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

{"title":"Response to: Refining the clinical interpretation of activity variability in cognitive impairment: The need for phenotypic specificity","authors":"Patrick T. Donahue, Jennifer A. Schrack, Johannes Thrul, Michelle C. Carlson","doi":"10.1002/trc2.70128","DOIUrl":"https://doi.org/10.1002/trc2.70128","url":null,"abstract":"<p>Dear Guo et al.,</p><p>We thank Guo et al.<span><sup>1</sup></span> for their interest in our article<span><sup>2</sup></span> and for providing innovative thoughts regarding clinical translation of our activity variability metric.</p><p>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.</p><p>We agree with Guo et al.<span><sup>1</sup></span> 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 <i>not</i> equivalent to a dementia diagnosis, nor do they distinguish subtypes of cognitive decline and impairment.<span><sup>2</sup></span> 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.</p><p>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":4.9,"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, Ziyu Yang, Xiongfei Zhao","doi":"10.1002/trc2.70129","DOIUrl":"https://doi.org/10.1002/trc2.70129","url":null,"abstract":"<p>To the Editor,</p><p>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.”<span><sup>1</sup></span> 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.</p><p>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.</p><p>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.<span><sup>2</sup></span> In contrast, early Alzheimer's disease may present with preserved routine variability but degraded memory recall and temporal disorientation.<span><sup>3</sup></span> 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.</p><p>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.</p><p>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":4.9,"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":"https://doi.org/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":4.9,"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":"https://doi.org/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":4.9,"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":"https://doi.org/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":4.9,"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":"https://doi.org/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":4.9,"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":"https://doi.org/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":4.9,"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}

{"title":"System readiness and the patient care pathway for Alzheimer's disease diagnosis and treatment","authors":"B. Joy Snider,&nbsp;Alessandro Biffi,&nbsp;Sasha Bozeat,&nbsp;Carolyn Clevenger,&nbsp;Gill Farrar,&nbsp;Darren Gitelman,&nbsp;Rachel Kolster,&nbsp;Soeren Mattke,&nbsp;Michelle Mielke,&nbsp;Debjani Mukherjee,&nbsp;Jennifer Murphy,&nbsp;Hamid Okhravi,&nbsp;Gil D. Rabinovici,&nbsp;Dorene Rentz,&nbsp;Jose Soria,&nbsp;Heather Synder,&nbsp;Gregg Walker,&nbsp;Simin Mahinrad,&nbsp;Maria C. Carrillo,&nbsp;Christopher J. Weber","doi":"10.1002/trc2.70094","DOIUrl":"https://doi.org/10.1002/trc2.70094","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Promising therapeutic interventions that target the underlying pathophysiology are changing the landscape of Alzheimer's disease (AD) research. The AD care pathway must be transformed to meet the challenge of bringing these new therapies to the increasing number of people living with AD within the existing healthcare framework. Challenges include identifying patients who may benefit from treatment interventions early in the course of the disease, ensuring that diagnostic tools are accessible and accurate, and developing capabilities to monitor the effectiveness of interventions over time. These challenges must be addressed at all levels, from primary care settings to tertiary treatment centers; this will require collaborative efforts between health systems, drug manufacturers, and research institutions to navigate this evolving landscape and ensure system readiness for patients and their families with AD. The Spring 2024 Alzheimer's Association Research Roundtable (AARR) meeting gathered industry representatives and clinicians to discuss insights, challenges, and solutions that will help researchers and health systems identify patients in the early stages of AD and deliver emerging therapies efficiently and safely. In this paper, we provide highlights from the Spring 2024 AARR meeting.</p>\u0000 </section>\u0000 </div>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 2","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70094","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144323583","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":"BDNF Val66Met polymorphism moderates associations between physical activity and neurocognitive outcomes in older adults","authors":"Claire J. Cadwallader,&nbsp;Anna M. VandeBunte,&nbsp;D. Luke Fischer,&nbsp;Coty Chen,&nbsp;Valentina E. Diaz,&nbsp;Shannon Y. Lee,&nbsp;Brandon Chan,&nbsp;Argentina Lario-Lago,&nbsp;Julio C. Rojas,&nbsp;Eliana Marisa Ramos,&nbsp;Jessica E. Rexach,&nbsp;Jennifer S. Yokoyama,&nbsp;Joel H. Kramer,&nbsp;Emily W. Paolillo,&nbsp;Rowan Saloner,&nbsp;Kaitlin B. Casaletto","doi":"10.1002/trc2.70106","DOIUrl":"https://doi.org/10.1002/trc2.70106","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;Increased brain-derived neurotrophic factor (BDNF) release through physical activity (PA) is thought to underlie protective effects of PA on brain aging. The &lt;i&gt;BDNF&lt;/i&gt; Val66Met single-nucleotide polymorphism (rs6265) reduces activity-dependent BDNF release and has been linked to early Alzheimer's disease (AD) pathology and cognition. We examined whether &lt;i&gt;BDNF&lt;/i&gt; genotype influences the association of PA with plasma markers of AD, axonal degeneration, and neuroinflammation, along with consequences for cognition, in older adults without dementia.