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

{"title":"A common outcome set for trials in dementia with Lewy bodies (DLB COS)","authors":"Joseph P. M. Kane,&nbsp;Rachel L. Fitzpatrick,&nbsp;Sara Betzhold,&nbsp;Gillian Daly,&nbsp;Emily Kalfas,&nbsp;Irina Kinchin,&nbsp;Dag Aarsland,&nbsp;Ken Greaney,&nbsp;Emilia Grycuk,&nbsp;Ann-Kristin Folkerts,&nbsp;Elke Kalbe,&nbsp;Federico Rodriguez-Porcel,&nbsp;Ian J. Saldanha,&nbsp;Valerie Smith,&nbsp;John-Paul Taylor,&nbsp;Rachel Thompson,&nbsp;Kathryn Wyman-Chick,&nbsp;Iracema Leroi,&nbsp;and The DLB COS Delphi Group","doi":"10.1002/trc2.70134","DOIUrl":"10.1002/trc2.70134","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Methodological heterogeneity in dementia with Lewy bodies (DLB) trials contributes to publication bias and makes evidence synthesis and meta-analysis challenging. We aimed to develop a core outcome set for DLB (DLB COS) trials to improve consistency and comparability in DLB research.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>We conducted a systematic review to identify outcomes and administered a two-stage Delphi survey to a diverse panel of lay and professional stakeholders. We asked respondents which outcomes should be prioritized and included in DLB COS.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>Forty-nine outcomes were presented to survey respondents. Consensus was reached regarding eight outcomes for the final DLB COS: delusions/paranoia; fluctuations in cognition, attention, and arousal; functioning; global cognition; hallucinations; quality of life; motor parkinsonism; and rapid eye movement sleep behavior disorder.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>If adopted, DLB COS can enhance the comparability of research findings and facilitate standardization and harmonization.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>A systematic review revealed heterogeneity in dementia with Lewy bodies (DLB) study outcomes.</li>\u0000 \u0000 <li>Our study produced a DLB Core Outcome Set (DLB COS) comprising eight outcomes.</li>\u0000 \u0000 <li>DLB COS sets the minimum reporting standards for future trials.</li>\u0000 \u0000 <li>DLB-specific rating scales incorporating these outcomes are needed.</li>\u0000 \u0000 <li>Addressing this gap is a strategic priority in DLB research.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 3","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70134","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144606447","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":"Correction to “The HOPE4MCI study: AGB101 treatment slows progression of entorhinal cortex atrophy in APOE ε4 non-carriers with mild cognitive impairment due to Alzheimer's disease”","authors":"","doi":"10.1002/trc2.70131","DOIUrl":"10.1002/trc2.70131","url":null,"abstract":"<p>Bakker A, Rani N, Moh3 R, Gallagher M. The HOPE4MCI study: AGB101 treatment slows progression of entorhinal cortex atrophy in <i>APOE</i> ε4 non-carriers with mild cognitive impairment due to Alzheimer's disease. <i>Alzheimers Dement</i>. 2024;10(4):e70004. doi: 10.1002/trc2.70004.</p><p>In the acknowledgement section the sentence “The authors would also like to thank Ken Payie at KGP-Biotech for the production and manufacture of the extended-release medication, Kevin Arauz at Worldwide Clinical Trials for project management, and Carrie L. Speck at Johns Hopkins University for project coordination” inadvertently left out two people that should be recognized. The sentence should read “<i>The authors would also like to thank Marilyn Albert at Johns Hopkins University for scientific guidance, Kevin Arauz at Worldwide Clinical Trials for project management, Ken Payie at KGP-Biotech for the production and manufacture of the extended-release medication, Sharon Rosenzweig-Lipson at AgeneBio for program development, and Carrie L. Speck at Johns Hopkins University for project coordination</i>.”</p><p>We apologize for this oversight and thank you for your assistance in this matter.</p><p>Arnold Bakker</p>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 3","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70131","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144589653","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":"Mind your nose: A randomized controlled trial of olfactory-based memory training for older people with subjective cognitive decline","authors":"Isabelle J. M. Burke,&nbsp;Courtney Chesser,&nbsp;Christopher P. K. Brown,&nbsp;Rachel Watkins,&nbsp;Peter Butterworth,&nbsp;Jonas K. Olofsson,&nbsp;Kate Laver,&nbsp;Benjamin M. Hampstead,&nbsp;Alex Bahar-Fuchs","doi":"10.1002/trc2.70120","DOIUrl":"10.1002/trc2.70120","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; INTRODUCTION&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Olfactory-based cognitive training may be of benefit to individuals at risk of dementia given the strong association between olfactory impairment and cognitive decline. The Mind Your Nose (MYN) trial compared an olfactory-based memory training protocol (OMT) to a visually-based memory training protocol (VMT) among older adults with subjective cognitive decline.