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

{"title":"Association of SPHK1 polymorphisms with Alzheimer's disease susceptibility: Functional impact of the rs2247856 SNP on transcriptional efficiency","authors":"Dong-Ju Kim,&nbsp;Yong-Chan Kim,&nbsp;Byung-Hoon Jeong","doi":"10.1002/trc2.70288","DOIUrl":"10.1002/trc2.70288","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Sphingosine kinase 1 (<i>SPHK1</i>) has been implicated in the regulation of pro-resolving lipid mediators relevant to neuroinflammation in Alzheimer's disease (AD). However, no studies have evaluated the genetic association between <i>SPHK1</i> polymorphisms and AD susceptibility.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>We analyzed genotype and allele frequencies of polymorphisms in the <i>SPHK1</i> gene between patients with AD and healthy controls. In addition, transcription factor binding sites were evaluated. Furthermore, promoter activities associated with rs2247856 single nucleotide polymorphism (SNP) were assessed using a luciferase reporter assay.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>Among the identified SNPs, the genotype distribution of rs2247856 showed a significant association with AD. Haplotype analysis revealed that haplotype 3 (CAGTACGG) was significantly more frequent in patients with AD than in controls. Profiler of Multi-Omics Data (PROMO) analysis suggested that the rs2247856 A allele disrupts the activating transcription factor 3 transcription factor binding site. Luciferase assays demonstrated significantly reduced promoter activity in constructs containing the A allele compared to the G allele (<i>p</i> &lt; 0.001), indicating allele-specific regulation of <i>SPHK1</i> transcription.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>Our findings identify rs2247856 as a functional regulatory SNP in the <i>SPHK1</i> gene associated with AD susceptibility. The reduced transcriptional activity of the A allele may impair SPHK1-mediated anti-inflammatory signaling, potentially contributing to AD pathogenesis.</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":"2026-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13337528/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148406834","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":"Reprogramming lipid metabolism for cognitive restoration in Alzheimer's via PLA2G4E","authors":"Sara Badesso,&nbsp;María Espelosín,&nbsp;Cristina Alonso,&nbsp;Alejandro Montilla,&nbsp;Maria Collantes,&nbsp;Mar Cuadrado-Tejedor,&nbsp;Ana García-Osta","doi":"10.1002/trc2.70285","DOIUrl":"10.1002/trc2.70285","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Growing evidence implicates dysregulated brain lipid metabolism in Alzheimer's disease (AD) pathogenesis, influencing membrane integrity, neuroinflammation, and amyloid beta and tau pathology, thereby representing a promising therapeutic target. However, therapeutic strategies targeting lipid pathways remain largely unexplored.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>The therapeutic potential of PLA2G4E, previously identified in our earlier work, was validated in the APP^NL-G-F AD mouse model using a translational gene-delivery approach with a blood–brain barrier–penetrant adeno-associated vector (AAV) (AAVP31) to achieve widespread brain expression. Brain lipidomics was performed to investigate the molecular mechanisms underlying treatment effects.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>PLA2G4E expression rescued memory deficits, reduced tau phosphorylation, and improved brain glucose metabolism and cognitive performance in AD models and aged wild-type mice. These effects were accompanied by partial normalization of disease-associated lipid metabolic alterations.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>These findings support PLA2G4E as a promising therapeutic target in AD and provide mechanistic evidence linking modulation of lipid metabolic pathways to synaptic and cognitive rescue.</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":"2026-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13333937/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148438892","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":"Multiracial participants in Alzheimer's research: scoping review and recommendations","authors":"Stacey Moeller,&nbsp;Katie Singsank,&nbsp;Grace Goodwin,&nbsp;Denise Lafont-Tanner,&nbsp;Elizabeth Lawrence,&nbsp;Brenna Renn,&nbsp;Samantha John","doi":"10.1002/trc2.70276","DOIUrl":"10.1002/trc2.70276","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Evidence suggests that Alzheimer's disease (AD) presents differently across ethnoracial groups, producing disparate risk and resilience profiles that may be measured through neuropsychological data. Extant AD research primarily examines monoracial groups, despite the