Alzheimer's Research & Therapy最新文献

{"title":"TREM2 risk variants and associated endophenotypes in alzheimer's disease.","authors":"Janna I R Dijkstra, Lisa Vermunt, Vikram Venkatraghavan, Georgii Ozhegov, Emma M Coomans, Rik Ossenkoppele, Elsmarieke van de Giessen, Marc Hulsman, Christa M de Geus, Wiesje M van der Flier, Sietske A M Sikkes, Frederik Barkhof, Betty Tijms, Alida A Gouw, Willem de Haan, Everard G B Vijverberg, Yolande A L Pijnenburg, Henne Holstege, Charlotte E Teunissen, Sven J van der Lee","doi":"10.1186/s13195-025-01700-2","DOIUrl":"10.1186/s13195-025-01700-2","url":null,"abstract":"<p><strong>Background: </strong>Rare variants of the triggering receptor expressed on myeloid cell 2 (TREM2) gene are strong risk factors for Alzheimer's disease (AD), and drugs targeting the TREM2 protein are being developed. However, it is unknown what the effect of TREM2 variants is on the AD phenotype.</p><p><strong>Methods: </strong>Here we studied a full range of clinical and biomarker measures in a large cohort of TREM2 variant carriers (n = 123, 7.8%, i.e., R62H n = 66, R47H n = 26, T96K n = 16, other TREM2 variants n = 17) compared to confirmed non-carriers (n = 1,459) with biomarker confirmed symptomatic AD from Amsterdam Dementia Cohort. Secondly, we explored whether specific TREM2 variants were associated with distinct clinical measures compared to the reference group, i.e. non-carriers, within the same cohort.</p><p><strong>Results: </strong>TREM2 variant carriers (64 ± 7 years, 54% female) did not show distinct clinical measures of AD at presentation compared to AD patients not carrying a TREM2 variant (64 ± 7 years, 52% female). We observed no differences in MMSE, neuropsychological domains (except less impaired visuospatial functioning in TREM2 carriers), MRI scores, CSF biomarkers, EEG, structural MRI (41 ROIs) and Tau-PET scans of four carriers (R62H, R47H, G58A, D87N). Carriers did show faster cognitive decline (MMSE points per year 0.6 ± 0.3, P _fdr = 0.099) compared to non-carriers. Notably, both R47H and T96K carriers exhibited faster cognitive decline (P < 0.05), and R47H carriers even showed an increased rate of death after diagnosis (P = 0.034). In contrast to the shared cognitive decline, these variants showed different results for other measures at baseline.</p><p><strong>Conclusions: </strong>This study shows that while carriers of TREM2 risk variants cannot be distinguished based on clinical presentation at baseline compared to non-carriers, they do exhibit a faster global cognitive decline. Variant-specific analyses indicate that especially R47H and T96K carriers drive this association. These results highlight the importance of considering variant-specific effects for understanding the role of TREM2 biology in AD. The rich phenotype information can inform clinical stage drug development.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"57"},"PeriodicalIF":7.9,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11883996/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143571817","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":"Synaptic protein CSF levels relate to memory scores in individuals without dementia.","authors":"Kirsten E J Wesenhagen, Diederick M de Leeuw, Jori Tomassen, Johan Gobom, Isabelle Bos, Stephanie J B Vos, Pablo Martinez-Lage, Mikel Tainta, Julius Popp, Gwendoline Peyratout, Magda Tsolaki, Rik Vandenberghe, Yvonne Freund-Levi, Frans Verhey, Simon Lovestone, Johannes Streffer, Valerija Dobricic, Kaj Blennow, Philip Scheltens, August B Smit, Lars Bertram, Charlotte E Teunissen, Henrik Zetterberg, Betty M Tijms, Pieter Jelle Visser","doi":"10.1186/s13195-025-01703-z","DOIUrl":"10.1186/s13195-025-01703-z","url":null,"abstract":"<p><strong>Background: </strong>We investigated how cerebrospinal fluid levels of synaptic proteins associate with memory function in normal cognition (CN) and mild cognitive impairment (MCI), and investigated the effect of amyloid positivity on these associations.</p><p><strong>Methods: </strong>We included 242 CN (105(43%) abnormal amyloid), and 278 MCI individuals (183(66%) abnormal amyloid) from the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) and the Alzheimer's Disease Neuroimaging Initiative (ADNI). For 181 (EMIF-AD MBD) and 36 (ADNI) proteins with a synaptic annotation in SynGO, associations with word learning recall were analysed with linear models.