&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;Participants (&lt;i&gt;N&lt;/i&gt; = 53; 17 males; M&lt;sub&gt;age &lt;/sub&gt;= 72.77, standard deviation [SD] = 6.12) were randomly assigned in a 2:1 ratio to daily OMT (&lt;i&gt;n&lt;/i&gt; = 36) or VMT (&lt;i&gt;n&lt;/i&gt; = 17) intervention for 20 days. Outcomes were evaluated at baseline (T0), post-intervention (T1), and 1-month follow-up (T2) and included standardized measures of global olfaction (Sniffin’ Sticks) and cognition (National Institutes of Health Toolbox), as well as performance on the olfactory memory (OM) and the visual memory (VM) tasks, and measures of mood and meta-cognition.&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;A significant interaction was found between treatment allocation, time, and modality of memory task at T1(β = −37.50, &lt;i&gt;p&lt;/i&gt; = 0.008) and T2(β = −28.75, &lt;i&gt;p&lt;/i&gt; = 0.041). Post-hoc comparisons revealed improvement in trained tasks; OMT led to improvement on the OM task (T1; &lt;i&gt;g&lt;/i&gt; = 0.71, &lt;i&gt;p&lt;/i&gt; = 0.036; T2; &lt;i&gt;g&lt;/i&gt; = 0.72, &lt;i&gt;p&lt;/i&gt; = 0.035), and VMT led to improvement on the VM task (T1; &lt;i&gt;g&lt;/i&gt; = 1.22, &lt;i&gt;p&lt;/i&gt; = 0.011; T2; &lt;i&gt;g&lt;/i&gt; = 1.29, &lt;i&gt;p&lt;/i&gt; = 0.006). Improvement on the untrained memory task only occurred in OMT (VM task, T1; g = 0.63, &lt;i&gt;p&lt;/i&gt; = 0.071; T2; &lt;i&gt;g&lt;/i&gt; = 0.74, &lt;i&gt;p&lt;/i&gt; = 0.033). No interaction between treatment allocation and time was observed post intervention or at follow-up for global olfactory ability (T1; β = 0.27, &lt;i&gt;p&lt;/i&gt; = 0.871; T2; β = −1.27, &lt;i&gt;p&lt;/i&gt; = 0.296).&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;Consistent with previous research, transfer gains from the OMT condition to an untrained VM task suggest that olfaction may contribute to a-modal representations of memory. We argue that memory-based olfactory training offers a new frontier for cognitive interventions among those at risk of dementia.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Highlights&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;Relatively few cognitive training programs engage the olfactory sense.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Olfactory memory trainin","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 3","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70120","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144581913","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":"Response to: Refining the clinical interpretation of activity variability in cognitive impairment: The need for phenotypic specificity","authors":"Patrick T. Donahue,&nbsp;Jennifer A. Schrack,&nbsp;Johannes Thrul,&nbsp;Michelle C. Carlson","doi":"10.1002/trc2.70128","DOIUrl":"10.1002/trc2.70128","url":null,"abstract":"&lt;p&gt;Dear Guo et al.,&lt;/p&gt;&lt;p&gt;We thank Guo et al.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; for their interest in our article&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; and for providing innovative thoughts regarding clinical translation of our activity variability metric.&lt;/p&gt;&lt;p&gt;We would first like to emphasize that we positioned our work as an exploratory analysis of a conceptually novel metric developed using available accelerometry data. It is fit for application in future longitudinal and clinical studies with accelerometry data, which can replicate our findings and establish clinically meaningful changes relevant to activity variability and cognition. Our cross-sectional study suggests that low activity variability is strongly associated with cognitive impairment, yet we acknowledge that this metric requires further validation before implementation as a digital biomarker of cognitive decline and impairment. We intend to extend this work to other studies and encourage other researchers and clinicians to pursue validation studies, which were beyond the scope of our analysis.&lt;/p&gt;&lt;p&gt;We agree with Guo et al.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; that cognitive impairment is heterogeneous and that it would be useful to distinguish subtypes of dementia, such as vascular versus Alzheimer's disease pathologies. The data we used have strengths and limitations, as noted in our article. As Guo et al. mention, and we discussed in our article, the National Health and Aging Trends Study (NHATS) dementia classification criteria are &lt;i&gt;not&lt;/i&gt; equivalent to a dementia diagnosis, nor do they distinguish subtypes of cognitive decline and impairment.