Alzheimer''s and Dementia: Translational Research and Clinical Interventions最新文献

{"title":"ABCA7-80 moderates vascular stiffness-p-tau217 association in older African Americans.","authors":"Miray Budak, Kevin S Heffernan, Martina Ishaq, Victoria Paruzel, Demiana Abdalla, Soodeh Moallemian, Bernadette A Fausto, Fanny M Elahi, Mark A Gluck","doi":"10.1002/trc2.70297","DOIUrl":"10.1002/trc2.70297","url":null,"abstract":"<p><strong>Introduction: </strong>Compromised vascular health is increasingly linked to Alzheimer's disease (AD) risk. Estimated pulse wave velocity (ePWV), derived from age and blood pressure, and provides a practical, non-invasive index of vascular stiffness and overall vascular health. Older African Americans experience a disproportionate burden of vascular disease and AD. Genetic risk factors such as APOE ε4 and ABCA7-80 (rs115550680) further increase AD susceptibility. However, whether these genetic risks influence vascular stiffness and how that may interact with AD pathology remains unknown, especially in African Americans.</p><p><strong>Methods: </strong>A total of 143 older African Americans (mean age = 71.10 ± 6.83 years; 109 women) were included. We examined the effects of both ABCA7-80 and APOE ε4 genotypes on ePWV and plasma phosphorylated tau 217 (p-tau217). All regression models controlled for sex, education, pulse pressure, waist-to-hip ratio, global cognitive status, hypertension status, and APOE genotype (APOE genotype only used for ABCA7-80 regression models).</p><p><strong>Results: </strong>ABCA7-80 risk allele carriers exhibited higher ePWV (<i>F</i> _(1,130) = 8.16, <i>p </i>= 0.005, <i>η² _p </i>= 0.064) and higher p-tau217 levels (<i>F</i> _(1,130) = 30.11, <i>p </i>< 0.001, <i>η² _p</i>  = 0.201). APOE ε4 allele carriers also showed higher p-tau217 levels (<i>F</i> _(1,131) = 12.96, <i>p </i>< 0.001, <i>η² _p </i>= 0.092). ABCA7-80 significantly moderated the relationship between ePWV and p-tau217 (F_(1,130) = 6.58, <i>p</i> < 0.001), such that higher ePWV was associated with higher p-tau217 among ABCA7-80 risk carriers (<i>β </i>= 0.52, <i>t</i> ₍₁₃₀₎ = 2.69, <i>p </i>= 0.008).</p><p><strong>Discussion: </strong>ABCA7-80 risk, but not APOE ε4, heightens susceptibility to the tau-related effects of compromised vascular health among older African Americans. These findings identify a genetically vulnerable subgroup in which vascular stiffness may disproportionately accelerate AD-related tau pathology and highlight vascular health as a modifiable target for reducing AD risk in African Americans.</p>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 3","pages":"e70297"},"PeriodicalIF":7.4,"publicationDate":"2026-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13459191/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148714629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential presence of cerebral microbleeds in an amyloid mouse model compared with a CADASIL mouse model.","authors":"Xiuli Yang, Yuguo Li, Adnan Bibic, Jiekang Wang, Mei Wan, Wenzhen Duan, Hanzhang Lu, Zhiliang Wei","doi":"10.1002/trc2.70308","DOIUrl":"10.1002/trc2.70308","url":null,"abstract":"<p><strong>Introduction: </strong>Cerebral microbleeds are commonly observed on susceptibility-based magnetic resonance imaging (MRI) in Alzheimer's disease (AD) and are often interpreted as markers of small-vessel disease. However, how microbleed occurrence differs between amyloid-associated vascular pathology and non-amyloid vascular conditions remains incompletely understood. In this study, we performed a comparative analysis between an amyloidosis mouse model and a non-amyloid arteriopathy cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) model to assess whether microbleed occurrence differs across these distinct vascular contexts.</p><p><strong>Methods: </strong>Multimodal in vivo MRI at 11.7T, including gradient echo (GRE), spin echo, and diffusion-weighted imaging, was performed in 5xFAD mice and a CADASIL mouse model across 9 to 20 months of age. Ex vivo high-resolution GRE imaging and Prussian blue staining were used to validate microbleeds. Quantitative analyses focused on microbleed counts, parenchymal and cerebrospinal fluid volumes, and regional apparent diffusion coefficient (ADC). In addition, blood-brain barrier (BBB) integrity was assessed in the CADASIL mice.