Davina Biel, Anna Steward, Anna Dewenter, Amir Dehsarvi, Zeyu Zhu, Sebastian N Roemer-Cassiano, Lukas Frontzkowski, Fabian Hirsch, Carla Palleis, Günter Höglinger, Matthias Brendel, Nicolai Franzmeier, for the Alzheimer's Disease Neuroimaging Initiative (ADNI)
{"title":"A systematic comparison of ATN biomarkers for monitoring longitudinal cognitive changes in Alzheimer's disease","authors":"Davina Biel, Anna Steward, Anna Dewenter, Amir Dehsarvi, Zeyu Zhu, Sebastian N Roemer-Cassiano, Lukas Frontzkowski, Fabian Hirsch, Carla Palleis, Günter Höglinger, Matthias Brendel, Nicolai Franzmeier, for the Alzheimer's Disease Neuroimaging Initiative (ADNI)","doi":"10.1002/alz.70783","DOIUrl":"10.1002/alz.70783","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>With anti-amyloid beta (Aβ) therapies approved for Alzheimer's disease (AD), surrogate biomarkers are needed to monitor clinical treatment efficacy. Therefore, we systematically compared longitudinal changes in A/T/N biomarkers (amyloid-positron emission tomography [PET], tau-PET, plasma phosphorylated tau at threonine 217 [p-tau<sub>217</sub>], and magnetic resonance imaging) for tracking cognitive changes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>We analyzed longitudinal biomarker and cognitive change rates from the Alzheimer's Disease Neuroimaging Initiative (<i>N </i>= 141) and Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) (<i>N</i> = 151), estimated using linear mixed models. Using linear models, we tested biomarker changes as predictors of cognitive changes, comparing predictive strengths across biomarkers using bootstrapping.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>Tau-PET, plasma p-tau217, and cortical thickness changes accurately tracked change rates in Mini-Mental State Examination, Alzheimer's Disease Assessment Scale-Cognitive Subscale 13-item version, Clinical Dementia Rating-Sum of Boxes, and Preclinial Alzheimer Cognitive Composite scores. In contrast, amyloid-PET change rates were not linked to cognitive changes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>Plasma p-tau<sub>217</sub> offers a cost-effective AD-specific alternative to tau-PET and could potentially be implemented for monitoring cognitive changes in AD trials, while amyloid-PET lacks utility. Cortical thickness changes accurately track cognitive changes but may be confounded by pseudo-atrophy in anti-Aβ treatments.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Longitudinal changes in tau-PET, plasma p-tau<sub>217</sub>, cortical thickness – but not amyloid-PET – effectively track cognitive decline.</li>\u0000 \u0000 <li>Cortical thickness may be confounded by pseudo-atrophy in anti-Aβ trials.</li>\u0000 \u0000 <li>Plasma p-tau<sub>217</sub> is a robust and cost-effective alternative to tau-PET as an AD-specific surrogate biomarker for monitoring cognitive changes.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 10","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://alz-journals.onlinelibrary.wiley.com/doi/epdf/10.1002/alz.70783","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145342682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Wenxin Zhang, Wenjie Cai, Yiwen Zhang, Albert Hofman, Anand Viswanathan, Susanne J. van Veluw, Deborah Blacker, Sudeshna Das, Yuan Ma
{"title":"Compression of cognitive decline and cognitive resilience in extreme longevity","authors":"Wenxin Zhang, Wenjie Cai, Yiwen Zhang, Albert Hofman, Anand Viswanathan, Susanne J. van Veluw, Deborah Blacker, Sudeshna Das, Yuan Ma","doi":"10.1002/alz.70683","DOIUrl":"10.1002/alz.70683","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> BACKGROUND</h3>\u0000 \u0000 <p>Compressing the duration of cognitive impairment is critical to preserve quality of life until the end. To what extent cognitive decline is compressed and cognitive resilience increases with extreme longevity is not well understood.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>We used data from 13,999 deceased participants from the National Alzheimer's Coordinating Center cohort, including 8,146 with neuropathological data. Cognitive function was assessed annually (median follow-up: 4.9 years). We evaluated cognitive trajectories before death and cognitive resilience (defined as high neuropathological burden without dementia) across lifespan groups (ages 50–100+ years).