</p><p><strong>Results: </strong>Subsets of synaptic proteins showed lower levels with worse recall in preclinical AD (EMIF-AD MBD: 7, ADNI: 5 proteins, none overlapping), prodromal AD (EMIF-AD MBD only, 27 proteins) and non-AD MCI (EMIF-AD MBD: 1, ADNI: 7 proteins). The majority of these associations were specific to these clinical groups.</p><p><strong>Conclusions: </strong>Synaptic disturbance-related memory impairment occurred very early in AD, indicating it may be relevant to develop therapies targeting the synapse early in the disease.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"56"},"PeriodicalIF":7.9,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11877693/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143539908","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":"Probing locus coeruleus functional network in healthy aging and its association with Alzheimer's disease biomarkers using pupillometry.","authors":"Junjie Wu, Aaron Toporek, Qixiang Lin, Felicia C Goldstein, David W Loring, Michael A Kelberman, David Weinshenker, Allan I Levey, James J Lah, Deqiang Qiu","doi":"10.1186/s13195-025-01701-1","DOIUrl":"10.1186/s13195-025-01701-1","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease (AD) is the leading cause of dementia, and the early detection of the disease-associated changes allows early interventions. The locus coeruleus (LC) has been reported to be the first brain region to develop tau pathology in AD. However, the functional brain network of the LC in both healthy aging and AD pathology is largely unknown due to technical difficulties associated with the small size of the LC. In this study, we used the measurement of spontaneous pupil constriction/dilation as a surrogate for LC activity to study LC brain network changes during healthy aging.</p><p><strong>Methods: </strong>Thirty-seven healthy younger and thirty-nine healthy older adults were included from the Emory Healthy Brain Study and underwent resting-state functional MRI while simultaneously tracking pupil diameter. The measurements of pupil diameter dynamics were used as reference signals in brain connectivity analysis. The connectivity of the identified networks was then compared between younger and older participants. Correlations of the identified regions with neuropsychological assessments and cerebrospinal fluid (CSF) biomarkers were also evaluated.</p><p><strong>Results: </strong>A brain network of 20 clusters associated with pupil diameter dynamics was identified, including the LC as well as brain regions functionally connected to the LC. The pupil diameter network was found to positively correlate with the salience network and negatively correlate with the central executive network. Functional connectivity decreased within the pupil diameter network with healthy aging. The pupil diameter connectivity was associated with memory, executive, and visuospatial functioning. CSF total tau closely correlated with pupil diameter network.</p><p><strong>Conclusions: </strong>Pupil diameter dynamics provide valuable insights into LC-related processes. While they are not solely influenced by LC activity, spontaneous pupil constrictor/dilatory activity shows promise as a non-invasive approach to probe the LC network and warrants further studies to evaluate its value as an early biomarker of AD.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"53"},"PeriodicalIF":7.9,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866666/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522278","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":"HCN2 deficiency correlates with memory deficits and hyperexcitability of dCA1 pyramidal neurons in Alzheimer's disease.","authors":"Xiaoqin Zhang, Yiping Zhang, Ting Zhang, Jing Wang, Chang Liu, Qing Shang, Xiaojie Wei, Huaqiang Zhu, Haowei Shen, Binggui Sun","doi":"10.1186/s13195-025-01704-y","DOIUrl":"10.1186/s13195-025-01704-y","url":null,"abstract":"<p><strong>Background: </strong>Abnormal excitability of hippocampal neurons may lead to dysfunction of neural circuits and then causes cognitive impairments in Alzheimer's disease (AD). However, the underlying mechanisms remain to be fully elucidated.</p><p><strong>Methods: </strong>Electrophysiology was performed to examine the intrinsic excitability of CA1 neurons and the activity of the hyperpolarization-activated cyclic nucleotide-gated ion channels (HCNs) of CA1 neurons in wild type (WT) and hAPP-J20 mice. The activity of CA1 pyramidal neurons (PNs) was modulated with chemogenetics. The activity of HCNs was regulated with nonselective facilitator (cAMP) or inhibitor (ZD7288) of HCNs. Immunohistochemical staining or western blotting were performed to examine the expression of HCN1 and HCN2 in the hippocampus of WT and hAPP-J20 mice, or AD patients and non-AD controls. AAVs were injected to specifically modulate the expression of HCN2 in dorsal CA1 (dCA1) PNs. Cognitive performance of mice was assessed with behavioral tests.