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; As Guo et al. compellingly state, it is important to further extend the conceptual link between activity variability and cognitive risk to clinical neurological outcomes, not limited to dementia (e.g., traumatic brain injury). Guo et al.’s proposal to link activity variability to specific brain regions via neuroimaging and associated cognitive domains via neuropsychological testing presents exciting additional mechanistic areas of research, which would greatly complement our findings. We agree that identifying underlying brain regions and cognitive domains that may be specifically related to activity variability would enhance this metric's clinical utility for greater sensitivity in detection of cognitive and functional impairment. In addition, if activity variability can be linked to specific brain regions, it may serve as a potential intermediate outcome for cognitive interventions.&lt;/p&gt;&lt;p&gt;Guo et al. commented that, because activity variability and gait speed were correlated, we cannot disentangle “the cognitive versus biomechanical determinants of variability”. Importantly, our study was not intended to examine the cognitive versus biological determinants of activity variability. Although activity variability and gait speed were correlated, activity variability remained strongly associated with cognitive impairment even after controlling f","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 3","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70128","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144514970","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":"Refining the clinical interpretation of activity variability in cognitive impairment: The need for phenotypic specificity","authors":"Hui Guo,&nbsp;Ziyu Yang,&nbsp;Xiongfei Zhao","doi":"10.1002/trc2.70129","DOIUrl":"10.1002/trc2.70129","url":null,"abstract":"&lt;p&gt;To the Editor,&lt;/p&gt;&lt;p&gt;We read with great interest the recent article by Donahue et al. entitled “Activity variability: a novel physical activity metric and its association with cognitive impairment.”&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; The authors proposed an innovative metric based on minute-to-minute accelerometry data to quantify behavioral complexity in older adults and demonstrated its strong association with cognitive impairment. This approach represents a valuable step forward in moving beyond threshold-based activity summaries, such as daily activity counts or activity fragmentation. The findings suggest that reduced activity variability may serve as a potential behavioral biomarker of cognitive decline, with promising implications for early detection.&lt;/p&gt;&lt;p&gt;From the perspective of neurological clinical care, however, we believe there is an opportunity to further refine the interpretation and application of activity variability by considering the heterogeneity of cognitive impairment phenotypes. While cognitive decline is often grouped into a single binary or trichotomous classification (e.g., no dementia, possible, probable), clinical experience teaches us that functional trajectories diverge markedly across individuals with similar test scores but different underlying pathologies.&lt;/p&gt;&lt;p&gt;For instance, individuals with predominant vascular contributions to cognitive impairment (VCI) often exhibit executive dysfunction and apathy early in the disease course, potentially manifesting as rigid, stereotyped behavioral patterns with low environmental reactivity.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; In contrast, early Alzheimer's disease may present with preserved routine variability but degraded memory recall and temporal disorientation.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; If activity variability truly reflects an individual's capacity to adapt behaviorally in real time, then grouping all types of cognitive impairment together without distinguishing their causes may obscure important differences in underlying mechanisms – ultimately reducing the metric's usefulness in clinical decision-making.&lt;/p&gt;&lt;p&gt;To better integrate activity variability into neurological assessment, we suggest future work link this measure with domain-specific cognitive performance and neuroimaging markers. For example, variability patterns could be examined in relation to frontal-subcortical network integrity via diffusion tensor imaging or task-based functional MRI. Alternatively, clustering patients based on variability signatures and comparing cognitive domain profiles (e.g., attention, planning, visuospatial processing) might help isolate phenotypes with differential progression risks or responsiveness to intervention.