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>Participants with longer lifespans, particularly centenarians, exhibited slower cognitive decline and shorter periods of cognitive impairment before death, although distinct cognitive trajectories existed among centenarians. Cognitive resilience also increased with longer lifespans, but associated factors varied. <i>Apolipoprotein</i> <i>E</i> <i>ε</i><i>2</i> was associated with higher cognitive resilience only in centenarians.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> CONCLUSION</h3>\u0000 \u0000 <p>Our findings support a general compression of cognitive decline and increased cognitive resilience in extreme longevity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Individuals with longer lifespans, especially centenarians, generally exhibited better cognitive function and slower cognitive decline toward the end of life, suggesting a compression of cognitive decline in extreme longevity.</li>\u0000 \u0000 <li>Although there was a compression of cognitive decline at the group level among centenarians, heterogeneous cognitive trajectories before death were observed across individuals.</li>\u0000 \u0000 <li>The relationship between neuropathological burden and dementia risk attenuated with longer lifespans, indicating greater cognitive resilience in individuals with extreme longevity.</li>\u0000 \u0000 <li>The associations of both genetic and modifiable factors with cognitive resilience varied by lifespan.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 10","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12541553/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145342647","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lata Chaunsali, Jiangtao Li, Erik Fleischel, Courtney E. Prim, Izabela Kasprzak, Shan Jiang, Silky Hou, Miguel Escalante, Elise C. Cope, Michelle L. Olsen, Bhanu P. Tewari, Harald Sontheimer
{"title":"Degradation of perineuronal nets in hippocampal CA2 explains the loss of social cognition memory in Alzheimer's disease","authors":"Lata Chaunsali, Jiangtao Li, Erik Fleischel, Courtney E. Prim, Izabela Kasprzak, Shan Jiang, Silky Hou, Miguel Escalante, Elise C. Cope, Michelle L. Olsen, Bhanu P. Tewari, Harald Sontheimer","doi":"10.1002/alz.70813","DOIUrl":"10.1002/alz.70813","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Loss of social cognition memory impairs Alzheimer's disease (AD) patients to recognize family members, friends, and caregivers. We investigate the role of perineuronal nets (PNNs), specialized coats of extracellular matrix around hippocampal CA2 neurons in AD-associated social memory impairments.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>We utilized 5XFAD mouse model of AD and employed immunohistochemistry, microscopy, bulk RNA-sequencing, animal behavior, gene-knockout, and drug-treatment approaches.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>AD mice showed profound disruption of CA2 PNNs with concomitant impairment of social cognition memory. Genetic or enzymatic CA2 PNN disruption in wild-type mice mimicked these impairments. Transcriptomic analysis shows upregulation of PNN-cleaving matrix metalloproteinases (MMP) in AD mice causing disequilibrium of PNN synthesis and remodeling. Chronic inhibition of MMPs retains CA2 PNN and delays social memory impairments in 5XFAD mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>AD-associated social memory impairments are caused by loss of CA2 PNNs. Inhibition of PNN proteolysis by MMPs preserves social memory, suggesting PNN as a promising therapeutic target.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Perineuronal nets (PNNs) are disrupted in the CA2 area of the hippocampus in 5XFAD Alzheimer's disease (AD) mice at 6 months of age and beyond.</li>\u0000 \u0000 <li>Social memory deficits in 5XFAD mice coincide with the disruption of CA2 PNNs and PNN loss alone is sufficient to cause loss of social memory.</li>\u0000 \u0000 <li>Bulk RNA sequencing of hippocampal CA2 tissue reveals alterations in PNN remodeling enzymes.</li>\u0000 \u0000 <li>Inhibition of matrix metalloproteinase (MMP) activity with GM6001 prevents PNN disruption and protects against social memory deficits in the 5XFAD AD mouse model.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 10","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12541281/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145342685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xueqin Li, Wanyu Zhao, Huirong Zheng, Bangshan Liu, Hongbo He, Jin Liu, Ling Jiang Li, Yan Zhang