</p><p><strong>Results: </strong>Both in vivo and ex vivo GRE MRI consistently revealed hippocampal microbleeds in 5xFAD mice, whereas no microbleeds were detected in CADASIL mice at any examined age. Microbleeds in 5xFAD mice occurred in the absence of brain atrophy or ventricular enlargement. ADC elevation was observed selectively in the midbrain of 5xFAD mice but not in other regions or in the CADASIL cohort. BBB permeability remained normal in CADASIL mice, indicating preserved vascular barrier integrity despite vascular smooth muscle cell loss.</p><p><strong>Discussion: </strong>Cerebral microbleeds emerged selectively in the amyloid model and were absent in a non-amyloid arteriopathy driven by vascular smooth muscle cell degeneration, suggesting that microbleed occurrence may depend on the underlying pathology. These findings show consistency with the possibility that cerebral microbleeds may reflect disease-associated vascular conditions, refining their interpretation as translational MRI biomarkers in AD.</p>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 3","pages":"e70308"},"PeriodicalIF":7.4,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13457348/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148714585","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SIRT6 signaling as an underexplored mechanistic node in nanoformulation-based neuroinflammation therapy for Alzheimer's disease.","authors":"Ahmed S Mancy","doi":"10.1002/trc2.70305","DOIUrl":"10.1002/trc2.70305","url":null,"abstract":"<p><p>Chronic microglial neuroinflammation is a core driver of Alzheimer's disease (AD). Wei et al. recently reported a blood-brain barrier (BBB)-penetrating, microglia-targeting nanomodulator (Res@TcMNP/ASO) that simultaneously suppressed NF-κB signaling and enhanced NRF2-dependent antioxidant defense in chronically activated microglia, yet the molecular node coupling these two opposing circuits was not identified. In this perspective, drawing on primary literature spanning microglial inflammation, neuronal genome maintenance, tau regulation, and oncology, I propose that sirtuin 6 (SIRT6) is a plausible upstream candidate for this coordinated effect. SIRT6, a NAD⁺-dependent chromatin deacetylase, restrains NF-κB through H3K9 deacetylation at RELA target promoters and, in parallel, deacetylates and stabilizes NRF2 to amplify antioxidant transcription; its decline in the aging and AD brain promotes DNA damage and GSK3-driven tau hyperphosphorylation. Because a microglia-restricted carrier confines pathway modulation to the relevant cell population, this delivery strategy is well matched to a SIRT6-centered mechanism, while the context-dependent, potentially oncogenic nature of systemic SIRT6 activation reinforces the rationale for such restricted delivery. I outline specific loss- and gain-of-function experiments to test whether microglial SIRT6 mediates the dual-pathway effects of Res@TcMNP/ASO, offering a falsifiable hypothesis to guide future mechanistic and therapeutic work.</p>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 3","pages":"e70305"},"PeriodicalIF":7.4,"publicationDate":"2026-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13445251/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148686636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Thalamic volume alterations mediate glymphatic function and cognitive dysfunction in Alzheimer's disease.","authors":"Leian Chen, Xiao Zhou, Bin Zhang, Ying Hou, Yu Sun, Dantao Peng","doi":"10.1002/trc2.70304","DOIUrl":"10.1002/trc2.70304","url":null,"abstract":"<p><strong>Introduction: </strong>Glymphatic dysfunction is implicated in Alzheimer's disease (AD), but its mechanism remains unclear. This study investigated the associations of the analysis along the perivascular space (ALPS) index, brain reserve, and cognitive outcomes across the AD continuum.</p><p><strong>Methods: </strong>This study enrolled two cohorts from the local hospital (<i>n</i> = 95) and the Alzheimer's Disease Neuroimaging Initiative (ADNI; <i>n</i> = 178). We calculated the diffusion tensor image ALPS to assess the whole-brain glymphatic function and evaluated its associations with cognition and brain structure.</p><p><strong>Results: </strong>A higher ALPS index was positively associated with better executive, memory, and language abilities (<i>p</i> < 0.05). A lower ALPS index correlated with thalamic atrophy, involving the anterior, lateral, ventral, and midline thalamic nuclei. Thalamic atrophy mediated the link between glymphatic dysfunction and worse cognition via structural association of full or part mediation.