The Journal of Prevention of Alzheimer's Disease最新文献

{"title":"Identifying the optimal combinations of modifiable dementia risk factors to target in multidomain intervention - Three-year longitudinal findings from the Canadian longitudinal study on aging.","authors":"Surim Son, Mark Speechley, Guangyong Zou, Manuel Montero-Odasso","doi":"10.1016/j.tjpad.2025.100321","DOIUrl":"10.1016/j.tjpad.2025.100321","url":null,"abstract":"<p><strong>Background: </strong>Recent multidomain prevention trials for dementia have shifted toward more targeted approaches, focusing on specific combinations of risk factors and interventions at certain times. However, the optimal combinations of modifiable risk factors that can be targeted to maximize intervention effect remain unclear. Identifying risk factor combinations with the highest prevalence and largest effect sizes can enhance efficiency of trial design.</p><p><strong>Objectives: </strong>To identify risk factor combinations that are both highly prevalent and have the most detrimental effect on cognition, and to assess their interaction effect and synergism.</p><p><strong>Design: </strong>Longitudinal analysis of Canadian Longitudinal Study on Aging (CLSA).</p><p><strong>Setting: </strong>Community.</p><p><strong>Participants: </strong>30,097 adults aged 45 to 85 at baseline MEASUREMENTS: The five most prevalent dyad, triad, and tetrad combinations of 12 modifiable risk factors were identified. Cognition was assessed with a composite Z-score from a neuropsychological test battery. Linear mixed effect models were used to examine the association between the identified combinations and 3-year cognitive changes. Interaction was assessed on additive scale, and synergism was explored.</p><p><strong>Results: </strong>The combinations that were both highly prevalent and had the most detrimental effect on global cognition were: hearing loss and physical inactivity for the dyad (mean difference in change score = -0.07 SD; 95 % CI: -0.09 to -0.06; p < 0.001; effect size = -0.28), hearing loss, physical inactivity, and hypertension for the triad (mean difference in change score = -0.07; 95 % CI: -0.09 to -0.06; p < 0.001; effect size = -0.28), and hearing loss, physical inactivity, hypertension, and sleep disturbance for the tetrad (mean difference in change score = -0.05; 95 % CI: -0.07 to -0.03; p < 0.001; effect size = -0.20). Similar patterns were observed for memory and executive function. A significant synergistic interaction was observed between hearing loss and physical inactivity for global cognition (p = 0.005).</p><p><strong>Conclusions: </strong>The combined effect of multiple risk factors varied by its combinations. The combination of hearing loss and physical inactivity offers a greater potential benefit than other dyad combinations. Hypertension and sleep disturbance can be further included for triad and tetrad combinations. Auditory health and exercise should be prioritized for multidomain interventions.</p>","PeriodicalId":22711,"journal":{"name":"The Journal of Prevention of Alzheimer's Disease","volume":" ","pages":"100321"},"PeriodicalIF":7.8,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12501350/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144859639","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 critical review and classification of dementia risk assessment tools to inform dementia risk reduction.","authors":"Md Hamidul Huque, Ranmalee Eramudugolla, Meiwei Li, Kim M Kiely, Ruth Peters, Kaarin J Anstey","doi":"10.1016/j.tjpad.2025.100333","DOIUrl":"10.1016/j.tjpad.2025.100333","url":null,"abstract":"<p><p>Addressing modifiable dementia risk factors requires reliable risk assessment methods. We aimed to synthesise knowledge on risk scores for all cause dementia, Alzheimer's disease (AD) and vascular dementia, classify them according to target population, evaluate their content, cost, appropriateness of validation studies, and suitability for implementing risk reduction guidelines. A systematic search was conducted of PubMed, Cochrane Collaboration, ProQuest, Scopus, Embase, and PsycINFO databases using a pre-registered protocol. Data on risk factors, target population, predictive validity, cost, and alignment with WHO guidelines were extracted. Random-effects meta-analysis was performed. Of 45 risk scores identified, 29 were for all-cause dementia, including 11 based on late-life cohorts, 