Alzheimer's Research & Therapy最新文献

{"title":"The economic burden of subjective cognitive decline, mild cognitive impairment and Alzheimer's dementia: excess costs and associated clinical and risk factors.","authors":"Eva Gläser, Ingo Kilimann, Moritz Platen, Wolfgang Hoffmann, Frederic Brosseron, Katharina Buerger, Marie Coenjaerts, Emrah Düzel, Michael Ewers, Klaus Fliessbach, Ingo Frommann, Maria Gemenetzi, Wenzel Glanz, Julian Hellmann-Regen, Enise I Incesoy, Daniel Janowitz, Frank Jessen, Oliver Peters, Josef Priller, Alfredo Ramirez, Anja Schneider, Annika Spottke, Eike Jakob Spruth, Stefan Teipel, Michael Wagner, Bernhard Michalowsky","doi":"10.1186/s13195-025-01785-9","DOIUrl":"https://doi.org/10.1186/s13195-025-01785-9","url":null,"abstract":"<p><strong>Background: </strong>With the availability of first disease-modifying treatments, evidence on costs across the entire Alzheimer's Continuum, especially for early disease stages, becomes increasingly important to inform healthcare planning, resource allocation, and policy decisions. This study assessed costs and cost-associated factors in patients with subjective cognitive decline (SCD), mild cognitive impairment (MCI) and Alzheimer's Disease (AD) dementia compared to healthy controls.</p><p><strong>Methods: </strong>The German DELCODE cohort study assessed clinical data, healthcare resource use, and informal care provision. Costs were calculated from payer and societal perspectives using standardized unit costs, and multivariate regression analyses identified cost-associated factors.</p><p><strong>Results: </strong>From a payer perspective, costs were elevated by 26% for SCD (adjusted mean 5,976€ [95%CI 4,598-7,355€]), 85% for MCI (8,795€ [6,200-11,391€]) and 36% for AD (6,454€ [2,796-10,111€]) compared to controls (4,754€ [3,586-5,922€]). Societal costs were elevated by 52% for SCD (adjusted mean 8,377€ [95%CI 6,009-10,746€]), 170% for MCI (14,886€ [9,524-20,248€]) and 307% for AD (22,481€ [9,994-34,969€]) compared to controls (5,522€ [3,814-7,230€]). APOE e4 negative patients showed higher costs compared to APOE e4 positive patients. Hypertension was associated with higher costs.</p><p><strong>Conclusions: </strong>Healthcare costs are already elevated in early subjective and objective cognitive impairment, driven by formal and informal care. The study emphasizes the importance of early interventions to reduce the economic burden and delay progression.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"142"},"PeriodicalIF":7.9,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144504476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Photobiomodulation mitigates blood-brain barrier disruption in APP/PS1 mouse model of Alzheimer's disease by activating the AMPK pathway.","authors":"Chunyan Ma, Yutong Ye, Xinyu Shi, Na Li, Zhiming Mu, Tao Tan, Huijuan Yin, Jianwu Dai, Yi Liu, Hongli Chen","doi":"10.1186/s13195-025-01787-7","DOIUrl":"10.1186/s13195-025-01787-7","url":null,"abstract":"<p><strong>Background: </strong>Photobiomodulation (PBM), which utilizes specific light wavelengths to regulate cellular metabolism, signal transduction, and gene expression, has emerged as a promising intervention for enhancing cognitive function in Alzheimer's disease (AD). The blood-brain barrier (BBB) plays a critical role in protecting the central nervous system, and its dysfunction is a major contributor to AD pathogenesis. Although PBM has shown therapeutic potential, its effects on BBB integrity and the underlying mechanisms remain unclear.</p><p><strong>Methods: </strong>Six-month-old female APP/PS1 transgenic mice were subjected to PBM intervention (808 nm, 20 mW/cm²) for six weeks. Cognitive function was assessed using behavioral tests, while biochemical and histological analyses were conducted to evaluate BBB integrity, β-amyloid (Aβ) deposition, and protein expression related to tight junction proteins (TJs). In vitro, an inflammatory model was established by treating brain microvascular endothelial cells (bEnd.3) with lipopolysaccharide (LPS) to induce an inflammatory response, and the mechanisms of PBM were further explored by analyzing mitochondrial function.