Alzheimer's & Dementia最新文献

{"title":"Does white matter and vascular injury from repetitive head impacts lead to a novel pattern on T2 FLAIR MRI? A hypothesis proposal and call for research","authors":"Annalise E. Miner,&nbsp;Jenna R. Groh,&nbsp;Chad Farris,&nbsp;Sarina Hattiangadi,&nbsp;Anna Cui,&nbsp;Adam M. Brickman,&nbsp;Mohamad Alshikho,&nbsp;Gil D. Rabinovici,&nbsp;Howie J. Rosen,&nbsp;Yann Cobigo,&nbsp;Breton Asken,&nbsp;Christopher J. Nowinski,&nbsp;Samantha Bureau,&nbsp;Fereydoun Shahrokhi,&nbsp;Yorghos Tripodis,&nbsp;Monica Ly,&nbsp;Caroline Altaras,&nbsp;Steven Lenio,&nbsp;Robert A. Stern,&nbsp;Grace Rosen,&nbsp;Hunter Kelley,&nbsp;Bertrand Russell Huber,&nbsp;Thor D. Stein,&nbsp;Jesse Mez,&nbsp;Ann C. McKee,&nbsp;Michael L. Alosco","doi":"10.1002/alz.70085","DOIUrl":"https://doi.org/10.1002/alz.70085","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>The goal of this paper is to introduce the hypothesis that white matter (WM) and vascular injury are long-term consequences of repetitive head impacts (RHI) that result in a novel T2 fluid attenuated inversion recovery (FLAIR) magnetic resonance imaging pattern. A non-systematic literature review of autopsy and FLAIR studies of RHI-exposed adults was first conducted as a foundation for our hypothesis. A case series of RHI-exposed participants is presented to illustrate the unique FLAIR WM hyperintensities (WMH) pattern. Current literature shows a direct link between RHI and later-life WM/vascular neuropathologies, and that FLAIR WMH are associated with RHI, independent of modifiable vascular risk factors. Initial observations suggest a distinctive pattern of WMH in RHI-exposed participants, termed RHI-associated WMH (RHI-WMH). RHI-WMH defining features are as follows: (1) small, punctate, non-confluent, (2) spherical, and (3) proximal to the gray matter. Our hypothesis serves as a call for research to empirically validate RHI-WMH and clarify their biological and clinical correlates.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Repetitive head impacts (RHI) have been associated with later-life white matter (WM) and vascular neuropathologies.</li>\u0000 \u0000 <li>T2 FLAIR MRI of RHI-exposed participants reveals a potentially unique WM hyperintensity (WMH) pattern that is termed RHI-associated WMH (RHI-WMH).</li>\u0000 \u0000 <li>RHI-WMH are characterized as (1) small, punctate, and non-confluent, (2) spherical, and (3) proximal to the gray matter at an area anatomically susceptible to impact injury, such as the depths of the cortical sulci.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 3","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.70085","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143707313","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":"Motor symptoms in autopsy-confirmed Alzheimer's disease increase the risk of progression to severe cognitive impairment","authors":"Jacob S. Shaw,&nbsp;Philip C. Huang,&nbsp;Paul B. Rosenberg,&nbsp;Matthew E. Peters","doi":"10.1002/alz.70039","DOIUrl":"https://doi.org/10.1002/alz.70039","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Motor symptoms may present throughout the Alzheimer's disease (AD) course. We evaluated the impact of motor symptoms on the risk of progression to severe cognitive impairment, severe neuropsychiatric symptoms (NPSs), and mortality in patients with autopsy-confirmed AD. We also examined the rates of non-AD pathology and identified the predictors of disease progression among these patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>Data from the National Alzheimer's Coordinating Center (NACC) were used for this analysis. Participants (<i>N</i> = 1167) were required to have autopsy-confirmed AD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>Motor symptoms were predictive of progression to severe cognitive impairment but not progression to severe NPSs or death. Presenting with gait disturbance and slowness but not falls or tremor was predictive of progression to severe cognitive impairment. Patients with motor symptoms had higher rates of Lewy body disease pathology on autopsy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>Our findings suggest that the presence of motor symptoms in autopsy-confirmed AD, particularly gait disturbance and slowness, are predictive of more rapid cognitive decline.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Clinician-defined motor symptoms in patients with Alzheimer's disease (AD) predicted more rapid progression to severe cognitive impairment but not to severe neuropsychiatric symptoms (NPSs) or death.