6 on midlife, and 7 covering mid to late-life. The pooled C-statistic across development and validation studies of dementia risk scores was 0.69 (95 % CI: 0.67, 0.71). Development study AUCs were higher than validation study AUCs and dropped from 0.74 to 0.66 for risk scores developed for clinical samples and from 0.79 to 0.71 for AD specific scores (which include functional indicators non-independent of disease). There were no validated risk scores for vascular dementia. Dem-NCD, CogDrisk, ANU-ADRI and LIBRA risk scores incorporated most WHO-recommended risk factors and demonstrated accuracy comparable to the overall pooled C-statistic. We conclude that across the field, there are methodological limitations relating to validation, and inappropriate comparison of tools designed for different purposes or target populations. However, there are now several validated, risk scores for all-cause dementia and AD that assess modifiable factors and offer cost-effective dementia risk assessment and risk reduction advice.</p>","PeriodicalId":22711,"journal":{"name":"The Journal of Prevention of Alzheimer's Disease","volume":" ","pages":"100333"},"PeriodicalIF":7.8,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12501348/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144993541","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":"Childhood maltreatment confers long-term risk for cognitive impairment: A prospective investigation.","authors":"Stephanie Assuras, Kellie Courtney, Molly Maxfield, Shaina Shagalow, Sara Sherer, Jennifer J Manly, Cathy Spatz Widom","doi":"10.1016/j.tjpad.2025.100303","DOIUrl":"10.1016/j.tjpad.2025.100303","url":null,"abstract":"<p><strong>Importance: </strong>Childhood maltreatment has been associated with greater risk for Alzheimer's disease and related dementias. Better understanding of this association will have implications for prevention and intervention efforts.</p><p><strong>Objective: </strong>To determine whether individuals with documented histories of childhood maltreatment and matched controls differ in cognitive functioning in late midlife and whether maltreatment leads to higher rates of cognitive impairment.</p><p><strong>Design: </strong>Prospective cohort design SETTING: Metropolitan Midwestern county area PARTICIPANTS: Children with documented maltreatment histories and demographically matched controls were followed up into late midlife (N = 447, Mage = 59.4). Control group children were matched to maltreated children on age, sex, race and ethnicity, and approximate family social class during the time the cases were processed.</p><p><strong>Exposure: </strong>Children with documented cases of physical and sexual abuse and neglect during 1967 to 1971 in the county juvenile (family) or adult criminal courts. Cases were restricted to children ages 0-11 at the time of the maltreatment to ensure that the temporal direction of consequences was clear.</p><p><strong>Main outcome and measures: </strong>Using a comprehensive neuropsychological assessment battery, multiple tests of cognitive functioning and the Functional Activities Questionnaire were administered. Participants were categorized as having cognitive impairment with no dementia (CIND) or dementia.</p><p><strong>Results: </strong>Individuals with histories of childhood maltreatment performed worse on all 12 neuropsychological tests, compared to matched controls (Cohen's d 0.28 to 0.42) and had significantly higher risk for CIND [AOR = 1.86), amnestic CIND [AOR = 1.68) and non-amnestic [AOR = 1.48). About 13 % of maltreated individuals met criteria for amnestic CIND. Few met criteria for dementia. Males, females, Blacks, Whites, older and younger individuals, and those physically or sexually abused or neglected showed the effects of maltreatment.</p><p><strong>Conclusions and relevance: </strong>Cognitive repercussions of childhood maltreatment continue into late midlife. Findings reinforce the importance of early detection and preventive interventions that may decrease risks associated with childhood maltreatment in later adulthood. Because we use documented court cases from childhood, this design reduces potential biases associated with reliance on retrospective self-reports of childhood adversities. To our knowledge, this is the first study to examine long-term consequences of childhood neglect for cognitive impairment.