</p><p><strong>Results: </strong>PBM significantly improved cognitive deficits and anxiety-like behaviors in AD mice. It enhanced BBB integrity by upregulating the TJs Occludin, Claudin-5, and ZO-1, while also facilitating Aβ clearance via the low-density lipoprotein receptor-related protein 1 (LRP1) pathway and microglial phagocytosis, thereby reducing Aβ accumulation in the brain. Mechanistically, PBM attenuated apoptosis and mitochondrial oxidative stress while promoting mitochondrial energy metabolism. Notably, PBM markedly increased phosphorylated AMPK (p-AMPK) levels in the brains of AD mice. In vitro, the protective effects of PBM on BBB integrity were substantially diminished upon AMPK inhibition, confirming that PBM exerts its neuroprotective effects through the activation of the AMPK pathway.</p><p><strong>Conclusion: </strong>This study demonstrates that PBM enhances BBB integrity and mitigates Aβ pathology in AD mice by activating the AMPK signaling pathway, underscoring its potential as a novel, non-invasive therapeutic strategy for AD.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"141"},"PeriodicalIF":7.9,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12183848/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144473683","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-term electroacupuncture and repetitive transcranial magnetic stimulation differentially slow the progression of Alzheimer's disease in App^NL-G-F mice.","authors":"Si-Min Song, Qian-Min Liu, Xi Huang, Ping Chen, Min Tao, Xia Pei, Hua-Ning Wang, Yan Han, Jian-Guo Chen, Wei Hong, Zhang-Jin Zhang","doi":"10.1186/s13195-025-01781-z","DOIUrl":"10.1186/s13195-025-01781-z","url":null,"abstract":"<p><p>Both electroacupuncture (EA) and repetitive transcranial magnetic stimulation (rTMS) possess the potential in combating the progression of Alzheimer's disease (AD). In this study, we compared the effects of the two regimens as early long-term intervention in App^NL-G-F mice, a new amyloid precursor protein (APP) knock-in model that recapitulates multiple AD-associated pathologies, including amyloid-β (Aβ) plaques, microgliosis, astrocytosis, dendritic and synaptic degeneration. The 2-month-old freely moving model mice randomly received EA or rTMS for 2~3 sessions a week for 6 months. Cognitive tests were conducted in Y maze and Barnes maze sequentially at the age of 4, 6, and 8 months. The cortex and hippocampus were dissected thereafter for neurohistological and molecular analysis. Both regimens markedly prevented cognitive deterioration at 6 months old. EA maintained its significant prevention to 8 months old, but rTMS did not. At this age, EA remarkably reduced Aβ burdens with particular dense-core plaques; rTMS had similar effects on Aβ plaques, but not on dense-core plaques. Both regimens displayed greater suppression on microgliosis in the cortex than in the hippocampus, and equivalently inhibited astrocytosis in the two brain regions. While both EA and rTMS protected against dendritic degeneration surrounding Aβ plaques, EA further mitigated synaptic loss. These results demonstrated that EA produced more long-lasting and broad-acting effects than rTMS in alleviating memory impairment and pathological products of AD. EA could serve as an early long-term intervention and rTMS as adjuvant therapy in slowing the progression of AD.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"140"},"PeriodicalIF":7.9,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12183856/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144473682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Edaravone-Dexborneol slows down pathological progression and cognitive decline via inhibiting S100A9 in APPswe/PS1dE9 mice.","authors":"Rui Mao, Shu Shu, Min Sun, Jiang Chen, Mengsha Hu, Lei Ye, Siyi Xu, Junqiu Jia, Wenxuan Shao, Xinyu Bao, Yun Xu, Xiaolei Zhu","doi":"10.1186/s13195-025-01777-9","DOIUrl":"10.1186/s13195-025-01777-9","url":null,"abstract":"<p><strong>Background: </strong>Edaravone-Dexborneol (EDB) presents therapeutic effects due to its anti-inflammatory, antioxidant and anti-apoptotic properties, and has been widely used in ischemic stroke. However, the detailed efficacy and potential target of EDB in Alzheimer's disease (AD) are still elusive.