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

{"title":"Alzheimer's disease drug development pipeline: 2026.","authors":"Jeffrey L Cummings, Yadi Zhou, Yuxin Yang, Kate Zhong, Jorge Fonseca, Amanda Leisgang Osse, Feixiong Cheng","doi":"10.1002/trc2.70251","DOIUrl":"https://doi.org/10.1002/trc2.70251","url":null,"abstract":"<p><strong>Introduction: </strong>Discovery and development of new therapies for Alzheimer's disease (AD) are urgently needed to address the world's growing population of individuals on the AD pathophysiological continuum. Clinicaltrials.gov is a resource for studying drugs in development for treatment of AD.</p><p><strong>Results: </strong>There are currently 158 drugs in 192 AD trials. Of the agents in trials, 39% are small molecule disease targeting therapies (DTTs); 34% are biologic DTTs; 18% are cognition enhancing symptom targeted therapies (STTs); and 10% are STTs being developed to treat neuropsychiatric symptoms of AD. Currently active trials require 54,728 participants of which 38,417 are in Phase 3. The biopharmaceutical industry sponsors 59% of AD trials including 72% of Phase 3 trials. Repurposed drugs represent 35% of the drugs in trials.</p><p><strong>Discussion: </strong>The AD drug development pipeline has a growing number of trials and drugs in trials. A diverse array of AD pathophysiological processes is being addressed by drugs in trials.</p>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 ","pages":"e70251"},"PeriodicalIF":6.8,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13140253/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147846025","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":"Population pharmacokinetics of remlifanserin (ACP-204), a serotonin 2A receptor inverse agonist.","authors":"Mona Darwish, Nancy Lin, Bryan Dirks, David Jaworowicz, Kelly Maxwell, Sanjeev Pathak","doi":"10.1002/trc2.70254","DOIUrl":"https://doi.org/10.1002/trc2.70254","url":null,"abstract":"<p><strong>Introduction: </strong>Remlifanserin, or ACP-204, is a potent serotonin 2A receptor inverse agonist under investigation for treatment of Alzheimer's disease psychosis and Lewy body dementia psychosis. A population pharmacokinetics (popPK) model for remlifanserin was developed to evaluate the impact of covariates affecting pharmacokinetic variability and assess the clinical relevance of these factors in a virtual population.</p><p><strong>Methods: </strong>A popPK model was developed using remlifanserin plasma concentrations (<i>n</i> = 3935) from 209 participants across seven Phase 1 trials (10 to 180 mg, oral). Data were pooled and analyzed using non-linear mixed-effects modeling. Intrinsic (demographics, hepatic/renal function) and extrinsic (food effect) factors were assessed. Model evaluation included goodness-of-fit plots and prediction-corrected visual predictive checks (pcVPCs). Interindividual variability was estimated for key parameters; residual variability was modeled using proportional error. Simulated steady-state exposures (maximum plasma concentration at steady state [C_max,ss] and area under the plasma concentration-time curve over the 24-h dosing interval at steady state [AUC_0-24,ss]) in a virtual population (<i>n</i> = 1000; 60 mg/day) were derived using PK parameters sampled from the final model. The clinical relevance of significant covariates was evaluated using geometric mean ratios and 90% confidence intervals (CIs) of exposures using a 0.8 to 1.25 boundary presented in a forest plot.</p><p><strong>Results: </strong>The final popPK model was a one-compartment model with first-order absorption with lag time and linear elimination. Typical parameter estimates included apparent oral clearance (35.4 L/h), apparentoral volume of distribution (V/F) (male, 930 L; female, 799 L), absorption lag time (ALAG1) (fasted, 0.720 h; fed, 0.929 h)and absorption rate constant (K_a) (0.692/h). Goodness-of-fit plots and pcVPCs demonstrated that the model adequately captured the central tendency and magnitude of variability in remlifanserin concentrations. Statistically significant relationships were found between food and ALAG1 and between sex and V/F (<i>P</i> < 0.001); however, neither factor had a clinically relevant impact on C_max,ss or AUC_0-24,ss.</p><p><strong>Discussion: </strong>The pharmacokinetics of oral remlifanserin (10 to 180 mg) are well described by dose-proportional linear kinetics. No intrinsic or extrinsic factors exhibited a clinically relevant effect on steady-state remlifanserin exposures.