{"title":"Biological and social reproductive factors and late-life cognitive function in middle-aged and older Chinese women","authors":"Xueqin Li, Wanyu Zhao, Huirong Zheng, Bangshan Liu, Hongbo He, Jin Liu, Ling Jiang Li, Yan Zhang","doi":"10.1002/alz.70824","DOIUrl":"10.1002/alz.70824","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Few studies have concurrently examined the biological and social reproductive factors in relation to women's cognitive aging.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>We analyzed 8577 women and 7872 men ≥45 years of age from the China Health and Retirement Longitudinal Study. Biological reproductive factors included reproductive span, age at menarche, and age at menopause; social reproductive factors included number of children and age at first live birth. Multivariable regression models were sequentially adjusted for age, childhood cognition proxy, education, and current health and lifestyle factors.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>Longer reproductive span was associated with better cognitive performance in women, whereas a higher number of children were linked to poorer cognition in both sexes, particularly in women. These associations remained robust after full adjustment, compared with age at menarche, age at menopause, and age at first birth.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> CONCLUSION</h3>\u0000 \u0000 <p>Integrating biological and social reproductive factors provides insights into sex-specific cognitive aging patterns and may inform tailored dementia prevention strategies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>A longer reproductive span was linked to better cognition in older Chinese women.</li>\u0000 \u0000 <li>More children were linked to poorer cognition in both sexes, especially in women.</li>\u0000 \u0000 <li>Reproductive span and number of children showed robust associations with late-life cognition, stronger than other reproductive factors.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 10","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12541285/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145342742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Dario Bachmann, Maha Wybitul, Andreas Buchmann, Christoph Gericke, Antje Saake, Sandro Studer, Katrin Rauen, Esmeralda Gruber, Kaj Blennow, Henrik Zetterberg, Roger M Nitsch, Christoph Hock, Valerie Treyer, Anton Gietl
{"title":"Predicting cognitive decline with amyloid-PET, plasma p-tau217, Aβ42/40, and p-tau217/Aβ42 in a community-based cohort – relevance for clinical trial enrollment","authors":"Dario Bachmann, Maha Wybitul, Andreas Buchmann, Christoph Gericke, Antje Saake, Sandro Studer, Katrin Rauen, Esmeralda Gruber, Kaj Blennow, Henrik Zetterberg, Roger M Nitsch, Christoph Hock, Valerie Treyer, Anton Gietl","doi":"10.1002/alz.70802","DOIUrl":"10.1002/alz.70802","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Identifying at-risk individuals and selecting sensitive cognitive outcome measures are critical for designing efficient clinical trials targeting early Alzheimer's disease (AD) stages.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>We compared amyloid beta (Aβ)-positron emission tomography (PET), plasma tau phosphorylated at threonine 217 (p-tau217), Aβ42/40, and p-tau217/Aβ42-related decline across neuropsychological and functional measures in 225 individuals (176 cognitively unimpaired (CU), 49 with mild cognitive impairment (MCI). Johnson–Neyman analysis identified the biomarkers, which were used as trial inclusion criteria to estimate sample sizes needed to detect a 30% slowing across cognitive outcomes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>In the CU, using combined plasma Aβ42/40 and p-tau217 cut-offs for eligibility yielded the lowest sample size estimates for a comprehensive multidomain cognitive composite score, whereas sample sizes were higher for all other inclusion criteria based on single biomarkers. In MCI, estimates were substantially lower and less variable across most inclusion criteria and outcome measures.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>These findings highlight the need for careful consideration of outcome measures, baseline diagnosis, and inclusion criteria, given their substantial effect on sample size estimation in trials.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Aβ SUVR, plasma p-tau217, and the p-tau217/Aβ42 ratio predicted decline across multiple cognitive domains.</li>\u0000 \u0000 <li>Using cohort-specific biomarker cutoffs, sample size estimates were similar for p-tau217 combined with Aβ42/40 or Aβ SUVR.</li>\u0000 \u0000 <li>A multidomain composite best detected AD-related decline.</li>\u0000 \u0000 <li>Outcome measures and eligibility criteria strongly impact sample size estimates, especially in CU.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 10","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12538628/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145336190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Anna E. Goodheart, Tess L. Brazier, Rong Ye, Patrick Stancu, Stephen N. Gomperts