</p><p><strong>Methods: </strong>Male APPswe/PS1dE9 mice were administered with EDB intraperitoneally from 3.5 to 8 months of age. The cognition of mice was assessed by behavioral tests. Synaptic alternations in the hippocampus were detected by electrophysiology and Golgi staining. β-amyloid (Aβ) pathology was mainly observed by immunofluorescence. Oxidative stress-related indicators were evaluated by dedicated kits, while quantitative PCR and ELISA were used to detect pro-inflammatory factors. Proteomics analysis further identified the potential target of EDB.</p><p><strong>Results: </strong>EDB was capable of delaying the cognitive decline and ameliorating the synaptic loss in APPswe/PS1dE9 mice. In addition to the anti-inflammation and anti-oxidation effects, EDB treatment mightily ablated the Aβ plaque by promoting microglial phagocytosis. Particularly, we first discovered that EDB could directly bind to S100A9, a pathological molecule that aggravates Aβ pathology and induces oxidative stress and neuroinflammation. EDB inhibited the expression, functional threonine phosphorylation and self-assembly of S100A9.</p><p><strong>Conclusion: </strong>Our results indicate that EDB can improve cognitive function and slow down AD progression, and it may serve as a potential agent for AD and other S100A9-related diseases.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"139"},"PeriodicalIF":7.9,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12181868/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144339816","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Delphinidin attenuates cognitive deficits and pathology of Alzheimer's disease by preventing microglial senescence via AMPK/SIRT1 pathway.","authors":"Ying Liu, Ting Hong, Mingxuan Lv, Xiaoyu Guo, Panpan Zhang, Aijuan Yan, Wenshi Wei","doi":"10.1186/s13195-025-01783-x","DOIUrl":"10.1186/s13195-025-01783-x","url":null,"abstract":"<p><strong>Background: </strong>Emerging evidence suggests that senescent microglia play a role in β-amyloid (Aβ) pathology and neuroinflammation in Alzheimer's disease (AD). Targeting senescent cells with naturally derived compounds exhibiting minimal cytotoxicity represents a promising therapeutic strategy.</p><p><strong>Objectives: </strong>This study aimed to investigate whether delphinidin, a naturally occurring anthocyanin, can alleviate AD-related pathologies by mitigating microglial senescence and to elucidate the underlying molecular mechanisms.</p><p><strong>Methods: </strong>We employed APP/PS1 mice, naturally aged mice, and an in vitro model using Aβ42-induced senescent BV2 microglia. Delphinidin's effects were evaluated through assessments of cognitive function, synaptic integrity (synapse loss), Aβ plaque burden, senescent microglia gene signatures, and cellular senescence markers (including senescence-associated β-galactosidase activity, SASP factor expression, oxidative stress, and cyclin p21/p16 levels). Mechanistic studies involved analyzing the AMPK/SIRT1 signaling pathway, testing direct delphinidin-SIRT1 interaction, and using the AMPK inhibitor Compound C.</p><p><strong>Results: </strong>Delphinidin treatment significantly alleviated cognitive deficits, synapse loss, Aβ peptides plaques of APP/PS1 mice via downregulated senescent microglia gene signature, prevented cell senescence, including senescence-associated β-galactosidase activity, senescence-associated secretory phenotype (SASP), oxidative stress, cyclin p21 and p16. And delphinidin treatment also prevented microglial senescence in naturally aged mice. In vitro, delphinidin treatment attenuated cell senescence induced by Aβ42 in BV2 microglia cells. Further research indicated that delphinidin treatment enhanced the AMPK/SIRT1 signaling pathway. Additionally, delphinidin was found to directly interact with SIRT1. It's noteworthy that AMPK inhibitor Compound C inversed the protective effect of delphinidin against microglial senescence.