</p>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 ","pages":"e70254"},"PeriodicalIF":6.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13133547/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147823347","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":"Blood DNA methylation signature of cognitive reserve moderates the association between CSF tau pathology and memory in prodromal Alzheimer's disease.","authors":"David Lukacsovich, Juan I Young, Lissette Gomez, Brian W Kunkle, Zhixin Mao, Wei Zhang, X Steven Chen, Deirdre M O'Shea, Tatjana Rundek, Eden R Martin, Lily Wang","doi":"10.1002/trc2.70257","DOIUrl":"10.1002/trc2.70257","url":null,"abstract":"<p><strong>Introduction: </strong>Cognitive reserve (CR) reflects variability in cognitive adaptability that modifies the impact of Alzheimer's disease (AD) pathology on cognition. However, blood-based biomarkers of CR have not been established in prodromal AD. We operationalized CR as memory reserve, defined by the attenuation of the cerebrospinal fluid (CSF) phosphorylated tau threonine 181 (pTau181)-memory association and aimed to identify blood DNA methylation (DNAm) loci involved in memory reserve.</p><p><strong>Methods: </strong>We studied 92 amyloid-positive participants with mild cognitive impairment (MCI) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with blood DNAm, CSF pTau181, and memory (PHC_MEM) measured at the same visit. Memory was residualized after adjustment for age, sex, <i>APOE</i> 𝜀4 allele count, and estimated immune cell-type proportions. For each CpG, linear models tested DNAm, pTau181, and DNAm×pTau181 interaction; inflation was corrected using the bacon method. In addition, we also identified differentially methylated regions (DMRs). Moreover, we constructed a methylation reserve score (MRS) from loci identified in this cohort at baseline and tested its associations with longitudinal memory using linear mixed-effects models in 88 participants with follow-up information.</p><p><strong>Results: </strong>After removing low-variability CpGs, we identified six CpGs with suggestive DNAm×pTau181 interaction (<i>p</i> value < 1 × 10^-5, none passed a 5% false discovery rate) and 11 DMRs passing multiple-comparisons correction. The suggestive CpGs and significant DMRs mapped to genes implicating synaptic function, vascular/blood-brain barrier integrity, and immune regulation, with minimal marginal associations with pTau181 or memory, consistent with a moderation model rather than mediation. In this cohort, higher baseline MRS was associated with attenuation of the pTau181-memory association and with slower subsequent memory decline, independent of age, sex, education<i>, APOE</i> ε4, and baseline pTau181.</p><p><strong>Discussion: </strong>Blood DNAm that moderates the pTau181-memory association may reflect epigenetic correlates of memory reserve (i.e., differential susceptibility to tau-related memory impairment), rather than reflecting variations in pTau181 levels. These DNAm patterns can be summarized as a MRS that, in this cohort, was associated with longitudinal memory trajectories in MCI. Further validation in independent cohorts is warranted.</p>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 ","pages":"e70257"},"PeriodicalIF":6.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13133550/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147823359","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":"Spiritual practices for dementia care of Black persons: An integrative review.","authors":"Peace Esther Johnson, Roxanne Vandermause","doi":"10.1002/trc2.70255","DOIUrl":"https://doi.org/10.1002/trc2.70255","url":null,"abstract":"<p><p>It is crucial to identify practices that effectively meet the unique spiritual needs of Black persons living with dementia. Currently, ≈ 7 million individuals in the United States are affected by dementia, a figure that is expected to rise alarmingly to nearly 13 million by 2050. National statistics indicate that Black persons are twice as likely to be diagnosed with Alzheimer's disease and related dementias as Whites. Health care often focuses on physical health at the expense of addressing the person's holistic needs, including emotional and spiritual well-being. This review focuses on literature related to spiritual practices for dementia care in a specific population, Black persons living with dementia. The Whittemore