{"title":"Towards optimizing the diagnosis of Lewy body dementia: Lessons from the NACC","authors":"Anna E. Goodheart, Tess L. Brazier, Rong Ye, Patrick Stancu, Stephen N. Gomperts","doi":"10.1002/alz.70794","DOIUrl":"10.1002/alz.70794","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>The diverse presentations and co-pathologies of Lewy body dementia (LBD) present a diagnostic challenge. Utilizing the National Alzheimer's Coordinating Center (NACC) dataset, this study aimed to evaluate the concordance of premorbid diagnoses of LBD in individuals with autopsy-confirmed neocortical Lewy body disease.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>Demographics, clinical and neuropsychological presentations, Lewy body pathology, and Alzheimer's disease (AD) co-pathology were related to clinical diagnosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>Diagnosis of LBD had high specificity but low sensitivity, with fewer than half of autopsy-confirmed cases having received an LBD diagnosis. AD was the most common misdiagnosis. Participants diagnosed with AD were more likely to be female, to have a more amnestic phenotype, and to harbor a higher burden of AD co-pathology, and were less likely to have documented clinical features characteristic of LBD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>These results highlight the need to improve LBD diagnosis in research and clinical settings, a need that emerging biomarkers may help address.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Less than half of cases with neocortical Lewy bodies were diagnosed with Lewy body dementia (LBD)</li>\u0000 \u0000 <li>Alzheimer's disease (AD) was the most common misdiagnosis</li>\u0000 \u0000 <li>Cases misdiagnosed were more likely to be female</li>\u0000 \u0000 <li>Cases diagnosed with AD presented with a more amnestic phenotype</li>\u0000 \u0000 <li>Cases diagnosed with AD had more AD co-pathology</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 10","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12538637/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145336253","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Discordant cerebrospinal fluid and positron emission tomography amyloid biomarkers in an APP mutation carrier presenting corticobasal syndrome","authors":"Feng-Tao Liu, Xin-Yi Li, Jia-Ying Lu, Chuan-Tao Zuo","doi":"10.1002/alz.70823","DOIUrl":"10.1002/alz.70823","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>While amyloid cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers are considered interchangeable indicators of Alzheimer's disease (AD) pathology, biomarker discrepancies can occur but remain poorly characterized.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>We evaluated <sup>18</sup>F-florbetapir amyloid PET, <sup>18</sup>F-Florzolotau PET (tau pathology), magnetic resonance imaging (MRI) findings, and CSF biomarkers in a 59-year-old man carrying the pathogenic <i>APP</i> p.K687Q mutation, who presented with possible corticobasal syndrome.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>CSF analysis revealed reduced amyloid beta (Aβ)<sub>1-42</sub> (503.44 pg/mL) and Aβ<sub>1-42</sub>/Aβ<sub>1-40</sub> ratio (0.044), indicating amyloid pathology. Conversely, <sup>18</sup>F-florbetapir PET was visually negative (standardized uptake value ratio [SUVR] 0.97; −11.8 Centiloids). <sup>18</sup>F-Florzolotau PET demonstrated AD-typical tau deposition, whereas MRI revealed extensive white matter hyperintensities, enlarged perivascular spaces, and a temporal microbleed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>The observed discordance suggests that CSF and PET amyloid biomarkers can diverge in certain patients. Potential mechanisms include polymorphic Aβ fibrils lacking <sup>18</sup>F-florbetapir binding sites, excess non-fibrillar aggregates, low fibril density, or contributions from cerebral amyloid angiopathy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>CSF Aβ and <sup>18</sup>F-florbetapir PET findings showed a mismatch in a patient with an APP mutation.