Alzheimer's Research & Therapy最新文献

{"title":"Prognostic value of plasma biomarkers for informing clinical trial design in mild-to-moderate Alzheimer's disease.","authors":"Yuqi Qiu, Diane M Jacobs, Karen Messer, David P Salmon, Cheryl L Wellington, Sophie Stukas, Carolyn Revta, James B Brewer, Gabriel C Léger, Brianna Askew, Lia Donahue, Stephen Kaplita, Vladimir Coric, Irfan A Qureshi, Howard H Feldman","doi":"10.1186/s13195-025-01745-3","DOIUrl":"https://doi.org/10.1186/s13195-025-01745-3","url":null,"abstract":"<p><strong>Background: </strong>Emerging evidence supports the diagnostic and prognostic utility of plasma biomarkers in Alzheimer's disease (AD), particularly in early disease stages. We sought to extend these findings by evaluating the prognostic value of plasma biomarkers in a clinical trial of mild-to-moderate AD.</p><p><strong>Methods: </strong>Post-hoc analyses investigated whether baseline concentrations of plasma biomarkers (Aβ42/Aβ40, T-tau, P-tau181, NfL, and GFAP) predicted change in ADAS-Cog11, CDR-SB, and volumetric MRI among participants in T2 Protect AD, a negative 48-week, phase-2, placebo-controlled trial of troriluzole in mild-to-moderate AD. All trial participants met diagnostic criteria for probable AD. Baseline concentrations of, and 48-week changes in, plasma biomarkers were assessed for association with 48-week change in outcomes using linear regression. Combinations of baseline biomarkers that best predicted change on the ADAS-Cog11 and CDR-SB were identified using least absolute shrinkage and selection operator (LASSO) regression. Biomarker-informed sample size calculations were modeled.</p><p><strong>Results: </strong>Of 350 trial participants, 319 had all requisite biomarker and clinical outcome data for inclusion in these analyses (mean age 71.5, SD = 8.03; 58.6% female). Higher plasma NfL at baseline predicted worsening scores on the ADAS-Cog11 (effect size (ES) = 1.42, 95%CI = [0.43, 2.41], p = 0.026) and CDR-SB (ES = 0.42, 95%CI = [0.10, 0.73], p = 0.048). LASSO regression revealed that worsening on the ADAS-Cog11 was best predicted by the combination of baseline plasma NfL, T-tau, and Aβ42/40 ratio, whereas baseline NfL alone best predicted worsening on CDR-SB. Higher baseline NfL predicted increasing ventricular volume (ES = 1.30cm³, 95%CI = [0.43, 2.17], p = 0.018) and decreasing mid-temporal cortical volume (ES = -0.47, 95%CI = [-0.74, -0.20], p = 0.003). Increasing NfL over the 48-week trial was associated with worsening on CDR-SB but not ADAS-Cog11. Modeling of biomarker-informed power calculations revealed that including high NfL as a trial entry criterion could substantially reduce requisite trial sample size.</p><p><strong>Conclusions: </strong>Elevated baseline plasma NfL predicted more rapid clinical decline and MRI volume loss. Furthermore, increasing plasma NfL concentration over time was associated with worsening on the CDR-SB. Plasma NfL is an easily accessible biomarker that may enhance the design of clinical trials in mild-to-moderate AD.</p><p><strong>Trial registration: </strong>The T2 Protect AD trial was registered as NCT03605667 on clinicaltrials.gov on 2018-07-27.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"97"},"PeriodicalIF":7.9,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12046789/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143953655","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":"Early presentation of spastic paraparesis in individuals carrying PSEN1 mutations: a clinical and genetic analysis.","authors":"Kang-Yang Jih, Ting-Rong Hsu, Jong-Ling Fuh, Tse-Hao Lee, Yung-Shuan Lin, Shih-Yu Fang, Yi-Chu Liao, Yi-Chung Lee","doi":"10.1186/s13195-025-01744-4","DOIUrl":"https://doi.org/10.1186/s13195-025-01744-4","url":null,"abstract":"<p><strong>Background: </strong>Mutations in the presenilin 1 gene (PSEN1) are well-known causes of early-onset familial Alzheimer's disease, but they can also present with atypical phenotypes such as pure spastic paraparesis. This study aims to investigate the clinical and genetic features of PSEN1 variants in patients mainly manifested with hereditary spastic paraparesis (HSP)-like phenotypes.</p><p><strong>Methods: </strong>Mutational analysis was performed in 242 unrelated Taiwanese patients with clinically suspected HSP using a targeted resequencing panel covering the entire coding regions of PSEN1, along with 76 genes associated with HSP and 55 genes linked to HSP-like phenotypes.