</p>","PeriodicalId":22711,"journal":{"name":"The Journal of Prevention of Alzheimer's Disease","volume":" ","pages":"100303"},"PeriodicalIF":7.8,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12501353/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144718722","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":"Pregnancy hypertension is associated with higher p-tau217 in healthy midlife women.","authors":"Eu-Leong Yong, Beverly Wen Xin Wong, Darren Yuen Zhang Tan, Liang Shen, Benecia Wan Qing Thia, Joyce Ruifen Chong, Christopher Li-Hsian Chen","doi":"10.1016/j.tjpad.2025.100316","DOIUrl":"10.1016/j.tjpad.2025.100316","url":null,"abstract":"<p><strong>Introduction: </strong>There is very limited knowledge on the relationship between pregnancy hypertension and the occurrence of pre-clinical Alzheimer's disease (AD).</p><p><strong>Methods: </strong>Community-dwelling midlife women without dementia were enrolled from well-woman clinics of the National University Hospital, Singapore. Sociodemographic parameters and history of pregnancy hypertension were obtained. Cognition was assessed using the Montreal Cognitive Assessment-Basic tool. Fasted blood samples were stored for batched analysis of renal function, APOE genotyping and p-tau217 levels using Simoa® ALZpath p-tau217 Advantage PLUS (Quanterix, MA, USA). General linear modelling was used to examine the association between pregnancy hypertension and p-tau217.</p><p><strong>Results: </strong>Among 743 women (mean age 62.9 ± 6.0; range: 50.7 to 76.6 years) enrolled, 68 (9.2%) reported pregnancy hypertension. General linear modelling showed that an older age [mean difference: 0.002 (95% CI: 0.001, 0.003)], mild cognitive impairment [0.016 (0.001, 0.032)], lower BMI [0.068 (0.027, 0.109)], eGFR<60 mL/min/1.73 m² [0.132 (0.072, 0.193)] and the APOE4 carrier genotype [0.038 (0.018, 0.058)] were independently associated with higher serum p-tau217 levels. History of pregnancy hypertension remained significantly associated with subsequent higher serum p-tau217 [0.040 (0.013, 0.067)], after adjustment for age, mild cognitive impairment, hypertension, BMI, renal function, and APOE4 genotype status.</p><p><strong>Discussion: </strong>Pregnancy hypertension was associated with AD pathology with mean differences similar to high risk APOE4 carrier genotypes. Information on pregnancy hypertension could help physicians to identify women who might benefit from early p-tau217 screening for Alzheimer's disease, allowing for early clinical intervention.</p>","PeriodicalId":22711,"journal":{"name":"The Journal of Prevention of Alzheimer's Disease","volume":" ","pages":"100316"},"PeriodicalIF":7.8,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12501320/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144733402","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":"Proportion of life spent in the United States and cognitive functioning in Spanish-speaking migrants: Findings from the Boston Latino Aging Study.","authors":"Isabel Solis, Randy Medrano, Lusiana Martinez, Nadeshka J Ramirez, Nikole A Bonillas Felix, Jorge Alcina, Averi Giudicessi, Jairo E Martinez, Clara Vila-Castelar, Liliana A Ramirez-Gomez, Marta Gonzalez Catalan, Daniel G Saldana, Yakeel T Quiroz","doi":"10.1016/j.tjpad.2025.100320","DOIUrl":"10.1016/j.tjpad.2025.100320","url":null,"abstract":"<p><p>Latino migrants are at increased risk for cognitive decline, yet the influence of immigration-related factors, such as time lived in the United States (U.S.), remains poorly understood. In the Boston Latino Aging Study (BLAST), 130 older Latino migrants completed a comprehensive neuropsychological assessment. We examined whether the proportion of years lived in the U.S. was associated with cognitive performance, adjusting for age, education, and acculturation. Greater time in the U.S was significantly associated with lower phonemic fluency, while no associations were found for other domains. Notably, 16 % of phonemic fluency errors involved English intrusions during a Spanish-language task, suggesting cross-linguistic interference. These findings underscore the importance of considering language dynamics and sociocultural context in studies of Latino cognitive aging.