</p><p><strong>Conclusions: </strong>Glymphatic system deterioration correlates with cognitive decline, potentially mediated by thalamic atrophy. The thalamic nuclei may be critical in this pathway.</p>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 3","pages":"e70304"},"PeriodicalIF":7.4,"publicationDate":"2026-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13445249/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148686679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The moderating effect of dietary fiber and protein on the relationship between symptoms of depression and anxiety and cognitive decline.","authors":"Samantha L Gardener, Hilal Salim Said Al Shamsi, Stephanie R Rainey-Smith, Hamid R Sohrabi, Kevin Taddei, Colin L Masters, Ralph N Martins, W M A D Binosha Fernando","doi":"10.1002/trc2.70292","DOIUrl":"10.1002/trc2.70292","url":null,"abstract":"<p><strong>Introduction: </strong>Depression and anxiety often co-occur with Alzheimer's disease, exacerbating the associated cognitive impairment. This study examined moderating effects of dietary protein and fiber intake on relationships between depressive and anxiety symptoms, and cognitive decline.</p><p><strong>Methods: </strong>Cognitively unimpaired (<i>n</i> = 553; 39.4% male, 70.6 ± 9.6 years) provided baseline fiber and protein intake, and had repeated cognitive testing and symptoms of depression/anxiety measured (baseline and up to eight follow-ups over 144 months). Moderation and simple slope analyses were employed in the cohort as a whole and following stratification by sex.</p><p><strong>Results: </strong>Fiber intake moderated the relationship between change in depressive symptoms and decline in language (<i>β</i> = -0.005, <i>p</i> < 0.001) and Preclinical Alzheimer Cognitive Composite (PACC); scores (<i>β</i> = -0.003, <i>p</i> = 0.010). In males, fiber intake moderated the relationship between change in anxiety symptoms and executive function decline (<i>β</i> = -0.003, <i>p</i> = 0.018), with protein intake moderating change in depressive symptoms and decline in attention (<i>β</i> = 0.006, <i>p</i> = 0.011).</p><p><strong>Discussion: </strong>Adequate dietary fiber and protein intake moderated association between depressive and anxiety symptoms and cognitive decline, supporting their potential role within multidomain strategies aimed at maintaining cognitive health in older adults.</p>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 3","pages":"e70292"},"PeriodicalIF":7.4,"publicationDate":"2026-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13445243/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148686662","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacodynamic and stage-dependent therapeutic efficacy of SFRP1 neutralization in a mouse model of Alzheimer's disease.","authors":"Pablo Miaja, Marcos Martinez-Baños, María Jesús Martin-Bermejo, Inmaculada Moreno, Mercedes Dominguez, Paola Bovolenta","doi":"10.1002/trc2.70301","DOIUrl":"10.1002/trc2.70301","url":null,"abstract":"<p><strong>Introduction: </strong>Alzheimer's disease (AD) is characterized by early synaptic dysfunction followed by progressive amyloid beta (Aβ) accumulation, neuroinflammation, and cognitive decline. We previously identified secreted frizzled-related protein 1 (SFRP1) as a multifactorial contributor to AD pathogenesis and provided initial evidence that its neutralization ameliorates pathological AD-like traits in mice. Here we evaluate the pharmacodynamics, biodistribution, and therapeutic window of an anti-SFRP1 monoclonal antibody (α-SFRP1) in double transgenic amyloid precursor protein (APP) and presenilin-1 (PS1) mice (APP/PS1).</p><p><strong>Methods: </strong>Pharmacokinetics and target engagement of α-SFRP1 were assessed in groups of both male and female APP/PS1 mice using biotinylated or Zirconium-89 labeled (⁸⁹Zr) antibodies, with tissue distribution and α-SFRP1 levels quantified by in-house enzyme-linked immunosorbent assay (ELISA) or positron emission tomography/computed tomography (PET/CT). Therapeutic efficacy was evaluated by administering α-SFRP1 or the SFRP1 inhibitor WAY-316606 at different stages of disease progression via retro-orbital injection, followed by analysis of AD-like pathology using ELISA and quantitative immunofluorescence assays and statistical analysis.