</p><p><strong>Results: </strong>Two of the 242 patients (0.8%) were found to carry the pathogenic PSEN1 variants (p.P284S and p.F386S). In addition to the two probands, six affected family members were further identified to have the pathogenic PSEN1 variants. Six of these eight patients (75%) presented with spastic paraparesis as their initial symptom, one suffered from cognitive decline, and another manifested with personality change. The average age of symptom onset was 40.1 ± 4.8 years. Except for one patient, cognitive decline developed in all subjects before the last follow-up. For the patient carrying the PSEN1 p.P284S variant, amyloid deposition in bilateral lateral temporal, frontal, precuneus, and parietal regions was evident by amyloid PET, but no hippocampus atrophy was found on brain MRI. For the three patients carrying the PSEN1 p.F386S variant, brain atrophy with dilated ventricles were noted in the patient initially presented with personality changes, but normal MRI findings in the other two patients manifested with spastic paraparesis.</p><p><strong>Conclusions: </strong>Spastic paraparesis can be the initial and isolated clinical presentation of PSEN1 mutations. We identified eight patients from two families carrying a pathogenic PSEN1 variant, all but one carriers have developed cognitive symptoms. PSEN1 related spastic paraparesis usually has a later age of onset compared to other common hereditary spastic paraparesis subtypes, and the family history of early onset dementia might be obscure. Our findings suggested that PSEN1 variants are a rare cause of spastic paraparesis but should be considered especially in those with a later age of onset.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"96"},"PeriodicalIF":7.9,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12042469/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143959702","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":"Repetitive prefrontal tDCS activates VTA dopaminergic neurons, resulting in attenuation of Alzheimer's Disease-like deficits in Tg2576 mice.","authors":"Maria Luisa De Paolis, Gilda Loffredo, Paraskevi Krashia, Livia La Barbera, Annalisa Nobili, Emma Cauzzi, Lucy Babicola, Matteo Di Segni, Roberto Coccurello, Stefano Puglisi-Allegra, Emanuele Claudio Latagliata, Marcello D'Amelio","doi":"10.1186/s13195-025-01736-4","DOIUrl":"https://doi.org/10.1186/s13195-025-01736-4","url":null,"abstract":"<p><strong>Background: </strong>Emerging evidence implicates early dysfunction of dopaminergic neurons in the Ventral Tegmental Area (VTA) as a key contributor to Alzheimer's Disease (AD) pathophysiology. Specifically, the VTA dopaminergic neurodegeneration and the consequent reduction of dopamine (DA) in mesocorticolimbic targets are associated with the onset of cognitive impairments and neuropsychiatric-like manifestations in AD animal models. Moreover, decreased midbrain volume and functional VTA disconnection are identified as predictors of accelerated progression from Mild Cognitive Impairment to AD-dementia in clinical populations. Given these findings, interventions capable of directly modulating VTA activity and augmenting DA release, despite the ongoing neurodegeneration, may hold therapeutic potential for mitigating DA-related deficits in AD. This study aims at evaluating the therapeutic potential of prefrontal transcranial Direct Current Stimulation (tDCS) in the Tg2576 mouse model of AD, exhibiting early VTA dopaminergic neurodegeneration.</p><p><strong>Methods: </strong>Repeated tDCS was applied to assess its ability to activate VTA DA neurons. We also evaluated tDCS effects on synaptic plasticity, cognitive and non-cognitive behaviours and AD-related pathology. Hippocampal DA release and Nucleus Accumbens (NAc) DA transporter (DAT) expression were measured. With immunohistochemistry we examined microglial density and morphological complexity at different disease stages. Additionally, intracellular amyloid-β (Aβ) levels and plaque burden were evaluated to determine the impact of tDCS on AD pathology.</p><p><strong>Results: </strong>Prefrontal tDCS enhanced the activity of VTA dopaminergic neurons, leading to increased hippocampal DA release and higher DAT levels in the NAc. The enhanced DA outflow is associated with restored CA3-CA1 synaptic plasticity and improvements in recognition memory and motivational behaviours. tDCS reduced microglial numbers and morphological complexity in Tg2576 mice at both pre-plaque stage (7-months) and at an advanced stage characterized by plaque accumulation (12-months). Notably, tDCS also decreased Aβ plaque burden, although no changes in intracellular Aβ levels were observed in younger Tg2576 mice.</p><p><strong>Conclusions: </strong>These findings highlight the multifaceted therapeutic potential of prefrontal tDCS in targeting key AD pathophysiological hallmarks, including dopaminergic dysfunction, synaptic impairments, neuroinflammation and plaque deposition. As a non-invasive neuromodulatory approach, prefrontal tDCS emerges as a promising early intervention strategy to complement existing AD treatments, with the potential to improve patient outcomes and quality of life.