fact that Multiracial individuals make up more than 10% of the US population. Failure to incorporate data from Multiracial participants (those endorsing two or more racial identities) limits research and clinical efforts to address AD in minoritized communities. A scoping review examined the use of neuropsychological data from Multiracial participants within AD research. Three databases were searched (APA PsycInfo, Embase, and Web of Science) for studies containing ethnoracially minoritized groups. Two independent researchers reviewed articles and included studies that met the following criteria: published in 2000 (the year the US Census formally allowed self-identification of multiple races) or later, in English, US-based cohort (as race is a social construct), reported neuropsychological data, and the research was AD-related. Searches yielded 855 original articles. Following abstract review, 484 articles were screened in full, resulting in 19 articles that met the inclusion criteria. Most excluded articles (66.67%) contained vague racial descriptions (e.g., use of an undefined Other Race group), making it difficult to know whether Multiracial participants existed in the dataset. Roughly one-third (29.03%) of articles were excluded because they described only monoracial groups. Analysis of neuropsychological outcomes showed that most articles included Multiracial participant data in larger group-level analyses (e.g., normal cognition versus dementia) or grouped their data with other, less represented ethnic or racial groups (e.g., Other Races). This review demonstrates the paucity of research and need for intentional consideration of the inclusion of Multiracial participants in AD research. Recommendations to improve reporting of data from Multiracial participants are offered, including considerations for the anticipation and adaptation to changes in the social definitions of ethnicity and race.</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":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13322995/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148377979","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":"Meeting report for the Second International Conference on Unconventional Animal Models of Alzheimer's Disease and Aging (UAMAA 2026)","authors":"Jane Alshami,&nbsp;Ginny Wu,&nbsp;B. Maximiliano Garduño,&nbsp;Afonso C. Silva,&nbsp;Stacey J. Sukoff Rizzo,&nbsp;Patricia Cogram,&nbsp;Xiangmin Xu","doi":"10.1002/trc2.70281","DOIUrl":"https://doi.org/10.1002/trc2.70281","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>The Second International Conference on Unconventional Animal Models of Alzheimer's Disease and Aging (UAMAA 2026) was held February 9 through 11, 2026, in Irvine, California. Building upon the inaugural meeting in Santiago, Chile (2023), this conference expanded an international effort to develop, characterize, and rigorously evaluate non-traditional animal models with enhanced translational relevance for Alzheimer's disease (AD) and aging research. The meeting convened leading investigators across genomics, systems neuroscience, comparative biology, and pathology to discuss naturally occurring and engineered models including degu (<i>Octodon degus</i>), dog (<i>Canis lupus familiaris</i>), marmoset (<i>Callithrix jacchus</i>), rhesus macaque (<i>Macaca mulatta</i>), naked mole-rat (<i>Heterocephalus glaber</i>), and emerging large animal species including elephants and whales. A central theme was the need for cross-species integration of multimodal and multi-scale approaches to interrogate cellular vulnerability, gene regulatory programs, and age-associated neuropathology and circuit alterations across species. UAMAA 2026 emphasized cross-species comparison, human brain atlas integration, and translational alignment with National Institutes of Health priorities. The conference highlighted growing momentum toward a diversified model ecosystem aimed at accelerating mechanistic insight and therapeutic discovery in AD and aging research. A special journal issue associated with the conference has been announced to extend these themes into peer-reviewed scientific discourse.</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":"2026-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70281","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148358070","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":"Cerebrovascular reactivity and plasma p-tau181 in Alzheimer's disease: Insights into APOE-related vascular phenotypes","authors":"Martina Gaia Di Donna,&nbsp;Maria Rosaria Bagnato,&nbsp;Chiara Giuseppina Bonomi,&nbsp;Caterina Motta,&nbsp;Diego Centonze,&nbsp;Alessandro Martorana,&nbsp;Marina Diomedi","doi":"10.1002/trc2.70250","DOIUrl":"https://doi.org/10.1002/trc2.70250","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Vascular dysfunction is increasingly recognized as a key contributor to Alzheimer's disease (AD). This study explored cerebrovascular reactivity (CVR), measured by the breath-holding index (BHI) via Transcranial Doppler (TCD), in relation to plasma AD biomarkers, metabolic dysfunction, cardiovascular burden, and apolipoprotein E (APOE) genotype.