</p><p><strong>Results: </strong>Using ⁸⁹Zr-labeled antibodies, we show that intravenously administered α-SFRP1 engages its target systemically and reaches the brain, although at substantially lower levels and with a rapid 24-h clearance. Treatment with α-SFRP1 had no apparent systemic side effects or sex-dependent differences, but its therapeutic efficacy against AD-like brain pathology was strongly dependent on disease stage. Although early administration reduced amyloid pathology in previous studies, treatment initiated at intermediate or advanced stages showed minimal benefit at standard doses. Higher antibody doses reduced amyloid burden and dystrophic neurites but were associated with increased mortality. Pharmacological inhibition of SFRP1 using a small-molecule inhibitor similarly failed to ameliorate pathology at intermediate stages.</p><p><strong>Discussion: </strong>Together, these findings demonstrate that SFRP1 remains a relevant therapeutic target in AD, but its effective modulation is constrained by limited brain exposure and a narrow therapeutic window, underscoring the importance of early intervention and prompting the search for improved brain-targeted delivery strategies.</p>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 3","pages":"e70301"},"PeriodicalIF":7.4,"publicationDate":"2026-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13409335/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148621953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The proteomic and metabolomic signature of inherited chromosomally integrated HHV-6 and its role in all-cause dementia and mortality risk: The UK Biobank study","authors":"May A. Beydoun,&nbsp;Minkyo Song,&nbsp;Choa Yun,&nbsp;Nicole Noren Hooten,&nbsp;Jordan Weiss,&nbsp;Hind A. Beydoun,&nbsp;Michael R. Duggan,&nbsp;Keenan A. Walker,&nbsp;Lenore J. Launer,&nbsp;Michele K. Evans,&nbsp;Alan B. Zonderman","doi":"10.1002/trc2.70286","DOIUrl":"10.1002/trc2.70286","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; OBJECTIVE&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;To examine associations of inherited chromosomally integrated human herpesvirus 6 (iciHHV-6) with incident dementia and mortality, characterize proteomic and metabolomic correlates of carrier status, and evaluate whether these biomarkers relate to dementia and mortality risk.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; METHODS&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;We analyzed UK Biobank participants ≥50 years of age with plasma metabolomics (&lt;i&gt;N&lt;/i&gt; = 138,676) and proteomics (&lt;i&gt;N&lt;/i&gt; ≤ 15,416) data and ≈15 years of follow-up. Cox proportional hazards models adjusted for key confounding factors evaluated associations of iciHHV-6 with dementia and mortality. Multivariable linear models assessed iciHHV-6 associations with metabolomic and proteomic profiles. Mediation and interaction were evaluated using structural equation models and Cox models with biomarker interactions. Least absolute shrinkage and selection operator regression identified independent proteomic and metabolomic predictors using imputed biomarker data.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; RESULTS&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;iciHHV-6 was associated with higher dementia risk (hazard ratio [HR] = 1.32), particularly among women (HR = 1.66) and individuals with elevated Alzheimer's disease polygenic risk (HR = 1.49). Branched-chain amino acids (leucine and isoleucine) were elevated among carriers without mediating dementia risk. Proteomic analyses identified 126 nominally associated iciHHV-6–related proteins, many of which (Neurofilament Light Chain (NEFL), Glial Fibrillary Acidic Protein (GFAP), Yes-Associated Protein 1 (YAP1), Sialic Acid-binding Immunoglobulin-like Lectin 5 (SIGLEC5), Interleukin 19 (IL19), A Disintegrin And Metalloproteinase with Thrombospondin Motifs 16 (ADAMTS16), Sphingomyelin Phosphodiesterase 1 (SMPD1)) were also associated with dementia and/or mortality. Exploratory pathway analyses suggested enrichment of proteins related to immune regulation and post-translational modification. Predictive models identified NEFL, GFAP, Vascular Endothelial Growth Factor A (VEGF), Brevican (BCAN), remnant cholesterol, and polyunsaturated fatty acids as dementia predictors (area under the curve [AUC] = 0.83), whereas NEFL, Growth Differentiation Factor 15 (GDF15) Latent Transforming Growth Factor Beta Binding Protein 2 (LTBP2), Ectodysplasin A2 Receptor (EDA2R) and Advanced Glycosylation End-product Specific Receptor (AGER) predicted mortality (AUC = 0.70).