</p>","PeriodicalId":22711,"journal":{"name":"The Journal of Prevention of Alzheimer's Disease","volume":" ","pages":"100320"},"PeriodicalIF":7.8,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12501318/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144790095","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":"Organ-specific proteomic aging and cognitive performance: Implications for risk prediction of Alzheimer's disease and related dementias in older adults.","authors":"Sujin Kang, Susan Baker, Benedict Hayhoe, Geraint Price, Gerald Novak, Janice Wong, Lefkos Middleton, Oliver Robinson","doi":"10.1016/j.tjpad.2025.100274","DOIUrl":"10.1016/j.tjpad.2025.100274","url":null,"abstract":"<p><strong>Background and objectives: </strong>Biological aging, characterized by cellular and molecular changes, may play a key role in neurodegenerative diseases. While recent proteomic advancements have introduced new aging clocks, widespread validation remains necessary. This study evaluated organ-specific and cognition-enriched proteomic clocks in relation to chronological age and cognitive change.</p><p><strong>Methods: </strong>We analyzed plasma proteomic data from the CHARIOT PRO SubStudy (N = 409), measured using the SomaScan assay (version 4.1) at four time points over three years (months 0, 12, 24, and 36). Using published proteomic organ age weights, we calculated conventional, organ-specific, and cognition-enriched biological ages and compared them with chronological age. Adjusted multilevel regression analyses assessed associations between baseline proteomic AgeGaps (biological-chronological age differences) and cognitive performance over 54 months.</p><p><strong>Results: </strong>The cohort (mean age: 71.8 ± 5.5 years; 50.1 % female) showed moderate to strong correlations between proteomic ages and chronological age (r = 0.37-0.80; MAE = 4.2-2.7). Over three years, AgeGaps increased across the conventional, organismal, muscle, liver, artery, and immune systems, ranging from 2.1 ± 1.9 to 1.0 ± 2.3 years. The artery AgeGap was most strongly associated with cognitive decline, with conventional and organismal AgeGaps showing similar patterns. Higher baseline AgeGap z-scores (i.e., greater biological age) in the artery and brain were associated with poorer cognition, as measured by the Repeatable Battery for the Assessment of Neuropsychological Status Total Scores (Coeff. -3.0, 95 % CI: -3.4, -2.5; and -1.1, 95 % CI: -1.5, -0.6) and the Preclinical Alzheimer's Cognitive Composite (Coeff. -0.5, 95 % CI: -0.6, -0.4; and -0.14, 95 % CI: -0.3, -0.03).</p><p><strong>Conclusions: </strong>These findings highlight the interplay between neurological function and cardiovascular aging in cognitive decline. Organ-specific biological age assessments may aid in the early detection of age-related changes, informing personalized interventions. Our study underscores the importance of proteomic aging signatures in elucidating Alzheimer's disease mechanisms and other neurodegenerative conditions, advocating for an integrated approach to brain and cardiovascular health.</p>","PeriodicalId":22711,"journal":{"name":"The Journal of Prevention of Alzheimer's Disease","volume":" ","pages":"100274"},"PeriodicalIF":7.8,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12501340/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144699620","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":"APOE ε4-related differences in brain structure, function, and connectivity at midlife: A scoping review.","authors":"Rikki Lissaman, Sidra Anjum, Andrea Quaiattini, M Natasha Rajah","doi":"10.1016/j.tjpad.2025.100364","DOIUrl":"10.1016/j.tjpad.2025.100364","url":null,"abstract":"<p><strong>Background: </strong>The apolipoprotein E (APOE) ε4 allele is a major genetic risk factor for late-onset Alzheimer's disease (AD), yet there is little consensus about how and when the allele exerts its influence on the brain.</p><p><strong>Methods: </strong>In this scoping review, we synthesized research examining APOE ε4-related differences on MRI-derived measures of brain structure, function, and connectivity in cognitively unimpaired, middle-aged adults (aged 40-65 years). Four online databases (Ovid MEDLINE, Ovid Embase, Ovid PsycINFO, Scopus) were searched on July 11, 2024, and forward/backward reference searching was conducted on identified studies. We extracted data on sample characteristics, methods, and key APOE ε4-related results.