</p><p><strong>Results: </strong>dCA1 PNs were more excitable in hAPP-J20 mice, but the excitability of PNs in the ventral CA1 (vCA1) or PV neurons was comparable between WT and hAPP-J20 mice. The activity of the HCNs was reduced in dCA1 PNs of hAPP-J20 mice, and pharmacologically increasing the activity of HCNs attenuated the hyperexcitability of dCA1 PNs in hAPP-J20 mice, suggesting that the reduced activity of HCNs is associated with the hyperexcitability of dCA1 PNs in hAPP-J20 mice. The expression of HCN2 but not HCN1 was reduced in the hippocampus of hAPP-J20 mice, and the expression of HCN2 was also reduced in the hippocampus of AD patients, suggesting that dysregulation of HCN2 is associated with the reduced activity of HCNs in AD. Overexpressing HCN2 rescued the activity of HCNs, attenuated the hyperexcitability of dCA1 PNs and improved memory of hAPP-J20 mice, and knocking down HCN2 impaired the function of HCNs, increased the excitability of dCA1 PNs and led to memory deficits in WT mice.</p><p><strong>Conclusions: </strong>Our data suggest that dysregulation of HCNs, particularly HCN2, contributes to the abnormal excitability of CA1 PNs in AD mice and probably in AD patients as well, and thus provide new insights into the mechanisms underlying the aberrant activity or excitability of hippocampal neurons in AD.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"55"},"PeriodicalIF":7.9,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866685/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522260","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":"Identification and characterization of variants in PSEN1, PSEN2, and APP genes in Chinese patients with early-onset Alzheimer's disease.","authors":"Haitian Nan, Min Chu, Deming Jiang, Wenping Liang, Yu Li, Yiming Wu, Zhe Wang, Liyong Wu","doi":"10.1186/s13195-025-01702-0","DOIUrl":"10.1186/s13195-025-01702-0","url":null,"abstract":"<p><p>Variants in PSEN1, PSEN2, and APP are major genetic causes of early-onset Alzheimer's disease (EOAD). Our study aimed to identify the genotypic and phenotypic spectrums in a Chinese EOAD cohort and confirm their pathogenicity by functional analysis. This study included 304 unrelated clinically diagnosed EOAD participants of Chinese Han ancestry. Whole-exome sequencing revealed that 26 out of 304 individuals (8.6%) carried rare variants in PSEN1, PSEN2, and APP, including 16 in PSEN1 (5.3%), 6 in PSEN2 (2.0%), and 4 in APP (1.3%). Eight variants were novel, including PSEN1 p.Q56R, PSEN1 p.L174P, PSEN1 p.S289P, PSEN1 p.Y466C, PSEN2 p.R17W, PSEN2 p.F331Y, APP p.D197N, and APP p.D252V. Functional study revealed that the PS1 L174P, S289P, R377M, Y466C, PS2 V214L, and M239T mutants increased Aβ42 levels and Aβ42/Aβ40 ratios. The PS1 L174P, R377M, and Y466C mutants decreased the maturation of presenilin-1. Our findings highlight the prevalence and pathogenic significance of APP /PSENs variants in a Chinese EOAD cohort and expand the phenotypic and genotypic spectrum of EOAD.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"54"},"PeriodicalIF":7.9,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866898/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522272","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":"Brain age mediates gut microbiome dysbiosis-related cognition in older adults.","authors":"Sang Joon Son, Dong Yun Lee, Hyun Woong Roh, Maria Ly, Antonija Kolobaric, Howard Aizenstein, Carmen Andreescu, Eldin Jašarević, Tharick A Pascoal, Pamela C L Ferreira, Bruna Bellaver, Yong Hyuk Cho, Sunhwa Hong, You Jin Nam, Bumhee Park, Narae Kim, Jin Wook Choi, Jae Youn Cheong, Yoon-Keun Kim, Tae-Seop Shin, Chil-Sung Kang, Cheol-O Kwon, Seo-Yoon Yoon, Chang Hyung Hong, Helmet T Karim","doi":"10.1186/s13195-025-01697-8","DOIUrl":"10.1186/s13195-025-01697-8","url":null,"abstract":"<p><strong>Background: </strong>Recent studies have focused on improving our understanding of gut microbiome dysbiosis and its impact on cognitive function. However, the relationship between gut microbiome composition, accelerated brain atrophy, and cognitive function has not yet been fully explored.