and Knafl framework was used for this integrative review. Findings are summarized through the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Nine studies met the inclusion criteria. Three main thematic categories were found: (1) Transformative faith-based programs to address the spiritual needs of Black persons living with dementia, (2) spiritual practices adapted to support caregiving experiences, and (3) spiritual practices tailored to both caregivers and the Black persons living with dementia. While caring for caregivers is important, it is equally crucial to focus on the unique challenges faced by individuals living with dementia. Most of the programs highlighted in this review aim to improve caregiving experiences. There is a lack of literature dedicated to developing practices specifically for individuals diagnosed with the disease. A notable gap exists in targeted practices that meet the unique spiritual needs of Black persons living with dementia. Future research should focus on developing spiritual interventions that address these essential needs.</p>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 ","pages":"e70255"},"PeriodicalIF":6.8,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13102678/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147789107","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":"Druggable genome-wide Mendelian randomization analysis identifies potential treatment targets in vascular dementia.","authors":"Matthew J Lennon, Ying Xu, Anbupalam Thalamuthu, Karen Mather, Perminder S Sachdev","doi":"10.1002/trc2.70258","DOIUrl":"https://doi.org/10.1002/trc2.70258","url":null,"abstract":"<p><strong>Background: </strong>There are currently no US Food and Drug Administration-approved treatments for vascular dementia (VaD). Genome-wide approaches have successfully identified druggable targets and treatments for various disorders. In this study, we performed druggable genome-wide two-sample Mendelian randomization (2SMR) analysis to identify possible treatment targets for VaD.</p><p><strong>Methods: </strong>2SMR analyses were used to estimate the causal effects of druggable gene expression on VaD risk. The exposure variables were significant cis-expression quantitative trait loci (eQTLs) and cis-protein quantitative trait loci (pQTLs) in the cerebrospinal fluid (CSF), brain, and plasma. The main outcome variable was genetic VaD risk, based on the Mega Vascular Cognitive Impairment and Dementia Consortium genome-wide association study. 2SMR analysis examined the causal relationship between eQTLs/pQTLs and imaging markers of VaD. A phenome-wide 2SMR analysis explored the relationships between significant druggable genes and phenotype summary statistics derived from the UK Biobank. False discovery rate (FDR) <i>P</i> value corrections were applied to all analyses.</p><p><strong>Results: </strong>A total of 12,224 druggable genes were identified from the Drug-Gene Interaction Database (DGIdb) and associated papers. Of these, the 2SMR analysis identified four FDR-significant genes in the pQTL analysis, with none identified among the eQTLs. In the CSF, <i>TOMM40</i> had a significant (<i>P</i> = 3.67E-36) effect on VaD outcomes as well as cerebral small vessel disease (cSVD), white matter hyperintensities (WMH; <i>P</i> = 0.0001) and fractional anisotropy (FA; <i>P</i> = 0.0028). In the brain, apolipoprotein E (<i>APOE</i>; <i>P</i> = 1.90E-54) was associated with VaD and three cSVD markers: WMH (<i>P</i> = 1.61E-06), FA (<i>P</i> = 0.0018), and mean diffusivity (<i>P</i> = 0.0244). <i>ERAP1</i> (<i>P</i> = 0.0163), and <i>SAA1-4</i> (<i>P</i> = 0.0163) showed weaker associations with VaD, did not show colocalization, and were not associated with cSVD imaging markers.</p><p><strong>Discussion: </strong>This study identified four potential drug targets for VaD, using a 2SMR analysis approach. Two genes, <i>APOE</i> and <i>TOMM40</i>, are well understood to be associated with both Alzheimer's disease and VaD, whereas the other two, <i>ERAP1</i> and <i>SAA1-4</i>, are novel targets involved in immune system regulation and inflammation.