</p><p><strong>Conclusion: </strong>Our study reveals for the first time that delphinidin effectively improved cognitive deficits, alleviated synapse loss and Aβ pathology in APP/PS1 mice by mitigating microglial senescence. These findings highlight delphinidin as a promising natural anti-aging agent against the development of aging and age-related diseases.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"138"},"PeriodicalIF":7.9,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12180243/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144336228","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A longitudinal study of the 5xFAD mouse retina delineates Amyloid beta (Aβ)-mediated retinal pathology from age-related changes.","authors":"Savannah A Lynn, Sudha Priya Soundara Pandi, Aida Sanchez-Bretano, Anna-Marie Muir, Lidia Parker, David S Chatelet, Tutte Newall, Jennifer A Scott, Eloise Keeling, Neil R Smyth, Jay E Self, Andrew J Lotery, Helena Lee, J Arjuna Ratnayaka","doi":"10.1186/s13195-025-01784-w","DOIUrl":"10.1186/s13195-025-01784-w","url":null,"abstract":"<p><strong>Background: </strong>Age-related macular degeneration (AMD) is the commonest cause of irreversible blindness in developed societies. AMD coincides with advanced age to which genetic and lifestyle factors contribute additional risks. High levels of the Alzheimer's-linked Amyloid beta (Aβ) proteins are correlated with aged/AMD retinas. To delineate the role of Aβ in retinopathy from age-related changes, we used transgenic 5xFAD mice in a longitudinal study to recapitulate the aged/AMD Aβ-burden of the human retina.</p><p><strong>Methods: </strong>Mice were genotyped to exclude the retinal degeneration alleles Pde6b^rd1, Pde6brd8, Agouti, Tyr and Oca2. Retinas of 5xFAD and wildtype littermates (97 males/females in total) were longitudinally assessed until 15 months using non-invasive retinal scans: multi-focal electroretinography, optokinetic tracking, optical coherence tomography (OCT), colour fundus photography and fluorescein angiography. Mice were killed at 4, 8 and 15 months, and eyes enucleated for analyses by light, confocal and electron microscopy.</p><p><strong>Results: </strong>Age-related changes included a gradual decline of retinal activity in all mice. Subretinal/drusen-like deposits increased with age, but, like retinal vessel morphology and vessel integrity, showed no differences between cohorts. Diminished PSD95 levels indicated impaired photoreceptor-bipolar connectivity which correlated with age. Ultrastructural imaging showed increased electron-dense granules and undigested outer segments within retinal pigment epithelial cells with age. 5xFAD pathology included significant weight reduction vs. wildtype/littermates, which were pronounced in females. 8 month old 5xFAD mice had diminished A and B waves, though the age-related decline in wildtype mice abolished these subsequently. Visual acuity/function was also reduced in 14 month 5xFAD eyes. OCT revealed thickened photoreceptor nuclei and inner segments in 8 month 5xFAD retinae. Scrutiny of chorioretinal tissues revealed diminished photoreceptor nuclei in 4 month 5xFAD eyes, though differences were abolished as both cohorts aged. From 8 months onwards, 5xFAD mice possessed fewer bipolar cell nuclei.</p><p><strong>Conclusions: </strong>Chronic Aβ exposure led to the earlier development of retinopathy-linked features, the identification of which advances our understanding of how Aβ contributes to multifaceted retinopathies. These were distinguishable from wider age-related changes and non-specific influences of retinal degeneration alleles in 5xFAD mice. Longitudinal analyses revealed sex and age-related limitations and important 3Rs considerations for future studies using 5xFAD mice.