&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; DISCUSSION&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;iciHHV-6 was associated with increased dementia risk, particularly among women and genetically susceptibl","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 3","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13385209/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148551151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cerebrospinal fluid α-synuclein and Aβ42 link with default mode and salience networks connectivity in dementia with Lewy bodies","authors":"Vincent Gabriel,&nbsp;Elena Chabran,&nbsp;Marion Sourty,&nbsp;Benjamin Cretin,&nbsp;Nathalie Philippi,&nbsp;Candice Muller,&nbsp;Pierre Anthony,&nbsp;Catherine Demuynck,&nbsp;Paulo Loureiro de Sousa,&nbsp;Anne Botzung,&nbsp;Léa Sanna,&nbsp;Olivier Bousiges,&nbsp;Frédéric Blanc","doi":"10.1002/trc2.70266","DOIUrl":"10.1002/trc2.70266","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) are neurocognitive disorders characterized by distinct but often overlapping pathological processes. These include <i>α</i>-synuclein, amyloid-beta 42 (Aβ42), and tau protein aggregation. While cerebrospinal fluid (CSF) biomarkers provide in vivo insight into these pathologies, their relationship with large-scale brain network dysfunction remains poorly understood. This study aimed to investigate the associations between CSF biomarker concentrations and resting-state functional connectivity in patients with DLB, AD, and mixed AD/DLB.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>Sixty-nine DLB patients, 17 AD patients, and 24 patients with mixed AD/DLB underwent clinical and neuropsychological evaluations, lumbar puncture for CSF biomarker analysis (total <i>α</i>-synuclein, Aβ42, pTau₁₈₁, and tTau), and resting-state functional MRI. Patients were stratified by disease stage for subgroup analyses. Besides CSF total <i>α</i>-synuclein levels, <i>α</i>-synuclein seeding activity was assessed using real-time quaking-induced conversion (RT-QuIC) assays. ROI-to-ROI analyses were conducted using the CONN toolbox to explore associations between CSF biomarker levels and functional connectivity within and between major brain networks.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>In DLB patients, lower CSF <i>α</i>-synuclein levels correlated with increased connectivity within the default mode network (DMN) (<i>p</i>_FDR &lt; 0.05). In dementia-stage DLB (d-DLB), lower Aβ42 levels correlated with reduced connectivity within the salience network (SN) (<i>p</i>_FDR &lt; 0.05). In AD, higher tTau levels correlated with decreased connectivity between the DMN and the SN (<i>p</i>_FDR &lt; 0.05). No significant associations were observed for CSF pTau₁₈₁ or any RT-QuIC metric in any group, and the mixed AD/DLB group showed no biomarker–connectivity correlations at all.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>We identified distinct patterns of DMN and SN connectivity changes associated with CSF <i>α</i>-synuclein and Aβ42 levels, respectively. These findings reflect key functional disruptions that may contribute to core clinical symptoms. They underscore the value of combining CSF biomarkers with functional MRI to elucidate DLB pathophysiology.</p>\u0000 </section>\u0000 </div>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 3","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13380670/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148521239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diversity and inclusivity in Australian dementia prevention research: A mixed methods review","authors":"Olivia E. Giameos,&nbsp;Maddison L. Mellow,&nbsp;Diana Karamacoska,&nbsp;Aaron Davis,&nbsp;Paul A Gardiner,&nbsp;Eddy Roccati,&nbsp;Kaarin J. Anstey,&nbsp;Nicolas Cherbuin,&nbsp;Jessica M. Adsett,&nbsp;Nikki-Anne Wilson,&nbsp;Kylie Radford,&nbsp;Louise Lavrencic,&nbsp;Perminder S. Sachdev,&nbsp;Simone Reppermund,&nbsp;Suraj Samtani,&nbsp;Annabel P. Matison,&nbsp;Zara A. Page,&nbsp;Philip J. Batterham,&nbsp;Sophie C. Andrews,&nbsp;Alex Bahar-Fuchs,&nbsp;Michelle K. Lupton,&nbsp;Andrew Pipingas,&nbsp;Adrienne Withall,&nbsp;Belinda M. Brown,&nbsp;Helen Macpherson,&nbsp;Hannah A. D. Keage,&nbsp;Britt Burton,&nbsp;James C. Vickers,&nbsp;David W Dunstan,&nbsp;Ashleigh E. Smith","doi":"10.1002/trc2.70296","DOIUrl":"10.1002/trc2.70296","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Minoritized communities are disproportionately impacted by modifiable dementia risk factors but are underrepresented in dementia