</p>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 ","pages":"e70258"},"PeriodicalIF":6.8,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13102677/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147789067","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":"Pharmacokinetic/pharmacodynamic analyses of plasma pathophysiology biomarkers in subjects with early Alzheimer's disease following lecanemab treatment.","authors":"Pratik Bhagunde, Natasha Penner, Brian A Willis, Robert Bell, Pallavi Sachdev, Arnaud Charil, Michael C Irizarry, Steven Hersch, Larisa Reyderman","doi":"10.1002/trc2.70246","DOIUrl":"https://doi.org/10.1002/trc2.70246","url":null,"abstract":"<p><strong>Introduction: </strong>Lecanemab, a novel monoclonal antibody targeting both neurotoxic amyloid beta (Aβ) protofibrils and Aβ plaques, substantially reduces markers of amyloid and significantly slows clinical decline on multiple measures of cognition and function in early AD in Phase 2 (Study 201) and Phase 3 (Study 301; Clarity AD) studies. In these clinical studies, several plasma biomarkers showed improvements comparing lecanemab with placebo. Herein, we utilized modeling and simulation to evaluate the long-term effects of lecanemab on pathophysiology biomarkers in plasma.</p><p><strong>Methods: </strong>Plasma Aβ42/40 ratio, tau phosphorylated at threonine 181 (p-tau181), and glial fibrillary acidic protein (GFAP) data were pooled from lecanemab Phase 2 and 3 studies. Individual serum lecanemab exposure estimated using a population pharmacokinetic model was correlated with plasma biomarker concentrations using indirect response pharmacokinetic/pharmacodynamic (PK/PD) models. Simulations were conducted to evaluate the effect of lecanemab (10 mg/kg IV every 2 weeks, LEC10-BW) after 4 years of continuous treatment, discontinuation after 18 months of treatment or transitioning to less frequent dosing at 18, 24, or 30 months.</p><p><strong>Results: </strong>PK/PD models describing the change in plasma biomarker levels over time in response to lecanemab treatment were developed, and simulations demonstrated that plasma biomarkers reverted toward pretreatment baseline after cessation of lecanemab treatment, with an average re-accumulation half-life of approximately 1 to 1.5 years, which was faster than amyloid plaque re-accumulation measured by positron emission tomography. Simulations illustrated transitioning to a lecanemab monthly dosing regimen was sufficient to stabilize plasma biomarker concentrations at levels consistent with ongoing inhibition of amyloid pathology and neuroinflammation.</p><p><strong>Discussion: </strong>PK/PD model simulations demonstrated that plasma biomarkers serve as early indicators of amyloid accumulation and downstream effects. Plasma biomarker simulations suggest the need for ongoing lecanemab treatment even after amyloid plaque clearance. Transition to a less frequent monthly IV regimen at 18 months was shown to maintain the changes in plasma biomarker levels consistent with lecanemab efficacy.</p>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 ","pages":"e70246"},"PeriodicalIF":6.8,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13095857/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147789095","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 attenuates the association between allostatic load and early Alzheimer's disease-related biomarkers in older adults.","authors":"Géraldine Poisnel, Mathilde Lhérault, Cassandre Palix, Anne-Laure Turpin, Francesca Felisatti, Agathe Vrillon, Claire Paquet, Anne Chocat, Laurent Coulbault, Vincent De La Sayette, Julie Gonneaud, Gaël Chételat","doi":"10.1002/trc2.70248","DOIUrl":"https://doi.org/10.1002/trc2.70248","url":null,"abstract":"<p><strong>Introduction: </strong>Allostatic load (AL), an index of cumulative physiological dysregulation from chronic stress, may contribute to Alzheimer's disease (AD) pathophysiology by accelerating brain aging. Higher AL has been associated with AD-related biomarkers, suggesting a mechanistic connection. Lifestyle factors influence both AL and AD vulnerability, but their moderating role in AL-AD biomarker associations remains unclear.</p><p><strong>Methods: </strong>We included 111 cognitively unimpaired older adults from the baseline visit of the Age-Well trial. AL was computed as a composite score of 18 biomarkers spanning neuroendocrine, immune, metabolic, cardiovascular-respiratory, and anthropometric systems. Plasma biomarkers included amyloid beta (Aβ)42, Aβ40, phosphorylated-tau (p-tau231), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). Physical activity, Mediterranean diet adherence, and cognitive activity were assessed using validated questionnaires. Multiple linear regressions tested associations between AL and (1) AD-related biomarkers and (2) lifestyle factors, as well as their interactions, controlling for age, sex, education, apolipoprotein E ε4 (APOE ε4) status, and glomerular filtration rate (GFR).