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

{"title":"Correlations of <i>PSEN1</i>, <i>PSEN2</i>, and <i>APP</i> missense variants on the production of Aβ peptides against variant effect prediction.","authors":"Jiyeon Song, Serina Yan, Sophia Liu, Adhvaith Sridhar, Kijung Sung, Joshua Pillai, Chengbiao Wu","doi":"10.1002/trc2.70320","DOIUrl":"10.1002/trc2.70320","url":null,"abstract":"<p><strong>Introduction: </strong>Early-onset Alzheimer's disease (EOAD) is mostly caused by mutations in <i>presenilin-1/2</i> (<i>PSEN1</i>, <i>PSEN2)</i> and amyloid precursor protein (<i>APP)</i> genes. Both genetic and experimental evidence have supported the PSEN-APP amyloid hypothesis as the leading pathogenesis of Alzheimer's disease (AD). Thus far, 276 missense variants from <i>PSEN1</i>, <i>2</i>, and <i>APP</i> have been identified. Herein, we report the abilities of variant effect predictors (VEPs) for identifying the degree of pathogenicity among alleles linked with EOAD.</p><p><strong>Methods: </strong>We performed pairwise correlations between 276 in vitro functional assays of missense variants from <i>PSEN1</i>, <i>PSEN2</i>, and <i>APP</i> and clinical data among EOAD patients against 37 VEPs. Furthermore, we used the predicted biophysical data of all three proteins to refine our understanding of the molecular basis of missense variants in dominant negative (DN) or loss-of-function (LoF) effects.</p><p><strong>Results: </strong>We found that VEPs were consistently correlated with age at onset (AAO) among EOAD patients and the amyloid-β (Aβ) 42/Aβ40 ratio biomarker. Regarding the ratio, we observed discrepancies in the predictor variables influencing the Aβ42/Aβ40 ratio, with conflicting evidence as to whether the elevated ratio stems from diminished Aβ40 levels or augmented Aβ42 production. We also identified that with increased predicted pathogenicity, there were decreased Aβ38 levels. Conversely, this study found no direct correlations with Aβ37 and Aβ43. Lastly, structural studies show characteristics of both DN and LoF mechanisms, as there are variants positioned in buried hydrophobic domains and charged surfaces.</p><p><strong>Discussion: </strong>Currently, a major clinical challenge in the field is the lack of reliable approaches for predicting the pathogenicity of variants in EOAD. Our study also illuminates the need for experimental studies to identify the predictor variable causing the increased Aβ42/Aβ40 biomarker.</p><p><strong>Highlights: </strong>We performed correlations of 37 VEPs against in vitro data of EOAD variants.VEPs demonstrate potential as diagnostic tools for early onset Alzheimer's disease.Pathogenic missense variants show characteristics of DN and LoF effects.</p>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 3","pages":"e70320"},"PeriodicalIF":7.4,"publicationDate":"2026-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13550504/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148914351","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":"Baseline plasma C1q and C3 as potential biomarkers for lecanemab efficacy and ARIA risk in early Alzheimer's disease.","authors":"Gihwan Byeon, Jung-Won Lee, Suhyung Kim, Yoo Hyun Um, Sheng-Min Wang, Seunggyun Ha, Sonya Youngju Park, Ilah Shin, Jinhee Jang, Chang Uk Lee, Hyun Kook Lim, Dong Woo Kang","doi":"10.1002/trc2.70313","DOIUrl":"10.1002/trc2.70313","url":null,"abstract":"<p><strong>Introduction: </strong>The classical complement cascade has been implicated in amyloid beta (Aβ) clearance and in the pathogenesis of amyloid-related imaging abnormalities (ARIA) during anti-amyloid monoclonal antibody therapy. Clinically accessible peripheral biomarkers of this cascade remain uncharacterized in real-world cohorts.</p><p><strong>Methods: </strong>We conducted a retrospective, hypothesis-generating cohort study of 62 patients with early Alzheimer's disease initiating lecanemab. ARIA risk was evaluated in the safety cohort (<i>N</i> = 62), and absolute amyloid reduction at week 26 was evaluated in the efficacy cohort with paired baseline and 26-week amyloid positron emission tomography (<i>N</i> = 34). Associations of baseline plasma C1q, C3, and apolipoprotein E ε4 (<i>APOE</i> ε4) carrier status with these outcomes were examined using Firth's penalized logistic regression and bootstrap linear regression (2000 iterations), with prespecified sensitivity analyses. Within-subject changes in C3 (<i>N</i> = 30) and C1q (<i>N</i> = 19) were assessed by paired Wilcoxon test.