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"94"},"PeriodicalIF":7.9,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12039073/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143953657","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":"The autocrine motility factor receptor delays the pathological progression of Alzheimer's disease via regulating the ubiquitination-mediated degradation of APP.","authors":"Jingjing Zhang, Congcong Liu, Jing Liu, Yuting Cui, Yuli Hou, Qiao Song, Xiaomin Zhang, Xiaoling Wang, Qian Zhang, Min Cao, Wenchao Wang, Peichang Wang, Yaqi Wang","doi":"10.1186/s13195-025-01741-7","DOIUrl":"https://doi.org/10.1186/s13195-025-01741-7","url":null,"abstract":"<p><strong>Background: </strong>The ubiquitin-proteasome system (UPS) is responsible for most protein degradation and its malfunction is normally observed in neurodegenerative diseases, including Alzheimer's disease (AD). The autocrine motility factor receptor (AMFR) is an E3 ubiquitin ligase that resides on the endoplasmic reticulum membrane and is involved in various essential biological processes. However, the role of AMFR in AD is still unidentified.</p><p><strong>Methods: </strong>Behavioral experiments, including open-field test (OFT), novel object recognition test (NORT) and morris water maze test (MWMT) were conducted after adeno-associated virus (AAV) microinjection into AD model mice. Western blot, co-immunoprecipitation (Co-IP), qPCR and ubiquitination assay were used to analyze AMFR mediated ubiquitination degradation of amyloid precursor protein (APP). ELISA was employed to evaluate changes in amyloidogenic cleavage products of APP following upregulation or downregulation of AMFR in neural cells and analyze AMFR levels in serum and cerebrospinal fluid (CSF) of AD patients.</p><p><strong>Results: </strong>The progressive decline in AMFR levels was found not only in the hippocampus of APPswe/PSEN1dE9 (APP/PS1) mice but also in the CSF and serum of patients with AD. Moreover, the interaction of AMFR and APP was observed both in hippocampal tissues and brain neurons. In addition, AMFR promoted the K11-linked polyubiquitination of APP to speed up its proteasomal degradation, resulting in decreased Aβ production. Importantly, AMFR overexpression largely rescued the cognitive and synaptic deficits in APP/PS1 mice.</p><p><strong>Conclusions: </strong>Taken together, our results demonstrated that AMFR reduced Aβ production and alleviated cognitive impairment by promoting the ubiquitination-mediated degradation of APP. This study indicated that AMFR could have the potential to be a therapeutic target of early-stage AD.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"95"},"PeriodicalIF":7.9,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12039061/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143955767","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":"Clinical phenotypes of Alzheimer's disease: investigating atrophy patterns and their pathological correlates.","authors":"Niels Reijner, I Frigerio, M M A Bouwman, B D C Boon, N Guizard, T Jubault, J J M Hoozemans, A J M Rozemuller, F H Bouwman, F Barkhof, E Gordon, W D J van de Berg, L E Jonkman","doi":"10.1186/s13195-025-01727-5","DOIUrl":"https://doi.org/10.1186/s13195-025-01727-5","url":null,"abstract":"<p><strong>Background: </strong>In Alzheimer's disease (AD), MRI atrophy patterns can distinguish between amnestic (typical) and non-amnestic (atypical) clinical phenotypes and are increasingly used for diagnosis and outcome measures in clinical trials. However, understanding how protein accumulation and other key features of neurodegeneration influence these imaging measurements, are lacking. The current study aimed to assess regional MRI patterns of cortical atrophy across clinical AD phenotypes, and their association with amyloid-beta (Aβ), phosphorylated tau (pTau), neuro-axonal degeneration and microvascular deterioration.</p><p><strong>Methods: </strong>Post-mortem in-situ 3DT1 3 T-MRI data was obtained from 33 AD (17 typical, 16 atypical) and 16 control brain donors. Additionally, ante-mortem 3DT1 3 T-MRI scans of brain donors were collected if available. Regional volumes were obtained from MRI scans using an atlas based parcellation software. Eight cortical brain regions were selected from formalin-fixed right hemispheres of brain donors and then immunostained for Aβ, pTau, neurofilament light, and collagen IV. Group comparisons and volume-pathology associations were analyzed using linear mixed models corrected for age, sex, post-mortem delay, and intracranial volume.