&lt;/p&gt;&lt;p&gt;Moreover, the strong correlation observed between activity variability and gait speed raises the question of whether variability reflects cognitive control, motor capacity, or both. Given that physical performance and neural degeneration often co-occur in aging, disentangling the ","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 3","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70129","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144514969","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 activity as a resistance or resilience mechanism in Down syndrome Alzheimer's disease","authors":"Victoria L. Fleming,&nbsp;Jamie Peven,&nbsp;Brian C. Helsel,&nbsp;Lauren T. Ptomey,&nbsp;Julianne Clina,&nbsp;Ashlyn Barry,&nbsp;Beau M. Ances,&nbsp;Benjamin L. Handen,&nbsp;Bradley T. Christian,&nbsp;Charles Laymon,&nbsp;Matthew Zammit,&nbsp;Elizabeth Head,&nbsp;Mark Mapstone,&nbsp;Ozioma Okonkwo,&nbsp;Sigan L. Hartley,&nbsp;for the Alzheimer Biomarkers Consortium – Down Syndrome","doi":"10.1002/trc2.70127","DOIUrl":"10.1002/trc2.70127","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Adults with Down syndrome (DS) are at risk for Alzheimer's disease (AD). Lifestyle factors such as engagement in moderate-to-vigorous physical activity (MVPA) reduce risk or delay the onset of AD. This study aimed to determine whether MVPA confers a <i>resistance</i> (AD pathology) or <i>resilience</i> (cognitive decline) effect on the relationship between AD pathology and cognitive decline in DS.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>Analyses included 69 adults with DS (aged 26–58) who participated in a longitudinal study across 3.29 years. An actigraphy accelerometer assessed MVPA across 7 days. Directly administered and informant-reported measures assessed cognitive functioning, specifically memory and dementia symptoms. Neuroimaging biomarkers quantified amyloid beta (Aβ) burden, as assessed via positron emission tomography imaging.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>In regression models, baseline MVPA was not associated with baseline level or change in global Aβ burden across 32 months. However, baseline MVPA (<i>β</i> = −0.005 to −0.004, <i>p</i> &lt; 0.05) significantly moderated the association between increases in Aβ burden and declines in cognitive functioning. Adults with DS who engaged in greater MVPA experienced less cognitive decline compared to adults with DS who engaged in less MVPA, who had similar Aβ load.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>MVPA may help maintain cognitive functioning early in the progression of AD pathology in adults with DS.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Adults with Down syndrome are genetically at risk for Alzheimer's disease (AD).</li>\u0000 \u0000 <li>Timing of AD clinical onset spans 30+ years.</li>\u0000 \u0000 <li>Physical activity has been linked to less cognitive decline and dementia symptoms.</li>\u0000 \u0000 <li>Physical activity may protect against dementia through resilience mechanisms.</li>\u0000 \u0000 <li>Physical activity could be a low-cost intervention to help prevent cognitive decline.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 3","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70127","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144503156","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 impact of estimated cardiorespiratory fitness on Alzheimer's disease biomarkers and their relationships with cognitive decline","authors":"Adam J Paulsen,&nbsp;Ira Driscoll,&nbsp;Brianne M. Breidenbach,&nbsp;Matthew Glittenberg,&nbsp;Sarah R. Lose,&nbsp;Yue Ma,&nbsp;Mark A. Sager,&nbsp;Cynthia M. Carlsson,&nbsp;Catherine L. Gallagher,&nbsp;Bruce P. Hermann,&nbsp;Kaj Blennow,&nbsp;Henrik Zetterberg,&nbsp;Sanjay Asthana,&nbsp;Sterling C. Johnson,&nbsp;Tobey J. Betthauser,&nbsp;Bradley T. Christian,&nbsp;Dane B. Cook,&nbsp;Ozioma C. Okonkwo","doi":"10.1002/trc2.70122","DOIUrl":"10.1002/trc2.70122","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; INTRODUCTION&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The accumulation of core Alzheimer's disease (AD) pathology contributes to cognitive decline. Cardiorespiratory fitness (CRF) influences AD pathological progression resulting in improvement or maintenance of cognitive function with age. CRF-related differences in accumulation rates or risk of reaching clinically relevant AD biomarker levels, and potentially interactive effects of core AD pathology and CRF on cognitive decline, remain largely unknown.