</p><p><strong>Results: </strong>Our pre-registered search strategy identified 30 relevant studies. Overall, we found little evidence of robust, consistent differences between APOE ε4 carriers and non-carriers at midlife, especially in relation to brain structure. However, among the studies identified, small samples were common, and limited consideration was afforded to factors such as sex and ethnocultural diversity.</p><p><strong>Conclusion: </strong>Overall, the existing literature indicates that APOE ε4 exerts little, if any, influence on brain structure at midlife, while differences in brain function and connectivity remain poorly characterized.</p>","PeriodicalId":22711,"journal":{"name":"The Journal of Prevention of Alzheimer's Disease","volume":" ","pages":"100364"},"PeriodicalIF":7.8,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12501331/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144969938","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":"Early Alzheimer's disease (mild cognitive impairment or mild dementia): Prevalence, diagnostics, treatment options, and guidelines in Asia, Australasia, and Pacific nations countries.","authors":"Jung-Lung Hsu, Kee Hyung Park, Peter K Panegyres, Yao Hsien Huang, Young In Eom, Vinay Prusty, Lolita Stephanie Tan, Yat Fung Shea","doi":"10.1016/j.tjpad.2025.100362","DOIUrl":"10.1016/j.tjpad.2025.100362","url":null,"abstract":"<p><p>Early diagnosis of mild cognitive impairment (MCI) and Alzheimer's disease (AD) with mild dementia is becoming increasingly important to enable patients to receive appropriate treatment with available amyloid-targeting therapies. Reviews of AD prevalence and diagnostic and treatment patterns typically focus on global or western populations, but the situation in Asia, Australasia, and Pacific Nations (AAPN) countries is less clear. We performed a narrative review of literature for AD in several AAPN countries, focusing on patients with MCI or mild dementia who may benefit from early treatment. Published information regarding AD incidence and prevalence and current practice in AAPN countries is limited and the nature of available information differs between countries. However, AAPN countries include some of the most rapidly aging populations and show the associated increasing trend of all-cause dementia prevalence observed globally. Although lecanemab and donanemab are now approved for AD with MCI and mild dementia in several AAPN countries, the most appropriate diagnostic pathway for patients with MCI and early AD is not established. Even though the AAPN region includes countries with routine access to advanced technologies, concerns have already been raised about the ability of healthcare systems in Australia, New Zealand, and Korea to respond to approvals of new AD therapies, including the need to ensure availability of biomarker testing and dementia specialists to allow patients to receive the early diagnosis required to enable appropriate treatment. Guidelines and national policies also need updating to differentiate between dementia subtypes and include amyloid-targeting therapies for eligible patients with early AD.</p>","PeriodicalId":22711,"journal":{"name":"The Journal of Prevention of Alzheimer's Disease","volume":" ","pages":"100362"},"PeriodicalIF":7.8,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12501334/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144969978","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":"Preclinical detection of Alzheimer's disease pathology using conceptual discrimination abilities.","authors":"Lara Huyghe, Yasmine Salman, Lise Colmant, Thomas Gérard, Vincent Malotaux, Gabriel Besson, Emma Delhaye, Christine Bastin, Quentin Dessain, Laurence Dricot, Renaud Lhommel, Adrian Ivanoiu, Lisa Quenon, Bernard Hanseeuw","doi":"10.1016/j.tjpad.2025.100332","DOIUrl":"10.1016/j.tjpad.2025.100332","url":null,"abstract":"<p><strong>Background: </strong>Performance on the Conceptual Matching Task (CMT), a measure of discrimination between conceptually confusable items, has been suggested as a cognitive marker of rhinal cortex atrophy, one of the first brain regions affected by Alzheimer's disease (AD) pathology.</p><p><strong>Objectives: </strong>We aimed to determine whether CMT can detect preclinical AD, and whether CMT performance is related to regional deposition of tau protein or other AD-associated lesions including amyloid (Aβ) accumulation and white matter hyperintensities (WMH).