</p><p><strong>Results: </strong>Compared to controls, both typical and atypical AD showed volume loss in the temporo-occipital cortex, while typical AD showed additional volume loss in the parietal cortex. Posterior cingulate volume was lower in typical AD compared to atypical AD (- 6.9%, p = 0.043). In AD, a global positive association between MRI cortical volume and Aβ load (βs = 0.21, p = 0.010), and a global negative association with NfL load (βs = - 0.18, p = 0.018) were observed. Regionally, higher superior parietal gyrus volume was associated with higher Aβ load in typical AD (βs = 0.47, p = 0.004), lower middle frontal gyrus volume associated with higher NfL load in atypical AD (βs = - 0.50, p < 0.001), and lower hippocampal volume associated with higher COLIV load in typical AD (βs = - 1.69, p < 0.001). Comparing post-mortem with ante-mortem scans showed minimal volume differences at scan-intervals within 2 years, highlighting the translational aspect of this study.</p><p><strong>Conclusion: </strong>For both clinical phenotypes, cortical volume is affected by Aβ and neuro-axonal damage, but in opposing directions. Differences in volume-pathology relationships between clinical phenotypes are region-specific. The findings of this study could improve the interpretation of MRI datasets in heterogenous AD cohorts, both in research and clinical settings.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"93"},"PeriodicalIF":7.9,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12032798/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143956352","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":"Differential effects of aging, Alzheimer's pathology, and APOE4 on longitudinal functional connectivity and episodic memory in older adults.","authors":"Larissa Fischer, Jenna N Adams, Eóin N Molloy, Niklas Vockert, Jennifer Tremblay-Mercier, Jordana Remz, Alexa Pichet Binette, Sylvia Villeneuve, Anne Maass","doi":"10.1186/s13195-025-01742-6","DOIUrl":"https://doi.org/10.1186/s13195-025-01742-6","url":null,"abstract":"<p><strong>Background: </strong>Both aging and Alzheimer's disease (AD) affect brain networks, with early disruptions occurring in regions involved in episodic memory. Few studies have, however, focused on distinguishing region-specific effects of AD-biomarker negative \"normal\" aging and early amyloid- and tau pathology on functional connectivity. Further, longitudinal studies combining imaging, biomarkers, and cognition are rare.</p><p><strong>Methods: </strong>We assessed resting-state functional connectivity (rsFC) strength and graph measures in the episodic memory network including the medial temporal lobe (MTL), posteromedial cortex (PMC), and medial prefrontal cortex alongside cognition over two years. For this preregistered study, we included 100 older adults who were amyloid- and tau-negative using CSF and PET measurements to investigate \"normal\" aging, and 70 older adults who had longitudinal CSF data available to investigate functional changes related to early AD pathology. All participants were cognitively unimpaired older adults from the PREVENT-AD cohort. We used region of interest (ROI)-to-ROI bivariate correlations, graph analysis, and multiple regression models.</p><p><strong>Results: </strong>In the amyloid- and tau-negative sample, rsFC strength within PMC, between parahippocampal cortex and inferomedial precuneus, and between posterior hippocampus and inferomedial precuneus decreased over time. Additionally, we observed a longitudinal decrease in global efficiency. Further, there was a steeper longitudinal decrease in rsFC and global efficiency with higher baseline age particularly of parahippocampal-gyrus regions. Further, lower rsFC strength within PMC was associated with poorer longitudinal episodic memory performance. In the sample with available CSF data, a steeper increase in rsFC between anterior hippocampus and superior precuneus was related to higher baseline AD pathology. Higher MTL-PMC rsFC strength was differentially associated with episodic memory trajectories depending on APOE4 genotype.</p><p><strong>Conclusions: </strong>Our findings suggest differential effects of aging and AD pathology. Hypoconnectivity within PMC was related to aging and cognitive decline. MTL-PMC hyperconnectivity was related to early AD pathology and cognitive decline in APOE4 carriers. Future studies should investigate more diverse samples, nonetheless, our approach allowed us to identify longitudinal functional changes related to aging and early AD pathology, enhancing cross-sectional research. Hyperconnectivity has been proposed as a mechanism related to early AD pathology before, we now contribute specific functional connections to focus on in future research.