</li>\u0000 \u0000 <li>Amyloid pathology should not be excluded despite negative <sup>18</sup>F-florbetapir PET findings.</li>\u0000 \u0000 <li>Mismatch may reflect altered ligand binding or fibril structural variants.</li>\u0000 \u0000 <li>Comorbid cerebral amyloid angiopathy may contribute to biomarker discrepancies.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 10","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12538635/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145336169","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Entwined processes in Alzheimer's disease: Brain cellular senescence and Alzheimer's disease pathology","authors":"Wen Li, Ying Han, Peichang Wang, Qiao Song","doi":"10.1002/alz.70803","DOIUrl":"10.1002/alz.70803","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Alzheimer's disease (AD) is one of the most common age-related neurodegenerative diseases with severe progressive dementia. Amyloid beta (Aβ) deposition and phosphorylated tau accumulation are two typical AD pathologies, which could drive senescence in various types of brain cells. These factors interact to form an entwined vicious cycle, in which each cell could play an irreplaceable role. Thus, it is essential to stress the cause-and-effect relationship in this process and to identify the key factor leading to the vicious cycle. In this narrative review, we discuss (1) how AD pathology induces cellular senescence in different brain cell types; (2) how various accumulated senescent brain cells exacerbate AD pathology; and (3) how cellular senescence and AD pathology are entwined, reinforcing each other through a vicious cycle that accelerates disease progression. We hope to provide insights into the integrated mechanisms linking cellular senescence and AD pathology.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Alzheimer's disease (AD) pathology could mediate senescence-like phenotypes in various brain cells, and each type of cell plays a key role in AD.</li>\u0000 \u0000 <li>Various senescent brain cells could contribute to AD pathology through diverse mechanisms, with each cell type being indispensable.</li>\u0000 \u0000 <li>The cause-and-effect relationship between cellular senescence and AD pathology is essential for identifying AD's earlier pathological events and the initiating factors, which still need further exploration.</li>\u0000 \u0000 <li>An entwined vicious circle exists between brain cellular senescence and AD pathology, in which chronic inflammation, blood–brain barrier damage, neuron loss, and synapse degeneration all play crucial roles.</li>\u0000 \u0000 <li>Clearance of senescent brain cells could be a promising therapeutic strategy for AD.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 10","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12538649/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145336228","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jackson A. Roberts, Mitchell S. V. Elkind, Minghua Liu, Stephanie Assuras, Bonnie E. Levin, Vanessa Guzman, Tatjana Rundek, Jose Gutierrez
{"title":"The association of common infectious exposures with cognitive performance in community-dwelling older adults","authors":"Jackson A. Roberts, Mitchell S. V. Elkind, Minghua Liu, Stephanie Assuras, Bonnie E. Levin, Vanessa Guzman, Tatjana Rundek, Jose Gutierrez","doi":"10.1002/alz.70457","DOIUrl":"10.1002/alz.70457","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>The Northern Manhattan Study (NOMAS) previously identified that a combined infectious disease exposure index correlates with impaired cognitive performance in older adults.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>We extended these findings by examining the association of serological titers of five common infectious diseases (herpes simplex virus [HSV] 1 and 2, cytomegalovirus [CMV], <i>Chlamydia pneumoniae</i>, and <i>Helicobacter Pylori</i>) with domain-specific cognitive performance and incident cognitive impairment and dementia in 593 community-dwelling older adults. We performed confounder-adjusted mixed linear regression between infectious serologies and longitudinal cognitive performance.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>CMV and HSV-2 serologies were associated with impaired executive function, whereas <i>C. pneumoniae</i> serology was associated with impaired performance on language testing. In univariate Cox proportional hazard models, CMV serologies were associated with incident cognitive impairment and dementia.