</p><p><strong>Methods: </strong>We recruited 292 participants from South Korean memory clinics to undergo brain magnetic resonance imaging, clinical assessments, and collected stool samples. We employed a pretrained brain age model- a measure associated with neurodegeneration. Using cluster analysis, we categorized individuals based on their microbiome profiles and examined the correlations with brain age, Mental State Examination (MMSE) scores, and the Clinical Dementia Rating Sum of Box (CDR-SB).</p><p><strong>Results: </strong>Two clusters were identified in the microbiota at the phylum level that showed significant differences on a few microbiotas phylum. Greater gut microbiome dysbiosis was associated with worse cognitive function including MMSE and CDR-SB; this effect was partially mediated by greater brain age even when accounting for chronological age, sex, and education.</p><p><strong>Conclusions: </strong>Our findings indicate that brain age mediates the link between gut microbiome dysbiosis and cognitive performance. These insights suggest potential interventions targeting the gut microbiome to alleviate age-related cognitive decline.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"52"},"PeriodicalIF":7.9,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866832/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522356","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":"Evaluation of cerebrospinal fluid levels of VAMP-2 and SNAP-25 in a dementia with Lewy bodies clinical cohort stratified by Alzheimer's pathophysiological biomarkers.","authors":"Alba Cervantes González, Julie Goossens, Elena Vera Campuzano, Isabel Sala, M Belén Sánchez-Saudinós, Íñigo Rodríguez-Baz, Laia Lidón, Danna Perlaza, Alexandre Bejanin, Annakaisa Haapasalo, Juan Fortea, Daniel Alcolea, Alberto Lleó, Eugeen Vanmechelen, Olivia Belbin","doi":"10.1186/s13195-025-01685-y","DOIUrl":"10.1186/s13195-025-01685-y","url":null,"abstract":"<p><strong>Background: </strong>Synaptic protein levels in cerebrospinal fluid (CSF) may represent much-needed objective biomarkers of cognitive impairment, disease progression and drug efficacy in patients with dementia with Lewy bodies (DLB). Soluble N-ethylmaleimide-sensitive factor attachment proteins receptors (SNARE) proteins, such as VAMP-2 and SNAP-25, are implicated in α-synuclein pathophysiology and CSF levels of these proteins are associated with pathophysiological biomarkers and cognitive decline in Alzheimer's disease (AD). The aim of the study was to compare CSF levels of VAMP-2 and SNAP-25 in patients with DLB to cognitively unimpaired controls and AD patients and study their association with cognitive performance and AD and neurodegeneration biomarkers.</p><p><strong>Methods: </strong>VAMP-2 and SNAP-25 were quantified in CSF from cognitively normal controls (n = 62), DLB (n = 44) and AD (n = 114) patients from the Sant Pau Initiative for Neurodegeneration (SPIN) cohort using homebrew Single Molecule Array assays (Simoa). The DLB group was stratified into two groups with (\"DLB + AD\", n = 28) or without AD co-pathology (\"pure DLB\", n = 16) using our validated cut-off for the CSF phosphorylated tau (p-tau)/Aβ42 ratio. We used linear regression to test for group differences (adjusting for age) and association with AD biomarkers. We used standardized w-scores of the cognitive tests to analyze the association of the synaptic markers with cognitive performance.</p><p><strong>Results: </strong>CSF VAMP-2 and SNAP-25 levels correlated across all groups (r = 0.71-0.9, p < 0.001). Both proteins were decreased in pure DLB (p < 0.001, p = 0.01) but increased in DLB + AD (p = 0.01, p = 0.02) compared to controls and showed good accuracy to discriminate pure DLB from DLB + AD (AUC = 0.84, 0.85). Both proteins were associated with CSF p-tau and total tau (t-tau) across all groups (r² = 0.49-0.88, p < 0.001), with the Aβ42/40 ratio in DLB + AD (r² = 0.29-0.36, p < 0.001) and in AD (r² = 0.12-0.23, p < 0.001) and with CSF neurofilament-light chain (NfL) in controls (r²=0.10-0.11, p < 0.001-0.01) and AD patients (r²=0.01-0.08, p = 0.01 - 0.001). SNAP-25 was associated with CSF NfL in the DLB + AD group (r²=0.15, p = 0.02). CSF VAMP-2 and SNAP-25 were associated with phonemic fluency in pure DLB (r² = 0.39 - 0.28, p = 0.01-0.03) and SNAP-25 with the Clock drawing test and the MMSE in DLB + AD (adj.r² = 0.15 - 0.14, p = 0.03-0.03) and DLB (adj.r² = 0.12 - 0.08, p = 0.02-0.04) groups.</p><p><strong>Conclusions: </strong>CSF VAMP-2 and SNAP-25 are promising surrogate markers of synapse degeneration in DLB. However, care should be taken when interpreting CSF levels of these synaptic markers in DLB in light of the confounding effect of AD pathophysiological markers.