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"136"},"PeriodicalIF":7.9,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12177965/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144332292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Kidney function is associated with plasma ATN biomarkers among Hispanics/Latinos: SOL-INCA and HCHS/SOL results.","authors":"Natasha Z Anita, Wassim Tarraf, Sayaka Kuwayama, Freddie Márquez, Charles DeCarli, Bharat Thyagarajan, Nora Franceschini, James P Lash, Tanya Johns, Kevin A González, Martha Daviglus, Haibo Zhou, Ariana M Stickel, Frank J Penedo, Tatjana Rundek, Doug Galasko, Hector M González","doi":"10.1186/s13195-025-01786-8","DOIUrl":"10.1186/s13195-025-01786-8","url":null,"abstract":"<p><strong>Background: </strong>Plasma amyloid-tau-neurodegeneration (ATN) biomarker levels may be influenced by non-brain systems, such as kidney function, which could impact the interpretation of ATN biomarker results, particularly in groups like Hispanic/Latino individuals with higher rates of cardiometabolic health issues. Here, we examine the association between kidney function and plasma ATN markers among a diverse sample of Hispanic/Latino individuals living in the U.S.</p><p><strong>Methods: </strong>Data was collected from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL, Visit 1, 2008-2011), the largest prospective cohort study of noninstitutionalized Hispanic/Latino adults in the U.S., and its ancillary study, the Study of Latinos-Investigation of Neurocognitive Aging (SOL-INCA) which was conducted during the second visit of the parent HCHS/SOL study (Visit 2, 2015-2018). SOL-INCA aimed to examine the neurocognitive decline of middle-aged and older Hispanic/Latino adults, and the inclusion criteria were the age of 50-years and older by Visit 2 and completion of battery of neurocognitive tests at Visit 1. Survey linear regression models were used to examine associations between CKD status (estimated glomerular filtration rate [eGFR] < 60 ml/min/1.73m² or urine albumin-creatinine ratio [uACR]) > = 30 mg/g) and the plasma ATN biomarkers (β-amyloid 42/40 ratio [Aβ42/40 ratio], phosphorylated-tau181 [p-Tau181], neurofilament light [NfL], and glial fibrillary associated protein [GFAP]), independently. All models adjusted for sociodemographic and cardiometabolic factors (BMI, diabetes, and hypertension).</p><p><strong>Results: </strong>5,968 participants were included in the study (mean age 63.4 ± 8.1, 54% women). CKD was associated with higher p-Tau181 (b = 0.82), NfL (b = 11.60) and GFAP levels (b = 31.41), and lower Aβ42/Aβ40 ratio (b=-0.004). Lower eGFR (i.e., reduced kidney function) was associated with higher p-Tau181, NfL, and GFAP levels (b ranges [-0.87 - -0.03]), and lower Aβ42/Aβ40 ratio (b = 0.000). Higher (natural log) uACR was associated with lower Aβ42/Aβ40 ratio and higher levels of all other biomarkers (b ranges [0.24-5.49]). Additionally, CKD, eGFR, and uACR were associated with ATN biomarkers in models adjusted for cardiometabolic risk factors, diabetes and hypertension.</p><p><strong>Conclusions: </strong>CKD status, kidney function and urinary markers of kidney damage are significant confounders in the interpretation of plasma ATN biomarker levels.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"137"},"PeriodicalIF":7.9,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12180232/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144332306","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proteome-wide association studies using summary pQTL data of brain, CSF, and plasma identify 30 risk genes of Alzheimer's disease dementia.","authors":"Tingyang Hu, Qiang Liu, Qile Dai, Aron S Buchman, David A Bennett, Shinya Tasaki, Yanling Wang, Nicholas T Seyfried, Philip L De Jager, Michael P Epstein, Jingjing Yang","doi":"10.1186/s13195-025-01774-y","DOIUrl":"10.1186/s13195-025-01774-y","url":null,"abstract":"<p><strong>Background: </strong>A proteome-wide association study (PWAS) that integrates proteomic data with genome-wide association study (GWAS) summary data is a powerful tool for studying Alzheimer's disease (AD) dementia. Existing PWAS analyses of AD often rely on the availability of individual-level proteomic and genetic data of a reference panel. Leveraging summary protein quantitative trait loci (pQTL) reference data of multiple AD-relevant tissues is expected to improve PWAS findings of AD dementia.