</p><p><strong>Results: </strong>Lower baseline C3 was nominally associated with higher ARIA risk (odds ratio [OR] per 1 SD = 0.44, 95% CI: 0.15 to 0.97, <i>p</i> = 0.040, uncorrected), and this association persisted in international normalized ratio (INR)-adjusted and simplified models. C3 ≤ 25th percentile (≤99 mg/dL) showed a trend (OR: 4.78, 95% CI: 0.98 to 26.34, <i>p</i> = 0.052). In the efficacy cohort, higher baseline C1q was associated with smaller amyloid reduction (<i>β</i> = -6.86, 95% CI: -12.19 to -3.06, <i>p</i> = 0.002); carriers of at least one <i>APOE</i> ε4 allele, a status that in this cohort jointly reflects genotype and dose-titration, showed less amyloid reduction (<i>β</i> = -19.50, 95% CI -31.57 to -8.40, <i>p</i> < 0.001). Within-subject changes in C1q and C3 were not significant (<i>p</i> = 0.248 and 0.114, respectively).</p><p><strong>Discussion: </strong>Lower baseline C3 was consistently associated with ARIA risk across sensitivity analyses and higher baseline C1q with smaller amyloid reduction at week 26. Findings are exploratory given the limited single-center sample.</p>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 3","pages":"e70313"},"PeriodicalIF":7.4,"publicationDate":"2026-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13550506/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148914354","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":"Physical inactivity in preclinical Alzheimer's disease: Risk factor, early symptom, or both?","authors":"Jiawei Zhao, Xin Li, Mengxuan Wu, Zhanjun Zhang","doi":"10.1002/trc2.70316","DOIUrl":"10.1002/trc2.70316","url":null,"abstract":"<p><p>Physical inactivity is a key modifiable risk factor for Alzheimer's disease (AD). However, emerging evidence suggests a bidirectional relationship where inactivity also serves as an early manifestation of AD pathology. This perspective synthesizes recent findings from long-term epidemiological cohorts, brainstem neuropathology, and digital phenotyping to reconceptualize the role of inactivity in preclinical AD. Early tau accumulation in catecholaminergic nuclei (locus coeruleus and ventral tegmental area) disrupts circuits essential for reward valuation and effort calculation. We hypothesize that this neurobiological failure may manifest as prodromal apathy and declining physical activity years before cognitive impairment. Standard metrics like step counts fail to capture these nuances. We propose a multidimensional digital phenotype - incorporating temporal complexity, circadian rhythms, and life-space mobility - to distinguish \"behavioral\" from \"biologically constrained\" inactivity. This framework has critical implications for trial enrichment and the design of personalized lifestyle interventions.</p>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 3","pages":"e70316"},"PeriodicalIF":7.4,"publicationDate":"2026-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13546402/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148901385","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":"Clinically altered brain activity may not look like aged brain activity: Implications for brain-age modeling and biomarker strategies.","authors":"Lukas A W Gemein, Sinead Gaubert, Claire Paquet, Joseph Paillard, Sebastian C Holst, Thomas Tveitstøl, Ira R J H Haraldsen, Tony Kam-Thong, David J Hawellek, Jörg F Hipp, Denis A Engemann","doi":"10.1002/trc2.70302","DOIUrl":"10.1002/trc2.70302","url":null,"abstract":"<p><strong>Introduction: </strong>Brain-age gap (BAG), the difference between predicted age and chronological age, is studied as a biomarker for the natural progression of neurodegeneration. The BAG captures brain atrophy as measured with structural magnetic resonance imaging (MRI). Electroencephalography (EEG) has also been explored for estimating the BAG (EEG-BAG). However, studies showed mixed results for the EEG-BAG including counterintuitive findings of younger predicted age in clinical populations, raising doubts about its utility as a clinical tool for mild cognitive impairment (MCI) and Alzheimer's disease (AD).</p><p><strong>Methods: </strong>This study critically examined brain-age estimation from spectral EEG power as a common measure of brain activity in two of the largest public EEG datasets containing heterogeneous clinical cases alongside controls including MCI and AD. EEG recordings were analyzed from individuals with heterogeneous neurological conditions (<i>n =</i> 898, Temple University Hospital Abnormal EEG corpus [TUAB] data; <i>n =</i> 417 MCI & <i>n =</i> 311 dementia, Chung-Ang University Hospital EEG [CAU] data) and controls (<i>n =</i> 1245, TUAB data; <i>n =</i> 459, CAU data).