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"51"},"PeriodicalIF":7.9,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11849174/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143490437","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":"γ-Secretase modulator resistance of an aggressive Alzheimer-causing presenilin mutant can be overcome in the heterozygous patient state by a set of advanced compounds.","authors":"Johannes Trambauer, Rosa Maria Rodriguez Sarmiento, Holly J Garringer, Katja Salbaum, Liliana D Pedro, Dennis Crusius, Ruben Vidal, Bernardino Ghetti, Dominik Paquet, Karlheinz Baumann, Lothar Lindemann, Harald Steiner","doi":"10.1186/s13195-025-01680-3","DOIUrl":"10.1186/s13195-025-01680-3","url":null,"abstract":"<p><strong>Background: </strong>Amyloid-β peptide (Aβ) species of 42 or 43 amino acids in length (Aβ42/43) trigger Alzheimer´s disease (AD) and are produced in abnormal amounts by mutants of the γ-secretase subunit presenilin-1 (PS1), which represent the primary cause of familial AD (FAD). Lowering these peptides by γ-secretase modulators (GSMs) is increasingly considered a safe strategy to treat AD since these compounds do not affect the overall cleavage of γ-secretase substrates. GSMs were shown to modulate not only wild-type (WT) γ-secretase but also FAD mutants, expanding their potential use also to the familial form of the disease. Unlike most other FAD mutants, the very aggressive PS1 L166P mutant is largely resistant to GSMs. However, these data were mostly obtained from overexpression models, which mimic more the less relevant homozygous state rather than the heterozygous patient situation.</p><p><strong>Methods: </strong>Mouse embryonic fibroblast and induced pluripotent stem cell-derived neuronal PS1 L166P knock-in (KI) cell models were treated with various GSMs and Aβ responses were assessed by immunoassays and/or gel-based analysis.</p><p><strong>Results: </strong>We identified GSMs that lower Aβ42 and/or Aβ43 when PS1 L166P is heterozygous, as it is the case in affected patients, and could reduce the amount of pathogenic Aβ species towards WT levels. RO7019009 was the most potent of these compounds, reducing both pathogenic species and concomitantly increasing the short Aβ37 and Aβ38, of which the latter has been associated with delayed AD progression. Another effective compound, the structurally novel indole-type GSM RO5254601 specifically acts on the Aβ42 product line leading to a selective increase of the beneficial Aβ38. Interestingly, we further found that this class of GSMs can bind not only one, but both presenilin fragments suggesting that it targets γ-secretase at an unusual binding site.</p><p><strong>Conclusion: </strong>Our data show that even highly refractory presenilin FAD mutants are in principle tractable with GSMs extending the possibilities for potential clinical studies in FAD with suitable GSM molecules.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"49"},"PeriodicalIF":7.9,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11837686/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456729","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":"Social frailty and its association with cognitive trajectories in older adults: a prospective cohort study.","authors":"Hui Zhang, Meng Hao, Zixin Hu, Shuai Jiang, Yi Li, Xiaofeng Wang, Xiangwei Li","doi":"10.1186/s13195-025-01687-w","DOIUrl":"10.1186/s13195-025-01687-w","url":null,"abstract":"<p><strong>Background: </strong>Social frailty, a multidimensional construct encompassing various social behaviors, resources, and needs, significantly impacts cognitive health in older adults. Despite existing studies linking specific social factors to cognitive function, the association between social frailty and long-term cognitive trajectories remains underexplored. This study aims to evaluate the longitudinal association between social frailty and trajectory of cognitive function in dementia-free older adults.</p><p><strong>Methods: </strong>This prospective cohort study used data from the National Health and Aging Trends Study (NHATS). Social frailty was assessed using the Makizako Social Frailty Index. According to the presence of social components, individuals were categorized into social frailty (≥ 2), pre-social frailty (1), and robust (0), respectively. Cognitive function was annually evaluated through memory, orientation, and executive function tests from 2011 to 2018. Mixed-effects linear models were employed to assess the associations between social frailty and changes in global and domain-specific cognitive function, adjusting for relevant covariates.