&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;Participants (&lt;i&gt;N&lt;/i&gt; = 533; Mean&lt;sub&gt;AGE&lt;/sub&gt; = 65, 70% female) from the Wisconsin Alzheimer's Disease Research Center and the Wisconsin Registry for Alzheimer's Prevention underwent serial blood draws, and cognitive and imaging assessments (Mean&lt;sub&gt;Follow-up&lt;/sub&gt; = 6.0 years). Positron emission tomography (PET) imaging of amyloid beta (Aβ) and tau (T) and plasma phosphorylated tau-217 (p-tau217) were used to determine biomarker status (±). Sex-specific estimated CRF (eCRF) tertiles were created using a validated equation. Kaplan–Meier survival curves and Cox proportional hazards examined the risk of becoming biomarker-positive. Linear mixed-effects models, stratified by biomarker status, estimated associations between baseline eCRF and core AD biomarker accumulation, and whether eCRF modified relationships between biomarker accumulation and cognitive decline.&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;There were no significant relationships between eCRF and biomarker trajectories. However, those in high eCRF group who were Aβ− at baseline had a significantly lower risk of becoming biomarker-positive (Aβ-PET: HR, 95% confidence interval [CI] = 0.42, 0.20–0.88; p-tau-217: 0.45, 0.21–0.97) compared to the low eCRF group. The detrimental relationship between Aβ accumulation and cognitive decline was significantly attenuated for Aβ+/T+ with high eCRF.&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;Although eCRF did not influence core AD biomarker accumulation trajectories, high eCRF seems protective against becoming biomarker-positive and attenuates the known deleterious relationship between biomarker accumulation and cognitive decline in Aβ+/T+.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Highlights&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;High estimated cardiorespiratory fitness (eCRF) is associated with a lesser likelihood of becoming AD biomarker positive.&lt;/li&gt;\u0000 ","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 2","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70122","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144472809","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 splice-switching antisense oligonucleotide targeting APP reduces accumulation of α-synuclein in a mouse model of Parkinson's disease","authors":"Rijwan U. Ahammad,&nbsp;Brian Spencer,&nbsp;Bao Quach,&nbsp;Sahar Salehi,&nbsp;Robert A. Rissman","doi":"10.1002/trc2.70117","DOIUrl":"10.1002/trc2.70117","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Introduction&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Alzheimer's disease (AD) and Parkinson's disease (PD) are neurodegenerative disorders characterized by abnormal protein aggregation, with amyloid beta (Aβ) and α-synuclein (α-syn) as key pathological markers. Increasing evidence highlights a pathological interplay between Aβ and α-syn, exacerbating neurodegeneration in both AD and PD. In this study, we evaluated the effects of reducing amyloid precursor protein (APP) processing on α-syn pathology using a splice-switching oligonucleotide (SSO) targeting APP exon 15 in Thy1-α-syn transgenic (α-syn-tg) mice.&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;α-syn-tg mice received systemic APP SSO treatment. Immunohistochemistry and immunoblotting assessed α-syn, phosphorylated α-syn (P-Syn), and APP C-terminal fragments (CTFs) in the cortex, hippocampus, and thalamus. Neuronal integrity in different brain regions were examined, and behavioral assessments evaluated cognitive and motor functions.&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;APP SSO treatment significantly reduced α-syn and P-Syn in the cortex, hippocampus, and thalamus while also reversing neuronal loss in the hippocampal CA3 region. Interestingly, α-syn-tg mice exhibited elevated levels of alternative APP CTFs, which were reduced by APP SSO treatment, implicating APP processing dysregulation in α-syn pathology. Although behavioral assessments revealed no significant impairments or improvements in female α-syn-tg mice.&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;Our findings demonstrate that targeting APP reduces α-syn pathology and rescues neuronal loss, supporting the therapeutic potential of APP modulation in synucleinopathies. While no behavioral changes were observed in transgenic mice, further research exploring different models and conditions may provide additional insights into the full range of therapeutic benefits. Future studies should optimize delivery methods and explore combination therapies to enhance outcomes in neurodegenerative diseases with overlapping proteinopathies.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Highlights&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;APP-targeting SSO reduces α-syn and P-Syn in α-syn-tg mice.