</p><p><strong>Methods: </strong>We conducted PWAS by integrating publicly available summary pQTL data of three tissues including brain, cerebrospinal fluid (CSF), and plasma, with the latest GWAS summary data of AD dementia. For each target protein per tissue, we employed our recently published OTTERS tool to obtain omnibus PWAS p-value, testing whether the genetically regulated protein abundance in the corresponding tissue is associated with AD dementia. Protein-protein interactions and enriched pathways of identified significant PWAS risk genes were analyzed by STRING. The potential causal effects of these PWAS risk genes were assessed by probabilistic Mendelian Randomization analyses.</p><p><strong>Results: </strong>We identified 30 unique significant PWAS risk genes for AD dementia, including 11 for brain, 10 for CSF, and 16 for plasma tissues. Five of these were shared by at least two tissues, and gene MAPK3 was found in all three tissues. We found that 11 of these PWAS risk genes were associated with AD dementia or AD pathology traits in GWAS Catalog; 18 of these were detected by transcriptome-wide association studies (TWAS) in dorsolateral prefrontal cortex brain tissue; and 25 of these, including 8 out of 9 novel genes, were interconnected within a protein-protein interaction network involving the well-known AD risk gene APOE. These PWAS risk genes were enriched in immune response, glial cell proliferation, and high-density lipoprotein particle clearance pathways. Mediated causal effects were validated for 13 PWAS risk genes (43.3%).</p><p><strong>Conclusions: </strong>Our findings provide novel insights into the genetic mechanisms of AD dementia in brain, CSF, and plasma, and provide targets for developing new therapies. This study also demonstrates the effectiveness of integrating summary pQTL and GWAS data for mapping risk genes of complex human diseases.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"135"},"PeriodicalIF":7.9,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12175411/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144324167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Independent validation and outlier analysis of EuroPOND alzheimer's disease staging model using ADNI and real-world clinical data.","authors":"Mandy M J Wittens, Diana M Sima, Arne Brys, Hanne Struyfs, Ellis Niemantsverdriet, Ellen De Roeck, Christine Bastin, Florence Benoit, Bruno Bergmans, Jean-Christophe Bier, Peter Paul de Deyn, Olivier Deryck, Bernard Hanseeuw, Adrian Ivanoiu, Gaëtane Picard, Eric Salmon, Kurt Segers, Anne Sieben, Evert Thiery, Jos Tournoy, Anne-Marie van Binst, Jan Versijpt, Dirk Smeets, Maria Bjerke, Maura Bellio, Neil P Oxtoby, Daniel C Alexander, Annemie Ribbens, Sebastiaan Engelborghs","doi":"10.1186/s13195-025-01788-6","DOIUrl":"10.1186/s13195-025-01788-6","url":null,"abstract":"<p><strong>Background: </strong>Event-based modeling (EBM) traces sequential progression of events in complex processes like neurodegenerative diseases, adept at handling uncertainties. This study validated an EBM for Alzheimer's disease (AD) staging designed by EuroPOND, an EU-funded Horizon 2020 project, using research and real-world datasets, a crucial step towards application in multi-center trials.</p><p><strong>Methods: </strong>The training dataset comprised 1737 subjects from ADNI-1/GO/2, using the EuroPOND EBM toolbox. Testing datasets included a research cohort from University of Antwerp (controls, CN (n = 46), subjective cognitive decline, SCD (n = 10), mild cognitive impairment, MCI (n = 47), AD dementia, ADD (n = 16)) and a real-world cohort from 9 Belgian Dementia Council memory clinics (CN (n = 91), SCD (n = 66), (non-amnestic) naMCI (n = 54), aMCI (n = 255), and ADD (n = 220). Biomarkers included: 2 clinical scores (Mini Mental State Examination (MMSE), Rey Auditory Verbal Learning Test (RAVLT)); 3 CSF-biomarkers (Aβ_1-42, P-tau₁₈₁, total-Tau); and 4 magnetic resonance imaging (MRI) biomarkers (volumes of the hippocampi, temporal, parietal, and frontal cortices) computed with icobrain dm. The naMCI and aMCI groups were compared by EBM stage proportions, and the model's effectiveness at patient level was evaluated.