (AD) is the most prevalent progressive neurodegenerative disorder, leading to significant cognitive decline and dementia. Oxytocin (OXT), a peptide hormone synthesized in the hypothalamus, has emerged as a critical player in cognitive functioning. Notably, alterations in OXT levels have been reported in individuals with Alzheimer's disease.</p><p><strong>Methods: </strong>This systematic review aims to synthesize existing literature from databases such as PubMed, Scopus, and Web of Science, focusing on the therapeutic potential of OXT in AD treatment. Two independent individuals conducted the screening procedure for all articles.</p><p><strong>Results: </strong>Our screening revealed that studies investigating OXT therapy primarily involve animal models. These studies consistently demonstrate that, OXT administration mitigates various memory deficits in animal models of AD. These improvements are linked to mechanisms such as reduced microglial-driven inflammation and decreased amyloid-beta (Aβ) deposition, but changes in plaque load do not always correspond directly to cognitive improvement.</p><p><strong>Discussion: </strong>While these findings are promising and oxytocin could be a potential therapeutic candidate for AD, the evidence is limited to animal studies. There is a lack of robust human data, making it difficult to draw firm conclusions about oxytocin's efficacy in people with AD. Ongoing and future clinical trials will be crucial to determine whether these preclinical benefits translate to humans.</p><p><strong>Conclusion: </strong>Despite the limited number of studies examining the effects of OXT on AD and the inherent challenges in conducting such research, the available evidence from animal studies suggests promising results. These findings can serve as a valuable foundation for future human and complementary studies aimed at exploring oxytocin's therapeutic potential in treating AD.</p>","PeriodicalId":94309,"journal":{"name":"Current Alzheimer research","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144145374","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IoMT Requirements, Integrated Diagnosis, and Future Trends for Multimodal Early Detection of Alzheimer's Disease.","authors":"Mohamadreza Mohammad Khosravi, Hossein Parsaei","doi":"10.2174/0115672050393916250520101258","DOIUrl":"https://doi.org/10.2174/0115672050393916250520101258","url":null,"abstract":"","PeriodicalId":94309,"journal":{"name":"Current Alzheimer research","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144145378","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Environmental Enrichment and Metformin Combination Improves Cognitive Function through BDNF and HPA Axis in Chronically Stressed Rats.","authors":"V Bhagya, K Tilak, L Kanimozhi, R Sushma","doi":"10.2174/0115672050379003250520072717","DOIUrl":"https://doi.org/10.2174/0115672050379003250520072717","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Introduction: &lt;/strong&gt;Chronic stress is a major global health issue linked to conditions such as anxiety, depression, and cognitive decline. In rodent studies, chronic immobilization stress (CIS) is commonly used to investigate the neuropsychological effects of prolonged stress, leading to behaviours such as anhedonia, anxiety, and depressive-like symptoms. An enriched environment (EE) provides physical, cognitive, and sensory stimulation, which promotes social interaction, supports brain development, and can enhance the effectiveness of pharmacological treatments, improving overall therapeutic outcomes. Metformin, commonly prescribed for type 2 diabetes, has antidiabetic effects and helps reduce oxidative stress, inflammation, and cell death in the brain, which may contribute to its neuroprotective properties. This study aims to evaluate the effectiveness of metformin, an enriched environment (EE), and its combination in alleviating anxiety and depression-like behaviours, memory impairments, and metabolic changes.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Materials and methods: &lt;/strong&gt;Rats were exposed to chronic immobilization stress (CIS) for 2 hours per day over a period of 10 days, followed by 14 days of treatment with metformin (200 mg/kg) and 6 hours of daily exposure to an enriched environment (EE). Behavioural tests, including the open field test (OFT), elevated plus maze (EPM), sucrose preference test (SPT), and novel object recognition test (NORT), were conducted. After completing the behavioural assessments, the animals were euthanized, and their plasma levels of corticosterone (CORT), high-density lipoprotein (HDL), low-density lipoprotein (LDL), cholesterol, triglycerides, and glucose were measured. Additionally, the concentration of brainderived neurotrophic factor (BDNF) in the hippocampus was analysed.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Rats exposed to chronic immobilization stress (CIS) exhibited increased anxiety and depressive- like behaviours, as well as poor performance in the novel object recognition test (NORT). These behavioural changes were linked to elevated levels of plasma corticosterone (CORT), LDL, cholesterol, triglycerides, and glucose, along with decreased HDL levels and lower hippocampal BDNF. Treatment with metformin, an enriched environment (EE), or their combination alleviated these effects, improving exploratory behaviour, sucrose preference, and recognition memory and reducing anxiety-like behaviours. These benefits were accompanied by increased hippocampal BDNF expression, elevated plasma HDL, and reduced levels of CORT, LDL, cholesterol, triglycerides, and glucose.