</p><p><strong>Results: </strong>In this study, 4956 dementia-free older adults (mean age 76.57 [7.41]) with complete at least 2 times of cognitive tests were included. Compared with the robust, social frailty was associated with significantly faster decline in global cognitive function (β = -0.041, 95% CI [-0.047, -0.036] z score per year) and domain-specific cognitive function (β_memory = -0.045, 95% CI [-0.055, -0.036] z score per year; β_orientation = -0.027, 95% CI [-0.034, -0.020] z score per year; β_executive = -0.042, 95% CI [-0.053, -0.032] z score per year) over the follow-up. Additionally, pre social frailty was associated with significantly faster decline in global cognitive function (β = -0.016, 95% CI [-0.021, -0.012] z score per year), memory function (β= -0.045, 95% CI [-0.055, -0.036] z score per year), and orientation function (β= -0.027, 95% CI [-0.034, -0.020] z score per year) over the follow-up.</p><p><strong>Conclusions: </strong>Social frailty is associated with faster decline in cognition in older adults, underscoring the necessity for enhanced social support and engagement to mitigate cognitive deterioration in vulnerable populations.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"50"},"PeriodicalIF":7.9,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11837587/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456712","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":"Cornuside alleviates cognitive impairments induced by Aβ_1-42 through attenuating NLRP3-mediated neurotoxicity by promoting mitophagy.","authors":"Fulin Zhou, Wenwen Lian, Xiaotang Yuan, Zexing Wang, Congyuan Xia, Yu Yan, Wenping Wang, Zhuohang Tong, Yungchi Cheng, Jiekun Xu, Jun He, Weiku Zhang","doi":"10.1186/s13195-025-01695-w","DOIUrl":"10.1186/s13195-025-01695-w","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a progressive neurodegenerative disorder in which mitochondrial dysfunction and neuroinflammation play crucial roles in its progression. Our previous studies found that cornuside from Cornus officinalis Sieb.Et Zucc is an anti-AD candidate, however, its underlying mechanism remains unknown. In the present study, AD mice were established by intracerebroventricular injection of Aβ_1-42 and treated with cornuside (3, 10, 30 mg/kg) for 2 weeks. Cornuside significantly ameliorated behavioral deficits, protected synaptic plasticity and relieved neuronal damage in Aβ_1-42 induced mice. Importantly, cornuside decreased NLRP3 inflammasome activation, characterized by decreased levels of NLRP3, ASC, Caspase-1, GSDMD, and IL-1β. Furthermore, cornuside promoted mitophagy accompanied by decreasing SQSTM1/p62 and promoting LC3B-I transforming into LC3B-II, via Pink1/Parkin signaling instead of FUNDC1 or BNIP3 pathways. In order to investigate the relationship between NLRP3 inflammasome and mitophagy in the neuroprotective mechanism of cornuside, we established an in-vitro model in BV2 cells exposed to LPS and Aβ_1-42. And cornuside inhibited NLRP3 inflammasome activation and subsequent cytokine release, also protected neurons from damaging factors in microenvironment of conditional culture. Cornuside improved mitochondrial function by promoting oxidative phosphorylation and glycolysis, decreasing the production of ROS and mitochondrial membrane potential depolarization. Besides, mitophagy was also facilitated with increased colocalization of MitoTracker with LC3B and Parkin, and Pink1/Parkin, FUNDC1 and BNIP3 pathways were all involved in the mechanism of cornuside. By blocking the formation of autophagosomes by 3-MA, the protective effects on mitochondria, the inhibition on NLRP3 inflammasome as well as neuronal protection in conditional culture were eliminated. There is reason to believe that the promotion of mitophagy plays a key role in the NLRP3 inhibition of cornuside. In conclusion, cornuside re-establishes the mitophagy flux which eliminates damaged mitochondria and recovers mitochondrial function, both of them are in favor of inhibiting NLRP3 inflammasome activation, then alleviating neuronal and synaptic damage, and finally improving cognitive function.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"47"},"PeriodicalIF":7.9,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11837312/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456708","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}