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"91"},"PeriodicalIF":7.9,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12023467/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143959369","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":"Response to Xing et al.: post-marketing safety concerns with Lecanemab: a pharmacovigilance study based on the FDA adverse event reporting system database.","authors":"Michael Irizarry, Ilona Surick, Ari Michael, Lynn D Kramer","doi":"10.1186/s13195-025-01735-5","DOIUrl":"https://doi.org/10.1186/s13195-025-01735-5","url":null,"abstract":"<p><p>A recent paper published a lecanemab analysis with data from the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database. While the authors mention the limitations of FAERS, such as \"voluntary (underreporting), the inability to establish causality, reporting bias, data quality issues, and the absence of a denominator, which precludes calculating incidence rates\", they proceed with generalizations, clinical conclusions, and even treatment recommendations based on the crude disproportionality analysis. Consideration of post-marketing safety reports, including those found in the FAERS database, is an essential component of pharmacovigilance. However, FDA guidance [2, 3] highlights that: (1) \"Rates of occurrence cannot be established with reports,\" (2) \"Documenting one or more of these outcomes in a report does not necessarily mean that the suspect product(s) named in the report was the cause of the outcomes,\" and (3) \"Importantly, the FAERS data by themselves are not an indicator of the safety profile of the drug.\" The FAERS database includes reports from many sources, including reports by companies, as well as from health care professionals and consumers. The reports in the FDA database have significant limitations, including submission of incomplete, inaccurate, untimely, duplicate, relatedness to drug uncertainty, and/or unverified information. Therefore, broader generalizations, clinical conclusions, and treatment recommendations should not be made based solely on FAERS databases analyses.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"92"},"PeriodicalIF":7.9,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12023665/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143952551","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":"Optimizing midlife metabolic syndrome thresholds for dementia: a prospective study of two UK population-based cohorts.","authors":"Sam Vidil, Archana Singh-Manoux, Benjamin Landré, Aurore Fayosse, Séverine Sabia, Marcos D Machado-Fragua","doi":"10.1186/s13195-025-01732-8","DOIUrl":"https://doi.org/10.1186/s13195-025-01732-8","url":null,"abstract":"<p><strong>Background: </strong>The concept of metabolic syndrome (MetS) was developed to identify individuals at higher risk of type 2 diabetes and cardiovascular disease, but its relevance for dementia remains unclear. We examined MetS in midlife for association with late-onset dementia, focusing on the thresholds of MetS components that carry risk for dementia.</p><p><strong>Methods: </strong>MetS components (waist circumference, blood pressure, triglycerides, HDL-C, and fasting glucose) were measured on 6,137 white participants < 60 years from the Whitehall II (WII) cohort study. A changepoint method in time-to-event analyses was used to identify optimal thresholds, and those exhibiting better performance for dementia were retained to develop a revised MetS definition. Results were validated on 171,886 participants in the UK Biobank (UKB) study.</p><p><strong>Results: </strong>Over a median follow-up of 22.6 years in WII and 13.8 years in UKB, 522 and 418 late-onset dementia cases were recorded, respectively. Optimized thresholds for triglycerides and fasting glucose performed better than original MetS thresholds in WII, and were used to develop a revised MetS definition. The MetS scale had a linear association with dementia, and 1-component increment (range 0 to 5) was associated with higher dementia risk using the revised MetS definition (HR, 95% CI: 1.11, 1.03-1.19) but not the original MetS definition (HR, 95% CI: 1.06, 0.98-1.14) in WII. In UKB, the revised MetS definition exhibited better performance for dementia risk than the original definition (p for HR comparison < 0.01).</p><p><strong>Conclusions: </strong>MetS in midlife is potentially an important target for dementia prevention. However, the thresholds for triglycerides and glucose that carry risk need to be tailored specifically for dementia.