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Discussion: &lt;/strong&gt;The combination of metformin and an enriched environment completely restored cognitive impairment and metabolic alterations in chronic stress conditions. Metformin's ability to improve energy metabolism and reduce oxidative stress could be further enhanced in an enriched environment, which promotes cognitive function and resil","PeriodicalId":94309,"journal":{"name":"Current Alzheimer research","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144145373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predictive Value of Complete Blood Count Parameters for Alzheimer's Disease in Relation to Periodontal Status.","authors":"Kubra Karaduran, Ahmet Aydogdu, Ozlem Gelisin, Sadiye Gunpinar","doi":"10.2174/0115672050388220250511174043","DOIUrl":"https://doi.org/10.2174/0115672050388220250511174043","url":null,"abstract":"<p><strong>Introduction/objective: </strong>Given the role of inflammation in the development of both Alzheimer's disease (AD) and periodontal disease, it is plausible that periodontal disease may influence the progression of AD. Complete blood count (CBC) parameters may also serve as predictive indicators for this condition. This study investigated the predictive value of CBC parameters on the progression of AD in patients with periodontal disease.</p><p><strong>Methods: </strong>Data from a prospective cohort study (n=90) with 6-month follow-up was analyzed. AD was assessed based on the Clinical Dementia Rating Scale. Records of C-reactive Protein (CRP) levels and CBC parameters measured within the 6 months preceding the participation date were evaluated. Cognitive assessments at the initial and 6th-month follow-up were performed using the Standardized Mini-Mental Test (SMMT). All patients underwent clinical periodontal examination.</p><p><strong>Results: </strong>The difference in SMMT score change (ΔSMMT) and platelet distribution width (PDW) value between groups with and without periodontitis was statistically notable (p<0.05). The presence of periodontitis was found to be significantly associated with age, ΔSMMT, and PDW values using the multivariate logistic regression model (p<0.05). Furthermore, having Stage II and Stage III AD, periodontitis, age factor, and mean platelet volume (MPV) value had a notable impact on ΔSMMT (p<0.05).</p><p><strong>Conclusion: </strong>PDW and MPV levels may have a predictive significance in clarifying the association between periodontitis and AD progression.</p>","PeriodicalId":94309,"journal":{"name":"Current Alzheimer research","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144113311","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association Between Serum Lipid Traits and Cognitive Function in Middle-aged and Elderly Adults: A Longitudinal Study.","authors":"Chuning Luo, Qin Li, Ran Gao, Yijun Zhang, Yijie Wang, Fengyi Huang, Quanmei Li, Xite Zheng, Xiaorui Zhang, Wanqi Liu, Fen Liu","doi":"10.2174/0115672050370810250430112549","DOIUrl":"https://doi.org/10.2174/0115672050370810250430112549","url":null,"abstract":"<p><strong>Background: </strong>It is debatable whether demographic factors alter the relationship between serum lipid traits and cognitive function. Few data have examined the effects of non-traditional lipid metrics on the lipid-cognition relationship. We aim to test the generality of relationships between lipid traits and cognitive function in Chinese adults.</p><p><strong>Methods: </strong>Data from 5,959 participants were obtained from the China Health and Retirement Longitudinal Study (2011-2020). The cognitive function was assessed via the Mini-Mental State Examination. Effects of traditional lipid metrics (Total Cholesterol, TC, Triglycerides, TG, Low-Density Lipoprotein, LDL, High-Density Lipoprotein, HDL) and non-traditional lipid metrics (TC/HDL, LDL/HDL) were analyzed. We employed mixed-effect models, Group-Based Trajectory Models (GBTM), and logistic regression to examine the associations between baseline serum lipid traits and cognitive function.</p><p><strong>Results: </strong>As continuous variables, higher TG levels were correlated with higher cognitive scores (P=0.036), and similar patterns were found in TC/HDL (P < 0.01) and LDL/HDL (P < 0.01). In contrast, higher HDL levels were associated with lower cognitive scores. Similar trends were observed when lipid traits were analyzed as categorical quartiles, and grouped by gender and age. Non-traditional lipid metrics (LDL/HDL, TC/HDL) had higher contributions to the variation of cognitive scores than traditional lipid metrics (TC, TG, LDL, HDL).</p><p><strong>Conclusion: </strong>Our study provided evidence for the generality of a significant association between traditional/non-traditional lipid metrics and cognitive function in middle-aged and elderly adults. The factors that vary with genders and age groups do not appear to significantly alter the lipid-cognition relationship.