</p><p><strong>Results: </strong>We found that age-prediction models trained on the reference population systematically underpredicted age in clinical conditions showing strong and systematic, age-related differences in EEG power compared to controls. Data exploration and simulations revealed how diverging age-related trends in specific EEG frequencies can account for a negative EEG-BAG.</p><p><strong>Discussion: </strong>The utility of brain age as an interpretable biomarker relies on the observation from structural MRI that progressive neurodegeneration often broadly resembles aging. This assumption can be violated for functional assessments such as EEG spectral power related to different neurological and psychiatric conditions or medications. The sign of the BAG may therefore not be meaningfully interpreted as an individual aging metric, hence hampering its utility as an endpoint or biomarker in MCI and AD.</p>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 3","pages":"e70302"},"PeriodicalIF":7.4,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13536007/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148882439","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":"Digital music intervention and music therapy across the dementia care continuum: Randomized controlled trial.","authors":"Lotta M Kaila, Ilja Salakka, Anni Pitkäniemi, Sari Laitinen, Milla Holma, Aleksi J Sihvonen, Teppo Särkämö","doi":"10.1002/trc2.70317","DOIUrl":"10.1002/trc2.70317","url":null,"abstract":"<p><strong>Introduction: </strong>Music interventions show promise in dementia care and digital approaches may increase availability and accessibility. We investigated the efficacy of a digital music intervention (DMI) and conventional music therapy (CMT) compared to standard care (SC) across the dementia care continuum.</p><p><strong>Methods: </strong>In an exploratory parallel-group randomized controlled trial, community-dwelling (HOME, <i>n </i>= 91) and care home-dwelling (CARE, <i>n </i>= 75) persons living with dementia (<i>n </i>= 166) were randomized to DMI, CMT, or SC. Group-based music interventions spanned 10 weeks (2 × 60-minute sessions/week) and included receptive (listening, reminiscing) and expressive (singing, movement) activity. DMI comprised pre-recorded video sessions followed on screen with a non-therapist facilitator; CMT was delivered live by professional music therapists. Outcomes were assessed at baseline (T1), 3 months (T2), and 6 months (T3), measuring cognition, mood, quality of life, and caregiver well-being. Primary outcomes were changes in general cognition (Montreal Cognitive Assessment, Consortium to Establish a Registry for Alzheimer's Disease Chandler total; T1-T2). Primary and sensitivity analyses used linear mixed-effects models in whole, HOME, and CARE samples.</p><p><strong>Results: </strong>No significant effects of CMT or DMI were found for primary general cognition outcomes in primary or sensitivity analyses. Across exploratory secondary outcomes, compared to SC, CMT improved naming (T1-T2) and verbal learning (T1-T3) in the whole sample and executive function in HOME (T1-T2). Compared to a decline in SC, prompted autobiographical memory was maintained by DMI and CMT in the whole sample (T1-T2) and by DMI in CARE (T1-T2). Sensitivity analyses largely supported these findings. No significant differences were observed between DMI and CMT.</p><p><strong>Discussion: </strong>CMT and DMI did not yield effects on primary general cognition outcomes. CMT showed modest but coherent effects on exploratory secondary cognitive outcomes across the dementia care continuum. The only exploratory secondary finding for DMI was maintenance of autobiographical memory against a decline in SC. These findings support existing evidence yet call for further research to optimize interventions.