</li>\u0000 \u0000 <li>Among AD patients with motor symptoms, presenting with gait disturbance and slowness was predictive of progression to severe cognitive impairment, whereas presenting with falls and tremor was not predictive of progression to severe cognitive impairment.</li>\u0000 \u0000 <li>Patients with motor symptoms, particularly gait disturbance and slowness, had higher rates of comorbid Lewy body disease pathology.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 3","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.70039","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143707227","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":"Intraneuronal Aβ accumulation causes tau hyperphosphorylation via endolysosomal leakage","authors":"Yang Gao,&nbsp;Lisha Wang,&nbsp;Tosca Doeswijk,&nbsp;Bengt Winblad,&nbsp;Sophia Schedin-Weiss,&nbsp;Lars O. Tjernberg","doi":"10.1002/alz.70091","DOIUrl":"https://doi.org/10.1002/alz.70091","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Alzheimer's disease (AD) is characterized by amyloid beta (Aβ) peptide plaques and intracellular neurofibrillary tangles formed by hyperphosphorylated tau. Many attempts have been made to clarify the link between Aβ and tau in the pathogenesis, but conclusive data describing a pathway for this connection are still lacking.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>We developed a neuronal model of Aβ-induced toxicity and studied downstream effects of intraneuronal Aβ42 accumulation on tau hyperphosphorylation using confocal microscopy and live cell imaging.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>Aβ42 added to the medium was endocytosed into neurons, inducing the formation of endolysosomal protofibrils and endolysosomal leakage, which in turn promoted tau hyperphosphorylation. Asparaginyl endopeptidase (AEP) was released from the disrupted lysosomes, and inhibition of this peptidase activity reduced tau hyperphosphorylation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>The data suggest a mechanism of AD in which Aβ42 accumulates and aggregates gradually in neurons over time, leading to endolysosomal leakage and release of AEP, which subsequently triggers tau hyperphosphorylation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Aβ42 endocytosis leads to its endolysosomal accumulation in neurons over time.</li>\u0000 \u0000 <li>Aβ42 polymerizes into protofibrils and causes endolysosomal leakage.</li>\u0000 \u0000 <li>Tau hyperphosphorylation is induced by endolysosomal asparagine endopeptidase leakage.</li>\u0000 \u0000 <li>Tau hyperphosphorylation is inhibited by an asparagine endopeptidase inhibitor.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 3","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.70091","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143707514","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":"Decreased water exchange rate across the blood–brain barrier throughout the Alzheimer's disease continuum: Evidence from Chinese data","authors":"Guanqun Chen,&nbsp;Hui Li,&nbsp;Xingfeng Shao,&nbsp;Danny J. J. Wang,&nbsp;Wenli Hu,&nbsp;Ying Han,&nbsp;Qi Yang","doi":"10.1002/alz.70089","DOIUrl":"https://doi.org/10.1002/alz.70089","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; INTRODUCTION&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Water exchange rate (Kw) across the blood–brain barrier (BBB) is used in magnetic resonance imaging (MRI) techniques to evaluate BBB functionality. Variations in BBB Kw across the Alzheimer's disease (AD) continuum remain uncertain.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; METHODS&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The study encompassed 38 cognitively normal individuals without AD biomarkers (CN_A–), 30 cognitively normal (CN_A+), and 31 cognitively impaired individuals (CI_A+) with positive AD biomarkers. Participants underwent clinical assessments, MRI/positron emission tomography scans, and assays of plasma biomarkers.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; RESULTS&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Significantly lower Kw was observed in multiple brain regions throughout the AD continuum. This alteration in Kw correlated with plasma biomarkers and neuropsychological performance. Elevated levels of phosphorylated tau 217 intensified the inverse relationship between Kw and neuropsychological performance. The integration of Kw, brain volume, and plasma biomarkers demonstrated potential in distinguishing stages within the AD continuum.