</p>","PeriodicalId":94309,"journal":{"name":"Current Alzheimer research","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144083127","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigating the Relationships Between Neurodegenerative Diseases and Cancer Types: A Computational Approach.","authors":"Claudia Cava, Isabella Castiglioni","doi":"10.2174/0115672050389561250429112631","DOIUrl":"https://doi.org/10.2174/0115672050389561250429112631","url":null,"abstract":"<p><strong>Introduction: </strong>Previous studies have shown a correlation between neurodegenerative diseases and cancers. However, the biological processes for these diseases are not completely known, and the genetic factors for their onset are not defined.</p><p><strong>Materials and methods: </strong>This study reports the genetic relationships of different neurodegenerative diseases, such as Multiple Sclerosis (MS), Alzheimer's Disease (AD), and Parkinson's disease (PD) and cancer types (squamous cell lung carcinoma, esophageal adenocarcinoma, and colorectal cancer), with other human traits, based on cross-trait Linkage Disequilibrium Score regression (LDSC). We then applied a clumping approach to select candidate genes for each disease, and via an miRNA analysis, we identified miRNAs that could regulate those genes.</p><p><strong>Results: </strong>LDSC revealed an inverse association of human traits with neurodegenerative diseases and cancer. Indeed, the cancer types studied were positively correlated with \"Body Mass Index (BMI),\" while AD, PD, and MS showed a negative correlation. miR-1-3p, miR-34a-5p, and miR-27a-3p were revealed as common biomarkers among the different pathological conditions.</p><p><strong>Conclusion: </strong>The present study suggests novel genetic associations between neurological diseases, cancer types and new targets to explain the genetic sharing between the diseases.</p>","PeriodicalId":94309,"journal":{"name":"Current Alzheimer research","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144051536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Framework for an Integrative Theory of Alzheimer's Disease.","authors":"Dmitry V Zaretsky, Maria V Zaretskaia","doi":"10.2174/0115672050381553250425062803","DOIUrl":"https://doi.org/10.2174/0115672050381553250425062803","url":null,"abstract":"<p><p>The manuscript describes how the framework of the integrative hypothesis of Alzheimer's disease (AD) can be deciphered using existing experimental and clinical data. First, the analysis of amyloid biomarkers and stable-isotope label kinetics (SILK) studies indicate a correlation between AD diagnosis and heightened cellular uptake of beta-amyloid. Since beta-amyloid must be taken up by cells to become toxic, its uptake rate correlates with neurodegeneration. Also, aggregation seeds cannot form extracellularly due to low beta-amyloid levels in interstitial fluid but can develop inside lysosomes. Consequently, the density of extracellular aggregates correlates positively with cellular amyloid uptake rate. The model, which ties both beta-amyloid cytotoxicity and aggregation to cellular uptake, accurately predicts AD diagnosis patterns in the population. Second, beta-amyloid enters cells through endocytosis. Endocytosed beta-amyloid induces lysosomal permeabilization that occurs without plasma membrane damage and explains intracellular ion disturbances (including calcium overload) after exposure to extracellular beta-amyloid. The permeabilization is caused by channels formed in lysosomal membranes by some amyloid fragments produced by proteolysis of full-length beta-amyloid. Some membrane channels are large enough to leak cathepsins to the cytoplasm, causing necrosis or apoptosis. Also, local spikes of calcium cytosolic concentration due to calcium leakage from lysosomes can activate calpains, contributing to cell death. In surviving cells, accumulation of damaged lysosomes results in autophagy failure and slow mitochondrial recycling, promoting the production of reactive oxygen species and further cell damage. In this framework, AD's etiology is the membrane channel formation by amyloid fragments produced in lysosomes. The pathogenesis includes lysosomal permeabilization and the appearance of activated proteases in the cytoplasm. The correlation between AD diagnosis and the density of amyloid aggregates occurs because both amyloid cytotoxicity and extracellular aggregate formation stem from cellular amyloid uptake. To reflect key processes, we call this framework the Amyloid Degradation Toxicity Hypothesis of Alzheimer's Disease. It explains various phenomena and paradoxes associated with AD pathobiology across molecular, cellular, and biomarker levels. The hypothesis also highlights the limitations of current AD biomarkers and suggests new diagnostic and prognostic tools based on disease pathogenesis. Additionally, the framework identifies potential pharmacological targets for preventing disease progression.</p>","PeriodicalId":94309,"journal":{"name":"Current Alzheimer research","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144060801","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}