research globally. In Australia, the number of dementia prevention cohort and intervention studies has rapidly increased in the past two decades, yet the representation of minoritized groups has not been synthesized. The aims of this mixed-methods review were to summarize the demographic characteristics of participants involved in Australian dementia prevention-focused cohort and intervention studies. A systematic search of published literature, funded grant outcomes, and clinical trial registrations was conducted in October 2023 and updated in February 2025 to identify any Australia-based cohort or intervention studies which focused on dementia prevention. Data custodians of eligible studies were contacted and invited to submit de-identified participant-level data for these studies. The demographic characteristics of participants involved in published manuscripts and submitted participant-level data were synthesized. These data were then presented to 23 Australian dementia prevention researchers during a 2-h workshop in March 2025. Using co-creation methodologies, the workshop aimed to generate consensus-based recommendations for governments, institutions, and individual researchers to improve inclusivity and representativeness in future dementia prevention research. Twenty-eight published dementia prevention studies were summarized alongside fourteen studies for which de-identified participant-level data were submitted. Compared to the modern Australian population, participants enrolled in dementia prevention studies have been predominantly female, highly educated, and less diverse in terms of culture, language, ethnicity and gender. Thirty-seven recommendations were generated by Australian researchers and ranked by importance, providing actionable changes for government and institutional policy and researcher practice. This review identified that participants enrolled in Australian dementia prevention research studies do not accurately represent those most at risk for dementia in the general population. Changes to recruitment and engagement practices and policies are recommended to improve the representativeness and inclusivity of Australian dementia prevention research.</p>\u0000 </section>\u0000 </div>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 3","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13380669/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148521276","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advances in pharmacotherapy for vascular cognitive impairment and vascular dementia: An update of 2025","authors":"Doan-Khanh Tran,&nbsp;Yi-Chun Kuan,&nbsp;Li-Kai Huang,&nbsp;Chaur-Jong Hu","doi":"10.1002/trc2.70293","DOIUrl":"https://doi.org/10.1002/trc2.70293","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Vascular cognitive impairment (VCI), including vascular dementia (VaD), encompasses a spectrum of cognitive deficits resulting from cerebrovascular pathology, ranging from mild impairment to dementia. As the second leading cause of dementia worldwide, VCI remains a major therapeutic challenge. A comprehensive search of ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) identified randomized controlled trials (RCTs) conducted or completed between 2012 and 2025. Trials enrolling participants diagnosed with VCI or VaD across all disease stages and all trial phases were included. Forty-one RCTs met the inclusion criteria encompassing diverse therapeutic mechanisms. Investigated agents included neuroprotective and vascular-targeted compounds, neurotransmitter modulators, symptom-focused drugs for behavioral and psychological symptoms of dementia (BPSD), traditional Chinese medicine (TCM) formulations, and agents acting on novel pathways. Recent trials in VCI and VaD show increasing methodological rigor and therapeutic diversity, signaling growing research momentum in the field. Nonetheless, progress is constrained by regional concentration of studies, limited publication of completed results, and inconsistent disease classification across stages. Strengthening global collaboration, ensuring transparent reporting, and standardizing disease staging will be critical to advancing pharmacological development for vascular cognitive disorders.</p>\u0000 </section>\u0000 </div>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 3","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70293","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148467460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}