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;APP SSO lowers APP CTFs, linking APP processing to α-syn pathology.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Neuronal loss in the hippocampal CA3 region is restored fol","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 2","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70117","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144367413","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":"Why testing and diagnosis for Alzheimer's disease are mission critical","authors":"Brent W. Beasley","doi":"10.1002/trc2.70126","DOIUrl":"10.1002/trc2.70126","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>The author, a physician who has younger-onset Alzheimer's disease (AD), recounts his recent lunch with a former coworker who has had a stroke. The author makes the point that because we now have an effective treatment for AD, and phosphorylated tau217 is a sensitive and specific screening test for AD, we should advocate for its usage in Medicare Wellness Visits, given that the adage “Time Is Brain” is just as apropos for AD as it has been in stroke care. However, at this time, Medicare is <i>not</i> paying for the lab test.</p>\u0000 </section>\u0000 </div>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 2","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70126","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144339262","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":"Alzheimer's disease genetic risk: Top African American risk allele frequencies and genetic architecture among Mexican-, African-, and non-Hispanic White Americans","authors":"Mohammad Housini,&nbsp;Zhengyang Zhou,&nbsp;Lubnaa Abdullah,&nbsp;Gita Pathak,&nbsp;Reem Ayoub,&nbsp;John Gutierrez,&nbsp;Shea Andrews,&nbsp;Nicole Phillips,&nbsp;Sid O'Bryant,&nbsp;Robert Barber,&nbsp;For the HABS-HD Study Team","doi":"10.1002/trc2.70124","DOIUrl":"10.1002/trc2.70124","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; INTRODUCTION&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Alzheimer's disease (AD) continues to be the sixth leading cause of death in the United States. Significant efforts are spent researching etiology and potential management strategies. Although minorities face a higher disease burden and are anticipated to make up 43% of the US population by 2060, most literature on inherited AD risk has been derived from studying European ancestry. Here we evaluate frequencies of top AD risk alleles for late-onset AD (LOAD) in African- (AA), Mexican- (MA) and non-Hispanic White (NHW)-American participants enrolled in the Health &amp; Aging Brain Study–Health Disparities (HABS-HD) cohort to determine ethnicity-specific differential genetic architecture.&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;Using DNA extracted from this community-based diverse cohort (&lt;i&gt;N&lt;/i&gt; = 3207), we calculated the genotype frequencies in each population to determine whether a significant difference is detected among the three populations. DNA genotyping was performed per manufacturer's protocols. Imputation was used for single nucleotide polymorphisms (SNPs) that were not directly genotyped. Statistical analysis was performed using R Studio.&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;Genotype frequencies for 12 out of 15 SNPs (2 apolipoprotein E [&lt;i&gt;APOE&lt;/i&gt;] variants&lt;i&gt;, SIPA1L2, PIK3C2G, GPC6, RBFOX1, ABCA7, VRK3, ALCAM, EDEM1, NSG/MSX2&lt;/i&gt;, and &lt;i&gt;WDR70)&lt;/i&gt; differed significantly between groups.&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;This analysis expands on our previous study supporting the notion that genetic risk for AD is heterogeneous across racial and ethnic populations. Our results continue to demonstrate the valuable nature of diversity in genetic risk investigations and suggest the importance of including diverse and underrepresented racial and ethnic populations in medical research. Perhaps the most interesting finding is observed in the SNPs not found to be significantly different between groups, indicating there may be shared pleiotropic gene architecture across ethnicities.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Highlights&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;Alzheimer's disease (AD) burden is rapidly increasing in the United States; minorities are disproportionally affected.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;We investigate genetic health disparities in our community-based diverse cohort.&lt;/li&gt;\u0000 ","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 2","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70124","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144315028","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}