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>We enrolled 64 patients with cerebrospinal fluid (CSF)-confirmed AD (30 APOE ε3, 34 APOE ε4) and 28 age-matched healthy controls in a cross-sectional blinded study. All participants underwent TCD to assess middle cerebral artery flow velocity and BHI. AD patients were further evaluated for insulin resistance (TyG index), magnetic resonance imaging markers of small vessel disease (SVD), and plasma biomarkers (phosphorylated tau 181 [p-tau181], amyloid beta [Aβ]42/Aβ40 ratio – AmyR). Multivariate regressions examined associations between BHI and AD-related parameters, stratified by APOE genotype.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>BHI was significantly reduced in both AD groups compared to controls (<i>p</i> &lt; 0.001), with no difference between ε3 and ε4 carriers. In ε3 patients, lower BHI was independently associated with higher plasma p-tau181. In the MRI subgroup analysis, ε3 patients showed a negative correlation between BHI and both TyG and mCSVD while showing a positive correlation with AmyR. None of these associations were observed in ε4 carriers.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>Our findings indicate that CVR impairment is present across AD genotypes but more strongly linked to AD pathology and vascular-metabolic dysfunction in APOE ε3 carriers. CVR may represent a non-invasive biomarker of early vascular contributions to cognitive decline in AD.</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":"2026-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70250","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148358069","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":"Person-centered intervention response in primary progressive aphasia: A secondary analysis of the Communication Bridge-2 randomized clinical trial.","authors":"Emily Rogalski, Ollie Fegter, Angela C Roberts, Matthew Bona, Emily Cummings, Marisa Esparza, Eric Polley, Alfred Rademaker","doi":"10.1002/trc2.70283","DOIUrl":"10.1002/trc2.70283","url":null,"abstract":"<p><strong>Introduction: </strong>Person-centered outcomes that capture clinically meaningful change are essential to non-pharmacological intervention research for Alzheimer's disease and related dementias. Primary progressive aphasia (PPA) is a neurodegenerative syndrome characterized by progressive language impairment. The Communication Bridge-2 (CB2) randomized controlled trial previously demonstrated the efficacy of a personalized, participation-focused speech-language intervention on Goal Attainment Scaling (GAS), a person-centered communication participation outcome. This secondary responder analysis characterized meaningful participant- and goal-level response following intervention and at 12 months after enrollment to inform clinical translation and future appropriate use criteria.</p><p><strong>Methods: </strong>Fifty participants with mild to moderate PPA in the CB2 experimental arm, each with three individualized communication participation goals (<i>N</i> = 150 goals), were included. Prespecified responder thresholds were defined as GAS ≥1 following each intervention block and GAS ≥0 at 12 months, reflecting improvement or maintenance relative to baseline in a progressive condition. Descriptive analyses examined responder patterns across time points, participants, baseline severity, PPA subtypes, and goal characteristics.</p><p><strong>Results: </strong>All participants met responder criteria at one or more evaluation time points. At 12 months, 79% of goals met responder criteria, and 60% of participants met responder criteria across all three goals. More than half of the goals (51.3%) met responder criteria at all three evaluation time points. Meaningful response was observed across PPA subtypes, baseline severity levels, and diverse goal characteristics. Exploratory patterns suggested higher 12-month responder rates for goals targeting speech, familiar communication partners, and familiar communication contexts.</p><p><strong>Discussion: </strong>This secondary responder analysis demonstrates that a person-centered, participation-focused speech-language intervention was associated with meaningful goal-level improvement or maintenance across a heterogeneous PPA population, with many responses sustained over 12 months. These findings support the value of GAS as a pragmatic, person-centered outcome for capturing meaningful response in progressive neurodegenerative disease and provide translational evidence to inform future appropriate use criteria and individualized dementia care.