&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;One hundred eighty older adults (M&lt;sub&gt;age&lt;/sub&gt; = 73.1; SD&lt;sub&gt;age&lt;/sub&gt; = 9.1; 61% female; 42% &lt;i&gt;BDNF&lt;/i&gt; Met allele carriers) from the University of California San Francisco (UCSF) Memory and Aging Center completed 30 days of actigraphy monitoring, plasma assays of phosphorylated tau (p-tau181), neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and &lt;i&gt;BDNF&lt;/i&gt; Val66Met genotyping. One hundred twenty-three of the sample completed comprehensive neuropsychological evaluation. Habitual PA levels were operationalized via average daily step count. Composite z-scores were calculated for cognitive domains of memory and executive functioning.&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;&lt;i&gt;BDNF&lt;/i&gt; genotype moderated the relationship between PA and plasma p-tau181, whereby higher PA was associated with lower plasma p-tau181 concentration in Val/Val participants only. In moderated mediation analyses examining cognitive outcomes, plasma p-tau181 selectively mediated the relationship between PA and executive function in Val/Val participants. In analyses including sex as a biological factor, there was a three-way interaction of PA, &lt;i&gt;BDNF&lt;/i&gt; genotype, and sex on plasma GFAP concentration, whereby higher PA was associated with lower plasma GFAP only in Val/Val male participants.&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;The Val/Val &lt;i&gt;BDNF&lt;/i&gt; genotype may facilitate the neuroprotective relationships of PA, including lower AD-relevant biology and better executive function. We further show there may be a sex-specific negative relationship of PA with neuroinflammation in Val/Val males. These results further elucidate sources of individual variation observed in relationships between PA and brain health and will contribute to guiding personalized neurotrophic treatments for older adults.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Highlights&lt;","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 2","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70106","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144323585","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":"Identification of cerebrospinal fluid pharmacodynamic biomarkers and molecular correlates of brain activity in a Phase 2 clinical trial of the Alzheimer's disease drug candidate CT1812","authors":"Valentina Di Caro,&nbsp;Eunah Cho,&nbsp;Hilary A. North,&nbsp;Jill Caldwell,&nbsp;Kiran Pandey,&nbsp;Duc Duong,&nbsp;Michael Grundman,&nbsp;Willem de Haan,&nbsp;Everard G. Vijverberg,&nbsp;Charlotte E. Teunissen,&nbsp;Anthony O. Caggiano,&nbsp;Nicholas T. Seyfried,&nbsp;Mary E. Hamby","doi":"10.1002/trc2.70119","DOIUrl":"https://doi.org/10.1002/trc2.70119","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;CT1812 (zervimesine) is an orally dosed modulator of the sigma-2 receptor (S2R) currently in clinical development for the treatment of Alzheimer's disease (AD). CT1812 has been shown in preclinical and early clinical trials to selectively prevent and displace binding of amyloid beta oligomers from their synaptic receptors and has improved cognitive function in animal models of AD.&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;SEQUEL (NCT04735536) is a completed Phase 2, randomized, placebo-controlled 4-week crossover trial in adults with mild-to-moderate AD that investigated the effect of CT1812 on safety, synaptic function using quantitative electroencephalography (qEEG), and biomarkers. CT1812 improved established qEEG markers of spontaneous brain activity, suggesting improved neuronal and synaptic function. In the present study, cerebrospinal fluid (CSF)-based tandem mass tag mass spectrometry (TMT-MS) was performed on participant samples to investigate proteomic effects and identify potential biomarkers of CT1812.&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;Biomarkers found through proteomics analyses to be significantly differentially abundant in CT1812- versus placebo-treated participants supported pathway engagement and proof of mechanism for CT1812. Impacted proteins support a role for CT1812 at synapses, in vesicle trafficking, and in lipoprotein biology. Biomarkers correlated with the previously reported improvements in qEEG-based functional connectivity (inferred through alpha band Amplitude Envelope Correlations) with CT1812 treatment were also identified and may be potential early surrogate biomarkers of efficacy for CT1812. The processes and functions supported by biomarkers were congruent with those previously revealed in CSF proteomics analyses from phase 1 and 2 AD clinical trials with CT1812.&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;After 1 month of treatment, the identification of biomarkers supporting pathway engagement, the replication of biomarker findings from prior trials, and the discovery of molecular correlates of improved functional connectivity with CT1812 treatment bolster support for and expound upon the mechanism of action for CT1812 in displacing Aβ oligomers at neuronal synapses, as well as underscores the CT1812 relevance to AD.&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;Exploratory pr","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 2","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70119","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144323584","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}