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; DISCUSSION&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Consistently lower Kw was evident across the AD continuum and may act as a diagnostic tool for early AD screening.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Highlights&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;Observations revealed a decline in water exchange rate (Kw) across multiple brain regions within the Alzheimer's disease (AD) continuum, notably in the hippocampus, parahippocampal gyrus, and deep brain nuclei during the preclinical stage of AD.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Strong correlations were established between Kw levels in various brain regions and plasma biomarkers, as well as neuropsychological performance in the AD continuum.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Interaction between plasma phosphorylated tau (p-tau)217 and Kw in the hippocampus was linked to executive function, indicating a combined detrimental impact on cognitive abilities stemming from both blood—brain barrier Kw and p-tau 217.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;The combined use of Kw, brain volume, and plasma biomarkers—neurofilament light chain and glial fibrillary acidic protein—demonstrated potential for distinguishing individuals within the AD continuum.&lt;/li&gt;\u0000 &lt;/ul&gt;\u0000 &lt;/div&gt;\u0000 &lt;/section","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 3","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.70089","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143707515","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":"Pathways underlying selective neuronal vulnerability in Alzheimer's disease: Contrasting the vulnerable locus coeruleus to the resilient substantia nigra","authors":"Alexander J. Ehrenberg,&nbsp;Cathrine Sant,&nbsp;Felipe L. Pereira,&nbsp;Song Hua Li,&nbsp;Jessica Buxton,&nbsp;Sonali Langlois,&nbsp;Marena Trinidad,&nbsp;Ian Oh,&nbsp;Renata Elaine Paraizo Leite,&nbsp;Roberta Diehl Rodriguez,&nbsp;Vitor Ribeiro Paes,&nbsp;Carlos Agusto Pasqualucci,&nbsp;William W. Seeley,&nbsp;Salvatore Spina,&nbsp;Claudia K. Suemoto,&nbsp;Sally Temple,&nbsp;Daniela Kaufer,&nbsp;Lea T. Grinberg","doi":"10.1002/alz.70087","DOIUrl":"https://doi.org/10.1002/alz.70087","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Alzheimer's disease (AD) selectively affects certain brain regions, yet the mechanisms of selective vulnerability remain poorly understood. The neuromodulatory subcortical system, which includes nuclei exhibiting a range of vulnerability and resilience to AD-type degeneration, presents a framework for uncovering these mechanisms.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>We leveraged transcriptomics and immunohistochemistry in paired samples from human <i>post mortem</i> tissue representing a vulnerable and resilient region—the locus coeruleus (LC) and substantia nigra (SN). These regions have comparable anatomical features but distinct vulnerability to AD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>We identified significant differences in cholesterol homeostasis, antioxidant pathways, KRAS signaling, and estrogen signaling at a bulk transcriptomic level. Notably, evidence of sigma-2 receptor upregulation was detected in the LC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>Our findings highlight pathways differentiating the LC and SN, potentially explaining the LC's selective vulnerability in AD. Such pathways offer potential targets of disease-modifying therapies for AD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Intraindividual comparative RNAseq was used to study selective vulnerability.</li>\u0000 \u0000 <li>Metallothionein genes are significantly enriched in the substantia nigra.</li>\u0000 \u0000 <li>Cholesterol homeostatic genes are significantly enriched in the locus coeruleus.</li>\u0000 \u0000 <li>The locus coeruleus is likely more susceptible to toxic amyloid beta oligomers.