</p><p><strong>Design, setting and participants: </strong>This cross-sectional study include 101 participants from the UCL2016-121 cohorts in Brussels, Belgium, classified as 56 Aβ-negative cognitively unimpaired (Aβ-CU), 25 Aβ-positive CU (Aβ+CU, preclinical AD), and 20 Aβ-positive mildly cognitively impaired (Aβ+MCI, prodromal AD) individuals.</p><p><strong>Measurements: </strong>Participants underwent CMT and a standard neuropsychological assessment that included the Preclinical Alzheimer Cognitive Composite (PACC5), an Aβ status examination, a 3D-T1 MRI and a [¹⁸F]MK-6240 tau-PET scan.</p><p><strong>Results: </strong>CMT performance was lower among Aβ+MCI and Aβ+CU than Aβ-CU individuals. The effect of Aβ on CMT performance was stronger in the presence of WMH, but rhinal tau burden did not explain CMT performance beyond the effects of Aβ and WMH. CMT performance correlated with executive, memory, and language performance. Finally, CMT was more sensitive than PACC5 to detect CU individuals with Aβ or tau pathology.</p><p><strong>Conclusion: </strong>Given that impaired performance is observed earlier in the CMT than in standard neuropsychological tests, this test shows promise as an early diagnostic tool for AD and may offer significant utility in the context of clinical trials.</p>","PeriodicalId":22711,"journal":{"name":"The Journal of Prevention of Alzheimer's Disease","volume":" ","pages":"100332"},"PeriodicalIF":7.8,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12501345/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144970044","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 phase 2 randomized, placebo-controlled study on the efficacy and safety of AR1001, a phosphodiesterase-5 inhibitor, in patients with mild-to-moderate Alzheimer's disease.","authors":"David Greeley, Marshall Nash, Brad Herskowitz, Fred Kim, James Rock, Neils Prins, SangYun Kim, Tianyang Xi, Jonathan A Busam, Benoit Tete, Jai Jun Choung, Sharon J Sha","doi":"10.1016/j.tjpad.2025.100337","DOIUrl":"10.1016/j.tjpad.2025.100337","url":null,"abstract":"<p><strong>Background: </strong>AR1001 is a phosphodiesterase-5 inhibitor that produces improved cognitive performance and reduces amyloid-β and phosphorylated tau burdens in preclinical models of Alzheimer's disease (AD).</p><p><strong>Objectives: </strong>To evaluate the safety and efficacy of AR1001 in participants with mild-to-moderate Alzheimer's disease (AD).</p><p><strong>Design: </strong>Randomized, double-blind, placebo-controlled phase 2 trial conducted at 21 sites in the United States.</p><p><strong>Participants: </strong>Adults aged 55-80 years with mild-to-moderate dementia as determined by National Institutes of Aging-Alzheimer's Association (NIA-AA) stage 4 or 5 and Mini-mental State Exam (MMSE) score 16-26.</p><p><strong>Intervention: </strong>Once daily oral administration of placebo, 10 mg AR1001, or 30 mg AR1001 for 26 weeks followed by 26 weeks optional extension.</p><p><strong>Measurements: </strong>Co-primary efficacy endpoints were changes from baseline at Week 26 in Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog 13) and Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC). Secondary endpoints included measures of cognition, daily living, and depression. Levels of plasma biomarkers pTau-181, pTau-217, Aβ42/40 ratio, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) were also examined.</p><p><strong>Results: </strong>A total of 210 participants were enrolled and 82% completed 26 weeks of treatment. AR1001 10 mg and 30 mg were well-tolerated with a similar safety profile compared to placebo. After 26 weeks, there were no differences in ADAS-Cog13, ADCS-CGIC, or in secondary efficacy endpoints between groups. Levels of plasma biomarkers pTau-181, pTau-217, and GFAP were improved in the 30 mg AR1001 group compared to placebo.</p><p><strong>Conclusion: </strong>AR1001 was safe and well tolerated. Although primary efficacy endpoints were not met after 26 weeks of treatment, participants receiving 30 mg AR1001 showed favorable changes in AD-related plasma biomarkers compared to placebo.</p><p><strong>Trial registration: </strong>clinicaltrials.gov; NCT03625622.</p>","PeriodicalId":22711,"journal":{"name":"The Journal of Prevention of Alzheimer's Disease","volume":" ","pages":"100337"},"PeriodicalIF":7.8,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12501329/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145006542","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}