</p><p><strong>Results: </strong>The research cohort's maximum likelihood event sequence comprised CSF Aβ_1-42, P-tau₁₈₁, T-tau, RAVLT, MMSE, and cortical volumes. The clinical cohort's order was frontal cortex volume, MMSE, and remaining cortical regions. aMCI subjects showed higher staging than naMCI, with 54% in the two most advanced stages compared to 38% in naMCI. In the research cohort, 10 outliers were identified with potential mismatches between assigned stages and clinical or biomarker profiles, with CN (n = 4) and SCD (n = 2) subjects assigned in stage 4, one control in stage 9 with abnormal imaging, and three aMCI cases in stage 0 despite clinical or volumetric signs of impairment.</p><p><strong>Conclusions: </strong>This study highlights the generalizability of EuroPOND's AD EBM model across research and real-world clinical datasets, supporting its use in multi-center trials. aMCI subjects generally reside in more advanced stages than naMCI, who may not necessarily have AD, demonstrating utility for precision recruitment/screening.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"134"},"PeriodicalIF":7.9,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12172318/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309420","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic background and multidomain interventions in mild cognitive impairment.","authors":"Kosuke Fujita, Tetsuaki Kimura, Akiko Yamakawa, Shumpei Niida, Kouichi Ozaki, Takashi Sakurai, Hidenori Arai, Daichi Shigemizu","doi":"10.1186/s13195-025-01764-0","DOIUrl":"10.1186/s13195-025-01764-0","url":null,"abstract":"<p><strong>Background: </strong>The growing prevalence of dementia emphasizes the need for effective prevention strategies. Although the partial efficacy of multidomain interventions for dementia prevention has been demonstrated, understanding the characteristics of individuals who benefit most from these interventions is crucial for optimizing resource allocation. This study investigated the association between participants' genetic backgrounds and the effectiveness of multidomain interventions for preventing dementia.</p><p><strong>Methods: </strong>This study utilized data from the Japan-Multimodal Intervention Trial for the Prevention of Dementia (J-MINT), where older adults with mild cognitive impairment underwent 18 months of multidomain intervention. The intervention included exercise, nutrition, cognitive stimulation, social participation, and vascular risk management. Participants who completed the J-MINT intervention and had genetic data, including whole-genome sequencing (WGS), were analyzed. Using Japanese polygenic risk scores (PRSs) for Alzheimer's disease, participants were stratified into high- and low-genetic-risk groups. Cognitive composite score (CPS) improvement rates at 6-, 12-, and 18-months were compared between intervention and control groups, with subgroup analyses performed by age (< 75 and <math><mo>≥</mo></math> 75 years). Additionally, a comprehensive variant analysis using WGS was conducted to identify genetic signals potentially associated with the intervention's effectiveness.</p><p><strong>Results: </strong>Among 289 participants analyzed (168 aged < 75 years; 121 aged ≥ 75 years), 99 were classified into the high-risk PRS group (56 intervention, 43 control) and 190 into the low-risk PRS group (92 intervention, 98 control). For participants aged ≥ 75 years, no statistically significant differences in CPS improvement rates were observed between the intervention and control groups, regardless of PRS classification. However, in participants aged < 75, those in the high-risk PRS group showed significant CPS improvement at the 6-month follow-up. Additionally, analysis of 9,978,605 genetic variants identified two loci, ID3 and LMO1 (rs2067053 and rs201082658), with suggestive associations (P < 1 × 10⁻⁴) to reduced intervention effectiveness.</p><p><strong>Conclusions: </strong>This study highlighted the utility of PRS in predicting cognitive improvement following multidomain interventions and identified genetic variants that may influence the intervention's effectiveness. The findings provide a valuable foundation for personalized dementia prevention strategies.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"130"},"PeriodicalIF":7.9,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12150445/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144257104","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}