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 3","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.70087","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143698957","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":"Generalizability of tau and amyloid plasma biomarkers in Alzheimer's disease cohorts of diverse genetic ancestries","authors":"Anthony J. Griswold,&nbsp;Farid Rajabli,&nbsp;Tianjie Gu,&nbsp;Jamie Arvizu,&nbsp;Charles G. Golightly,&nbsp;Patrice L. Whitehead,&nbsp;Kara L. Hamilton-Nelson,&nbsp;Larry D. Adams,&nbsp;Jose J. Sanchez,&nbsp;Pedro R. Mena,&nbsp;Takiyah D. Starks,&nbsp;Maryenela Illanes-Manrique,&nbsp;Concepcion Silva,&nbsp;William S. Bush,&nbsp;Michael L. Cuccaro,&nbsp;Jeffery M. Vance,&nbsp;Mario R. Cornejo-Olivas,&nbsp;Briseida E. Feliciano-Astacio,&nbsp;Goldie S. Byrd,&nbsp;Gary W. Beecham,&nbsp;Jonathan L. Haines,&nbsp;Margaret A. Pericak-Vance","doi":"10.1002/alz.14367","DOIUrl":"https://doi.org/10.1002/alz.14367","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Plasma phosphorylated threonine 181 of tau (pTau181) and amyloid beta (Aβ) are biomarkers for differential diagnosis and preclinical detection of Alzheimer disease (AD). Given differences in AD risk across diverse populations, the generalizability of existing biomarker data is not assured.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>In 2086 individuals of diverse genetic ancestries (African American, Caribbean Hispanic, and Peruvian), we measured plasma pTau181 and Aβ42/Aβ40. Differences in biomarkers between cohorts and clinical diagnosis groups and the potential discriminative performance of the two biomarkers were assessed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>pTau181 and Aβ42/Aβ40 were consistent across cohorts. Higher levels of pTau181 were associated with AD, while Aβ42/Aβ40 had minimal differences. Correspondingly, pTau181 had a greater predictive value than Aβ42/Aβ40; however, the area under the curve differed between cohorts.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>pTau181 as a plasma biomarker for clinical AD is generalizable across genetic ancestries, but its predictive value may vary. Combining genomic and biomarker data from diverse individuals will increase understanding of genetic risk and refine clinical diagnoses.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>This is a diverse ancestry study of plasma biomarkers for AD.</li>\u0000 \u0000 <li>Plasma biomarkers were assessed in African Americans, Caribbean Hispanics, and Peruvians.</li>\u0000 \u0000 <li>Biomarker levels were consistent across the diverse cohorts.</li>\u0000 \u0000 <li>Plasma phosphorylated tau was higher in AD in all cohorts.</li>\u0000 \u0000 <li>Plasma biomarker findings in diverse cohorts largely generalize with existing European studies.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 3","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.14367","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143698708","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":"Carbonic anhydrase inhibitors prevent presymptomatic capillary flow disturbances in a model of cerebral amyloidosis","authors":"Eugenio Gutiérrez-Jiménez,&nbsp;Peter Mondrup Rasmussen,&nbsp;Irene Klærke Mikkelsen,&nbsp;Sreekanth Kura,&nbsp;Signe K. Fruekilde,&nbsp;Brian Hansen,&nbsp;Luca Bordoni,&nbsp;Jasper Carlsen,&nbsp;Johan Palmfeldt,&nbsp;David A. Boas,&nbsp;Sava Sakadžić,&nbsp;Sergei Vinogradov,&nbsp;Mirna El Khatib,&nbsp;Jaime Ramos-Cejudo,&nbsp;Boris Wied,&nbsp;Desiree Leduc-Galindo,&nbsp;Elisa Canepa,&nbsp;Adam C. Mar,&nbsp;Begona Gamallo-Lana,&nbsp;Silvia Fossati,&nbsp;Leif Østergaard","doi":"10.1002/alz.70023","DOIUrl":"https://doi.org/10.1002/alz.70023","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Disturbances in microvascular flow dynamics are hypothesized to precede the symptomatic phase of Alzheimer's disease (AD). However, evidence in presymptomatic AD remains elusive, underscoring the need for therapies targeting these early vascular changes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>We employed a multimodal approach, combining in vivo optical imaging, molecular techniques, and ex vivo magnetic resonance imaging, to investigate early capillary dysfunction in C57BL/6-Tg(Thy1-APPSwDutIowa)BWevn/Mmjax (Tg-SwDI) mice without memory impairment. We also assessed the efficacy of carbonic anhydrase inhibitors (CAIs) in preventing capillary flow disturbances.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>Our study revealed capillary flow disturbances associated with alterations in capillary morphology, adhesion molecule expression, and amyloid beta (Aβ) load in 9- to 10-month-old Tg-SwDI mice without memory impairment. CAI treatment ameliorated these capillary flow disturbances, enhanced oxygen availability, and reduced Aβ load.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>These findings underscore the importance of capillary flow disturbances as early biomarkers in presymptomatic AD and highlight the potential of CAIs for preserving vascular integrity in the early stages of AD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Uncovered early capillary dysfunction in a presymptomatic Alzheimer's disease (AD) mouse model.