</p>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 2","pages":"e70283"},"PeriodicalIF":7.4,"publicationDate":"2026-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13290644/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148334005","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":"Reanalyzing the impact of cognitive training over 20 years in the ACTIVE study: Losing the forest in the trees.","authors":"William T Dickens","doi":"10.1002/trc2.70280","DOIUrl":"https://doi.org/10.1002/trc2.70280","url":null,"abstract":"<p><strong>Introduction: </strong>This paper reanalyzes the 20-year follow-up to the Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) cognitive training trial, which evaluated whether memory, reasoning, and speed-of-processing training reduce dementia risk in older adults.</p><p><strong>Methods: </strong>Published hazard ratios and confidence intervals from the follow-up were used to conduct Bonferroni-Dunn corrections, sign tests on the pattern of hazard ratios, and parametric modeling.</p><p><strong>Results: </strong>After Bonferroni-Dunn correction, all confidence intervals include a hazard ratio of 1. Sign tests reject both the hypothesis of no training effect and the hypothesis that only one training type is effective. Generalized method of moments estimation of parametric models suggests a common protective effect for all treatments concentrated in the youngest age group.</p><p><strong>Discussion: </strong>Preregistration strengthens claims of statistical significance, but interpretation need not be limited to the preregistered analytical framework when alternative analyses reveal consistent patterns.</p>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 2","pages":"e70280"},"PeriodicalIF":7.4,"publicationDate":"2026-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13284741/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148310467","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":"How well is messaging about the importance of vaccination for people living with dementia being communicated? A jurisdictional scan of National Immunization Technical Advisory Groups and dementia advocacy organizations.","authors":"Melissa K Andrew, Shanna C Trenaman","doi":"10.1002/trc2.70261","DOIUrl":"10.1002/trc2.70261","url":null,"abstract":"<p><p>Vaccination is particularly important for people living with dementia (PLWD), who are at risk for meaningful declines in function and cognition after acute illnesses including vaccine-preventable infections. Even so, vaccine uptake remains suboptimal. Optimal tailoring of messaging relies on awareness in advisory, decision-making, and advocacy settings that PLWD are an important population for immunization. This policy forum paper discusses why vaccination is particularly important for PLWD and whether this is translated into public-facing and policy audience messaging. Jurisdictional scans investigated three questions: the inclusion of geriatrics expertise in a sample of eight National Immunization Technical Advisory Groups (NITAGs; Australia, Canada, France, Germany, Switzerland, the UK, United States, World Health Organization), whether PLWD are included in high-risk groups particularly recommended to receive adult vaccinations, and whether dementia advocacy organizations from these same jurisdictions discuss and recommend vaccination. We conclude that there remain important opportunities for improvement in understanding and communicating the benefits of vaccination for PLWD, and present policy recommendations for NITAGs, dementia advocacy organizations, and clinicians.</p>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 2","pages":"e70261"},"PeriodicalIF":7.4,"publicationDate":"2026-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13286738/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148320694","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":"Travel barriers to amyloid-targeting infusion access among older adults.","authors":"Jeremy Burke, Albert Weerman, Mark Hanson, Quanwu Zhang, Amir Abbas Tahami Monfared, Soeren Mattke","doi":"10.1002/trc2.70282","DOIUrl":"10.1002/trc2.70282","url":null,"abstract":"<p><strong>Introduction: </strong>Amyloid-targeting treatments (ATT) for Alzheimer's disease require regular infusions and caregiver accompaniment for approximately 80% of patients. Travel time to infusion sites and caregiver availability can therefore impede access to care, especially in rural and lower income populations.</p><p><strong>Methods: </strong>We conducted a survey in a nationally representative Internet panel with more than 2300 adults aged ≥65 years to estimate willingness to travel for bi-weekly infusion treatment, and access to an accompanying caregiver. Addresses of respondents and infusion sites were geocoded and driving times to the nearest infusion centers were calculated using Google Maps road network data. To estimate potential access gains under subcutaneous (SC) delivery, we estimated access by relaxing the travel and accompaniment requirements in a scenario analysis.