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>CMV seropositivity may accelerate domain-specific cognitive worsening and could confer increased risk for cognitive impairment and dementia, warranting further evaluation in observational and experimental datasets.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Infectious exposures may contribute to neurodegeneration and risk of cognitive impairment.</li>\u0000 \u0000 <li>Cytomegalovirus (CMV) and herpes simplex virus 2 exposure were associated with impaired executive function.</li>\u0000 \u0000 <li><i>Chlamydia pneumoniae</i> was associated with decreased performance on language testing.</li>\u0000 \u0000 <li>CMV may be associated with incident cognitive impairment and dementia.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 10","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12538643/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145336233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"ARTS as a cardiometabolic biomarker to bridge gaps in dementia diagnostics and therapeutics","authors":"Timothy Daly, Bruno P. Imbimbo","doi":"10.1002/alz.70811","DOIUrl":"10.1002/alz.70811","url":null,"abstract":"<p>Cerebral arteriolosclerosis is a form of small vessel disease characterized by the hardening and thickening of deep arterioles of the brain, and is commonly observed in conditions such as hypertension, diabetes, and dementia. In a diverse community sample, Fleischman et al. found that an in vivo magnetic resonance imaging-based classifier of arteriolosclerosis (shortened to ARTS), based on demographic data, white matter hyperintensity burden, and measures of diffusion tensor imaging fractional anisotropy, was a reliable marker for risk of mild cognitive impairment, dementia, and stroke.<span><sup>1</sup></span> Arteriolosclerosis is a pathogenic mechanism that serves not just as a marker, but also provides an upstream explanation of reductions in brain blood flow, infarcts, and downstream impacts on cognitive impairment.<span><sup>2</sup></span> In dementia research and clinical practice, ARTS could thus provide a polyvalent biomarker of cardiometabolic contributions to cognitive impairment due to underlying conditions such as hypertension and diabetes,<span><sup>3</sup></span> for example, alongside neurodegenerative biomarkers of amyloid beta (Aβ) and tau of Alzheimer's disease (AD) in both diagnostics and therapeutics.</p><p>Concerning diagnostics, in the absence of neurodegenerative pathologies such as AD, ARTS could be used to confirm the diagnosis of vascular dementia in cognitively impaired persons, which currently relies on gross measures of infarcts, white matter damage, and atrophy.<span><sup>4</sup></span> In the presence of AD neuropathology, ARTS could provide a quantifiable measure of cardiometabolic comorbidities that independently contribute to cognitive decline.<span><sup>5</sup></span> Indeed, Section 7.2 of the Alzheimer's Association 2024 revised criteria for the diagnosis of AD<span><sup>6</sup></span> discusses “Biomarkers of common non-AD copathologies” and recognizes that while there are multiple neuroimaging markers of cerebrovascular disease, none of them are specific, and there is no unified summary measure for vascular brain injury, creating diagnostic ambiguity. ARTS is a promising alternative to current imaging-based markers of cerebrovascular disease that provides a quantifiable measure that is also specific, mechanistic, and clinically relevant.</p><p>As a therapeutic example of ARTS’ application, take the example of autosomal dominant AD, for which Müller et al. found that World Health Organization–defined high levels of physical activity were associated with up to 15 years longer cognitive function, but not due to reduced global Aβ burden.<span><sup>7</sup></span> Cardiometabolic biomarkers such as ARTS could thus be used complementarily alongside neurodegenerative biomarkers to provide a mechanistic explanation of the positive impacts of physical activity on cognitive function. In clinical trials, such as those testing the therapeutic value of cardioprotective glucose-lowering drugs such as metformin<span><su","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 10","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12538623/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145336006","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}