</p><p><strong>Results: </strong>Higher AL was associated with higher Aβ42/Aβ40 ratio (<i>b</i> = 0.004, 95% CI [0.001, 0.007], <i>p</i> = 0.010, false discovery rate [FDR] = 0.040) and lower NfL levels (<i>b</i> = -0.035, 95% CI [-0.063, -0.008], <i>p</i> = 0.013, FDR = 0.026). AL correlated negatively with physical activity (<i>b</i> = -0.899, 95% CI [-1.568, -0.230], <i>p</i> = 0.009, FDR = 0.027). A significant interaction was observed between physical activity and AL in relation to the p-tau231/Aβ42 ratio (<i>b</i> = -0.339, 95% CI [-0.588, -0.091], <i>p</i> = 0.008, FDR = 0.032), such that higher AL was associated with lower p-tau231/Aβ42 ratio among more physically active individuals compared with less active individuals.</p><p><strong>Discussion: </strong>Regular physical activity was associated with a weaker relationship between AL and early AD-related biomarkers in this cross-sectional sample. Longitudinal studies should confirm whether maintaining physical activity attenuates stress-related physiological dysregulation and reduces AD vulnerability.</p>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 ","pages":"e70248"},"PeriodicalIF":6.8,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13095858/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147789059","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 multifaceted roles of the transcription factor <i>SP1</i> in the pathogenesis of Alzheimer's disease: From molecular regulation to therapeutic targets.","authors":"Zhengxiang Lv, Xiaodong Liu, Qin Huang, Haijun Liu, Zucai Xu, Ping Xu","doi":"10.1002/trc2.70211","DOIUrl":"10.1002/trc2.70211","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is driven by interrelated pathologies, including the accumulation of amyloid β (Aβ), tau pathology, chronic neuroinflammation, and oxidative stress (OS). These pathological processes collectively lead to progressive neurodegeneration. The transcription factor specificity protein 1 (<i>SP1</i>) functions as a key transcriptional regulator in AD pathogenesis. By binding to GC-box elements, <i>SP1</i> promotes Aβ production and tau hyperphosphorylation. It also activates microglia, perpetuating neuroinflammation; disrupts oxidative balance; and ultimately induces neuronal death through ferroptosis and apoptosis. Furthermore, environmental toxins exacerbate AD progression by enhancing <i>SP1</i>-DNA binding activity via epigenetic mechanisms such as DNA methylation and histone modifications. <i>SP1</i> activity is tightly controlled by diverse post-translational modifications, which adds another layer of complexity to its function. Small-molecule inhibitors, natural compounds, and epigenetic interventions can modulate the <i>SP1</i>-regulated network, thereby ameliorating key pathological features and demonstrating broad therapeutic potential. Future efforts must address developing brain-targeted delivery systems and precise epigenetic editors for effective clinical translation.</p><p><strong>Highlights: </strong><i>SP1</i> functions as a master transcriptional hub in Alzheimer's disease, simultaneously driving amyloid beta production, tau hyperphosphorylation, neuroinflammation, oxidative stress, and ferroptotic cell death.Environmental toxins epigenetically activate <i>SP1</i> via altered DNA methylation and histone modifications, establishing a molecular link between external risk factors and late-onset Alzheimer's pathogenesis.Post-translational modifications and microRNAs tightly regulate <i>SP1</i> activity; their dysregulation in AD amplifies pathogenic gene expression networks.Small-molecule inhibitors and natural compounds targeting <i>SP1</i> demonstrate multi-pathway therapeutic potential in preclinical Alzheimer's models.Cell-type-specific <i>SP1</i> functions, compensatory upregulation of <i>SP3/SP4</i> family members, and limited blood-brain barrier penetration present major challenges for clinical translation.</p>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 ","pages":"e70211"},"PeriodicalIF":6.8,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13088148/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147724583","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":"Neuroprotection trial design in progressive supranuclear palsy: challenges and solutions.","authors":"Lawrence I Golbe, Ronald G Thomas","doi":"10.1002/trc2.70247","DOIUrl":"https://doi.org/10.1002/trc2.70247","url":null,"abstract":"<p><strong>Introduction: </strong>We review the specific challenges posed to neuroprotective trial design by progressive supranuclear palsy (PSP), a rare disorder difficult to diagnose and to assess quantitatively.