</p><p><strong>Results: </strong>Median willingness-to-travel time was 97.5 minutes (interquartile range [IQR]: 67.5-187.5 minutes) one way for bi-weekly infusions over a 5-year period. Approximately 90% of respondents were willing to travel the required time to reach an infusion site. However, 18% indicated that it would be unlikely that they could identify someone to accompany them. When caregiver accompaniment was incorporated as a constraint, 75% met both the travel and caregiver criteria. In regression analysis, respondents with annual incomes above $60,000 and those residing in metropolitan areas were 9 and 19 percentage points more likely, respectively, to meet travel and caregiver criteria. In a scenario analysis, SC delivery increased overall access by up to 33%, in relative terms, with larger proportional gains for low income and rural respondents.</p><p><strong>Discussion: </strong>A meaningful number of individuals in a nationally representative sample live farther from their nearest site than they would be willing to travel, and obstacles to access worsen if individuals need a caregiver to accompany them, as is common among early-stage AD patients. Treatments that do not require infusion delivery could improve equitable access to care.</p>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 2","pages":"e70282"},"PeriodicalIF":7.4,"publicationDate":"2026-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13284744/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148310459","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":"A combination of ketones and NAD⁺ precursor preserves white matter integrity in mild cognitive impairment.","authors":"Maggie Roy, Mélanie Fortier, Valérie St-Pierre, Marie-Christine Morin, Arnaud Boré, Manon Edde, Camille Vandenberghe, Karine Groulx, Étienne Croteau, Gabriel Richard, Stanislas Thoumyre, Tamas Fulop, Christian Bocti, François Rheault, Bernard Cuenoud, Maxime Descoteaux, Stephen C Cunnane","doi":"10.1002/trc2.70278","DOIUrl":"10.1002/trc2.70278","url":null,"abstract":"<p><strong>Introduction: </strong>Brain glucose metabolism declines and myelin deteriorates as Alzheimer's disease (AD) develops. Adequate energy supply to white matter (WM) is critical to maintain myelin integrity and axonal function. An exogenous source of ketones bypasses the glucose‑specific brain energy deficit and improves cognitive outcomes in mild cognitive impairment (MCI). The BREAK-AD (BRain Energy Activation with Ketones in AD) trial tested a ketone salt and nicotinamide adenine dinucleotide (NAD⁺) precursor mixture to compensate for reduced brain glucose uptake in MCI.</p><p><strong>Methods: </strong>Participants were randomized to a placebo (<i>n</i> = 15) or active supplement (<i>β</i>-hydroxybutyrate salts + nicotinamide riboside (NR); <i>n</i> = 15). Brain ketone and glucose metabolism (quantified by positron emission tomography [PET]), and cognitive performance were assessed before and at the end of the 6-month intervention. For WM analysis, seven tracts of interest were extracted using diffusion magnetic resonance imaging (MRI), and myelin density measures were derived from magnetization transfer (MT) imaging.</p><p><strong>Results: </strong>Total gray matter ketone uptake increased by 2.4-fold (<i>p</i> < 0.001) in the active group, with no change in gray matter glucose uptake in either group. In WM, ketone uptake increased in the active group by 3.1-3.6-fold across all seven tracts of interest (<i>p</i> < 0.001). In the placebo group, myelin density declined by up to 10% in specific regions of the fornix (<i>p</i> = 0.027), with no change in the active group. Improved processing speed was significantly associated with post-intervention change in myelin density (<i>r</i> = -0.39 to -0.59; <i>p</i> = 0.002-0.046) and ketone uptake (<i>r</i> = -0.40 to -0.52; <i>p</i> = 0.010-0.046) in WM tracts. Ketone uptake in specific WM tracts (fornix, uncinate and arcuate fasciculi), as well as in the composite of all tracts of interest was strongly associated with myelin density.</p><p><strong>Discussion: </strong>This study shows for the first time that improved myelin density may help explain the positive association between increased WM ketone uptake and improved processing speed in MCI after a ketone salt and NAD⁺ precursor supplementation.</p>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 2","pages":"e70278"},"PeriodicalIF":7.4,"publicationDate":"2026-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13286740/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148320691","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}