</p>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 3","pages":"e70317"},"PeriodicalIF":7.4,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13529809/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148876448","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":"Sex- and <i>APOE</i>-specific transcriptomic drug repurposing identifies four candidate therapeutics for Alzheimer's disease.","authors":"Francesca Vitali, Adam C Raikes, Simona Merlini, Yuan Shang, Georgina Torrandell-Haro, Gerson D Hernandez, Fei Yin","doi":"10.1002/trc2.70303","DOIUrl":"10.1002/trc2.70303","url":null,"abstract":"<p><strong>Introduction: </strong>Alzheimer's disease (AD) risk is strongly modified by biological sex and apolipoprotein E (<i>APOE</i>) genotype, yet these factors are rarely incorporated into drug discovery efforts. We hypothesized that sex- and <i>APOE</i>-specific transcriptomic signatures define distinct molecular endotypes of AD which can be therapeutically targeted through precision drug repurposing using an integrative data framework.</p><p><strong>Methods: </strong>We analyzed frontal cortex RNA sequencing data from 369 individuals in the Religious Orders Study Rush Memory and Aging Project cohort (<i>APOE</i> ε3/ε3 and <i>APOE</i> ε3/ε4) to derive sex- and genotype-specific AD gene expression signatures. Differential expression and Gene Ontology enrichment analyses identified biological processes uniquely or differentially perturbed across groups. Drug-induced perturbation signatures from the Library of Integrated Network-Based Cellular Signatures database were queried to identify US Food and Drug Administration-approved compounds predicted to reverse AD-associated signatures. Top candidates were validated using the PearlDiver-Mariner claims database to assess AD risk associations.</p><p><strong>Results: </strong>Transcriptomic dysregulation varied markedly across groups. Female <i>APOE</i> ε3/ε3 AD brains exhibited the greatest number of differentially expressed genes (<i>n</i> = 8903), whereas male <i>APOE</i> ε3/ε3 showed the fewest (<i>n</i> = 640). <i>APOE</i> ε4 carriers demonstrated enrichment of immune and inflammatory pathways, including cytokine signaling and extracellular signal-regulated kinase cascade activation, whereas <i>APOE</i> ε3/ε3 groups exhibited downregulation of synaptic organization, vesicle trafficking, and bioenergetic processes. Drug reversal analysis identified four candidates: riluzole, chloroquine, acetazolamide, and anagrelide. In population-level validation, riluzole (relative risk [RR] = 0.52; 95% confidence interval [CI]: 0.40-0.68), chloroquine (RR = 0.56; 95% CI: 0.55-0.58), and acetazolamide (RR = 0.76, 95% CI: 0.73-0.79) were associated with significantly reduced AD risk, whereas anagrelide exhibited increased risk. Protective associations for riluzole, chloroquine, and acetazolamide held in both sexes, with stronger effects in women.</p><p><strong>Discussion: </strong>Sex and <i>APOE</i> genotype define biologically distinct AD transcriptomic states, with subgroup-specific and shared pharmacologic reversibility. Integrating stratified transcriptomics with population-scale validation identified clinically actionable candidates supporting an AD precision drug repurposing framework.</p>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 3","pages":"e70303"},"PeriodicalIF":7.4,"publicationDate":"2026-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13499011/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148801497","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":"Factors affecting representativeness in home-based dementia activity interventions: a literature review.","authors":"Jiska Cohen-Mansfield","doi":"10.1002/trc2.70310","DOIUrl":"10.1002/trc2.70310","url":null,"abstract":"<p><p>Most persons living with dementia (PLwD) reside in community settings, which has driven the development of a wide range of home-based activity interventions. However, the external validity of these studies remains uncertain because the representativeness of study samples is rarely reported. Assessing representativeness is essential for estimating intervention reach and informing health equity and resource allocation decisions. This review evaluates the extent to which participants in home-based activity trials reflect the population of community-dwelling PLwD and identifies sources of selection bias. A targeted review was conducted using three complementary strategies: analyses of two prior systematic reviews, a PubMed search (2020 to 2025), and a review of relevant follow-up publications. Inclusion was limited to peer-reviewed studies that reported detailed recruitment flowcharts and screening data and had initial recruitment pools exceeding 70 participants. The review revealed that most studies provided limited detail on participant selection and frequently initiated recruitment reporting only after caregiver-care recipient dyads had