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"89"},"PeriodicalIF":7.9,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12016442/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143952153","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":"Associations of choroid plexus volume with white matter hyperintensity volume and susceptibility and plasma amyloid markers in cerebral small vessel disease.","authors":"Pengcheng Liang, Meng Li, Yiwen Chen, Zhenyu Cheng, Na Wang, Yuanyuan Wang, Nan Zhang, Yena Che, Jing Li, Changhu Liang, Lingfei Guo","doi":"10.1186/s13195-025-01740-8","DOIUrl":"https://doi.org/10.1186/s13195-025-01740-8","url":null,"abstract":"<p><strong>Background: </strong>White matter hyperintensity (WMH) is a key feature of cerebral small vessel disease (CSVD). The impact of the choroid plexus (CP) volume on disease progression remains largely unexplored. This study evaluated the relationship between CP volume and CSVD severity via WMH volume and susceptibility values. Additionally, we explored whether Alzheimer's disease (AD)-related plasma proteins influence the volume of the CP.</p><p><strong>Methods and materials: </strong>Our study included 291 CSVD individuals, with 84 participants completing subsequent brain MRI at a mean follow-up of 20 months. To explore the potential CP-associated pathways, we assessed the relationships between AD-related plasma biomarkers and CP volume via multiple linear regression analysis. The longitudinal associations between CP volume and WMH characteristics (WMH volume and susceptibility) were analyzed via linear mixed-effects models. Finally, we employed random forest analysis with the Boruta algorithm to identify key predictors of CSVD severity.</p><p><strong>Results: </strong>Plasma Aβ1‒40 levels were positively correlated with CP volume (β = 0.115, P = 0.009), whereas Aβ42‒40 ratio were negatively associated with CP volume (β = -0.135, P = 0.03). Notably, increased CP volume was associated with both greater WMH burden (β = 0.191, P = 0.011) and decreased WMH susceptibility (β = -0.192, P = 0.012). Furthermore, random forest modeling identified CP volume and WMH susceptibility as the strongest predictors of CSVD severity.</p><p><strong>Conclusions: </strong>CP volume changes were significantly correlated with both WMH volume and WMH susceptibility in CSVD patients. These findings suggest that CP-mediated pathways may link amyloid metabolism to CSVD progression.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"90"},"PeriodicalIF":7.9,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12016351/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143959661","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":"DNA methylation signature of a lifestyle-based resilience index for cognitive health.","authors":"Wei Zhang, David Lukacsovich, Juan I Young, Lissette Gomez, Michael A Schmidt, Eden R Martin, Brian W Kunkle, X Steven Chen, Deirdre M O'Shea, James E Galvin, Lily Wang","doi":"10.1186/s13195-025-01733-7","DOIUrl":"https://doi.org/10.1186/s13195-025-01733-7","url":null,"abstract":"<p><p>Cognitive resilience (CR) contributes to the variability in risk for developing and progressing in Alzheimer's disease (AD) among individuals. Beyond genetics, recent studies highlight the critical role of lifestyle factors in enhancing CR and delaying cognitive decline. DNA methylation (DNAm), an epigenetic mechanism influenced by both genetic and environmental factors, including CR-related lifestyle factors, offers a promising pathway for understanding the biology of CR. We studied DNAm changes associated with the Resilience Index (RI), a composite measure of lifestyle factors, using blood samples from the Healthy Brain Initiative (HBI) cohort. After corrections for multiple comparisons, our analysis identified 19 CpGs and 24 differentially methylated regions significantly associated with the RI, adjusting for covariates age, sex, APOE ε4, and immune cell composition. The RI-associated methylation changes are significantly enriched in pathways related to lipid metabolism, synaptic plasticity, and neuroinflammation, and highlight the connection between cardiovascular health and cognitive function. By identifying RI-associated DNAm, our study provided an alternative approach to discovering future targets and treatment strategies for AD, complementary to the traditional approach of identifying disease-associated variants directly. Furthermore, we developed a Methylation-based Resilience Score (MRS) that successfully predicted future cognitive decline in an external dataset from the Alzheimer's Disease Neuroimaging Initiative (ADNI), even after accounting for age, sex, APOE ε4, years of education, baseline diagnosis, and baseline MMSE score. Our findings are particularly relevant for a better understanding of epigenetic architecture underlying cognitive resilience. Importantly, the significant association between baseline MRS and future cognitive decline demonstrated that DNAm could be a predictive marker for AD, laying the foundation for future studies on personalized AD prevention.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"88"},"PeriodicalIF":7.9,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12016380/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143958953","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}