</p><p><strong>Methods: </strong>Focusing on reducing the size and cost of trials, we review elements of PSP neuroprotection trial methodology and formulate a new minimum clinically important difference (MCID) for PSP to be used as a potential outcome milestone.</p><p><strong>Results: </strong>While the original, 28-item version of the PSP Rating Scale (PSPRS) remains the best-validated and most widely published clinical outcome measure, promising improvements include the PSPRS-15 and -10; magnetic resonance imaging (MRI) volumetry; wearable movement-sensitive devices; platform, futility, basket, factorial, adaptive, and multistage designs; customized endpoints; baseline predictor stratification; and the replacement of a continuous disability scale with attainment of milestones, possibly including our newly calculated MCID.</p><p><strong>Discussion: </strong>The specific assessment tools we deem most valuable could be used individually or in combination to reduce the required N and cost of PSP neuroprotection trials.</p>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 ","pages":"e70247"},"PeriodicalIF":6.8,"publicationDate":"2026-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13084695/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147724575","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 potential multimodal biomarker – cognitive signature associated with the conversion from subjective cognitive decline to mild cognitive impairment","authors":"Mohamed Haddad,&nbsp;Mohamed Raâfet Ben Khedher,&nbsp;Chadi Ouechtati,&nbsp;Tamás Fülöp,&nbsp;the Consortium for the early identification of Alzheimer's disease-Quebec (CIMA-Q),&nbsp;Charles Ramassamy","doi":"10.1002/trc2.70240","DOIUrl":"https://doi.org/10.1002/trc2.70240","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>The disruption of key mechanisms involved in amyloid beta (Aβ) clearance during the early stages of dementia may contribute to the progression of cognitive decline toward irreversible brain damage. In this study, we investigated multiple immune-related pathways implicated in the management and clearance of Aβ within circulating extracellular vesicles (cEVs) and serum from individuals with subjective cognitive decline (SCD) who later progressed to mild cognitive impairment (MCI).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>A cytokine panel and the levels of Aβ_1–42 were quantified in both cEVs and serum from a longitudinally followed cohort of elderly with SCD, using mesoscale and Luminex technologies. We investigated associations with Aβ burden, cognitive performance, <i>APOE</i> ε4 allele status, and the likelihood of conversion to MCI.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>In SCD patients, the concentrations of Aβ_1–42 and macrophage-colony stimulating factor (M-CSF) were higher, respectively, in cEVs and serum. No difference was observed for fraktaline, interleukin (IL)-4, IL-13, interferon gamma (IFN-γ), and sCD40L in either cEVs or serum between SCD and control patients. Based on receiver operating characteristic curve analysis, regression modeling, and correlations with cognitive performance, M-CSF levels in serum effectively distinguished individuals with SCD who converted to MCI from those who remained stable. Interestingly, combining M-CSF and cEVs Aβ_1–42 with the Rey Auditory Verbal Learning Test (RAVLT) cognitive scores provided an excellent classification for SCD converted to MCI up to 2 years prior to clinical diagnosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>Our findings support the potential value of integrating serum M-CSF levels with RAVLT performance and cEVs Aβ_1–42 concentrations into a multimodal biomarker panel for longitudinal monitoring of progressive neurocognitive impairment.</p>\u0000 </section>\u0000 </div>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 2","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://alz-journals.onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70240","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147668567","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}