already been assembled. Among the nine studies included, the mean refusal rate among eligible individuals was 57%. In addition, only 24% of initial referrals, on average, completed the first phase of an intervention. Primary barriers to participation included caregiver refusal, lack of an available caregiver/facilitator, and health-related issues. Based on these observed recruitment flows and pre-selection processes, home-based intervention models are estimated to reach fewer than 20% of the target population. These findings suggest that home-based activity interventions for PLwD are applicable to only a limited segment of the intended population. This \"representativeness gap\" appears largely attributable to reliance on facilitator-care recipient dyads, which inherently excludes the growing number of PLwD living alone and fails to account for the substantial burdens experienced by primary caregivers. Future research should prioritize the development and evaluation of alternative models, such as technology-assisted and community-supported approaches, to enhance scalability, inclusiveness, and equity.</p>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 3","pages":"e70310"},"PeriodicalIF":7.4,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13494667/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148801438","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":"Engaging Hispanic/Latino young adults in Alzheimer's disease research through boot camp translation.","authors":"Michelle N Martinez, Stacey Moeller, Mirna Arroyo-Miranda, Denise Lafont-Tanner, Samantha E John, Mark Kunik, Jennifer Vardeman, Rebecca Mullen, Peter Pressman, Michelle Stocker, Natalie Lopez-Esquibel, Steven Paul Woods, Luis D Medina","doi":"10.1002/trc2.70309","DOIUrl":"https://doi.org/10.1002/trc2.70309","url":null,"abstract":"<p><strong>Introduction: </strong>Despite increased risk for Alzheimer's disease and related dementias (ADRDs), Hispanic/Latino (H/L) populations remain underrepresented in research due to several barriers (e.g., stigma, health literacy). Considering family dynamics and cultural values, young H/L individuals may serve as liaisons to help communicate ADRD information and mitigate barriers to research participation.</p><p><strong>Methods: </strong>We recruited two groups of predominantly H/L young adults, ages 18-35, to carry out Boot Camp Translation (BCT) of ADRD in Houston, Texas (<i>n</i> = 12), and Las Vegas, Nevada (<i>n</i> = 15). Through BCT, we sought to identify (1) key AD-related messages, (2) target message recipients, and (3) effective strategies to convey these messages. ADRD knowledge was assessed pre- and post-BCT.</p><p><strong>Results: </strong>Members endorsed improvements in subjective understanding (Cohen's <i>d</i> = 1.37; <i>p</i> = .001) and objective knowledge of ADRD (Cohen's <i>d</i> = 0.96; <i>p</i>< .001). Suggested central messaging conveyed urgency and responsibility (e.g., \"Alzheimer's is real. Healthy or not: On which side do you want to be?\"), provided ADRD educational information (e.g., common symptoms), and represented H/L cultural values (<i>familismo</i>; e.g., \"Alzheimer's is not the end. You are not alone\"). Identified target age groups differed by city; Houston: 50+ years, 30-49 years, 18-29 years; Las Vegas: 40- and 50-year-olds. Members emphasized visual materials that are intergenerational, representative of the diverse H/L community, informative, and straightforward.</p><p><strong>Discussion: </strong>Extending our prior work with BCT in middle-age and older adults, we leveraged intra-familial communication to better understand ADRD-specific health education in H/L communities. While several messaging strategies appeared consistent across sites, regional differences in target audiences and preferred communication strategies highlight the importance of locally tailored messaging. Results identified culturally relevant avenues by which young adults may communicate ADRD research to older family members, fostering engagement. Future work is needed to examine the efficacy and effectiveness of these strategies in service of increasing H/L representation in ADRD research.</p>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 3","pages":"e70309"},"PeriodicalIF":7.4,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13487545/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148801506","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":"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}