</li>\u0000 \u0000 <li>Evidence linking capillary stalls and capillary dysfunction with oxygen delivery issues in AD.</li>\u0000 \u0000 <li>Novel use of carbonic anhydrase inhibitors to prevent early capillary flow disturbances in AD.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 3","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.70023","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143698707","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":"Decreased practice effects in cognitively unimpaired amyloid betapositive individuals: a multicenter, longitudinal, cohort study","authors":"Adrià Tort-Merino,&nbsp;Agnès Pérez-Millan,&nbsp;Neus Falgàs,&nbsp;Sergi Borrego-Écija,&nbsp;Diana Esteller,&nbsp;Bea Bosch,&nbsp;Magdalena Castellví,&nbsp;Jordi Juncà-Parella,&nbsp;Andrea del Val-Guardiola,&nbsp;Guadalupe Fernández-Villullas,&nbsp;Anna Antonell,&nbsp;María Belén Sanchez-Saudinós,&nbsp;Sara Rubio-Guerra,&nbsp;Nuole Zhu,&nbsp;María García-Martínez,&nbsp;Ana Pozueta,&nbsp;Ainara Estanga,&nbsp;Mirian Ecay-Torres,&nbsp;Carolina López de Luis,&nbsp;Mikel Tainta,&nbsp;Miren Altuna,&nbsp;Eloy Rodríguez-Rodríguez,&nbsp;Pascual Sánchez-Juan,&nbsp;Pablo Martínez-Lage,&nbsp;Alberto Lleó,&nbsp;Juan Fortea,&nbsp;Ignacio Illán-Gala,&nbsp;Mircea Balasa,&nbsp;Albert Lladó,&nbsp;Lorena Rami,&nbsp;Raquel Sánchez-Valle","doi":"10.1002/alz.70016","DOIUrl":"https://doi.org/10.1002/alz.70016","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>We aimed to determine whether cognitively unimpaired (CU) amyloid- beta-positive (Aβ+) individuals display decreased practice effects on serial neuropsychological testing.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>We included 209 CU participants from three research centers, 157 Aβ− controls and 52 Aβ+ individuals. Participants underwent neuropsychological assessment at baseline and annually during a 2-year follow-up. We used linear mixed-effects models to analyze cognitive change over time between the two groups, including time from baseline, amyloid status, their interaction, age, sex, and years of education as fixed effects and the intercept and time as random effects.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>The Aβ+ group showed reduced practice effects in verbal learning (β = −1.14, SE = 0.40, <i>p </i>= 0.0046) and memory function (β = −0.56, SE = 0.19, <i>p </i>= 0.0035), as well as in language tasks (β = −0.59, SE = 0.19, <i>p </i>= 0.0027).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>Individuals with normal cognition who are in the Alzheimer's continuum show decreased practice effects over annual neuropsychological testing. Our findings could have implications for the design and interpretation of primary prevention trials.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>This was a multicenter study on practice effects in asymptomatic Aβ+ individuals.</li>\u0000 \u0000 <li>We used LME models to analyze cognitive trajectories across multiple domains.</li>\u0000 \u0000 <li>Practice-effects reductions might be an indicator of subtle cognitive decline.</li>\u0000 \u0000 <li>Implications on clinical and research settings within the AD field are discussed.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 3","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.70016","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699019","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":"Association update","authors":"","doi":"10.1002/alz.14554","DOIUrl":"https://doi.org/10.1002/alz.14554","url":null,"abstract":"&lt;p&gt;Registration is open for the 2025 Tau Global Conference, which brings together three major tau-focused conferences (Global Tau, EuroTau, and CurePSP Neuro) and is hosted by the Alzheimer's Association, CurePSP, and the Rainwater Charitable Foundation. Taking place April 24–25 in London, UK, and online, the Tau Global Conference plays a critical role in bringing together interdisciplinary researchers and perspectives to move tau research forward.&lt;/p&gt;&lt;p&gt;The hybrid conference provides a forum for members of academia, industry, philanthropy, and government to explore tau-related biology, biomarkers, therapeutics, and phenotypes; enhance interdisciplinary collaboration and alignment to address challenges in tau research; and foster talent development and secure funding for the study of tauopathies.&lt;/p&gt;&lt;p&gt;The program aims to provide a deeper understanding of research advancements in tauopathies, including primary tauopathies such as progressive supranuclear palsy (PSP), cortical basal degeneration (CBD), and frontotemporal dementia (FTD), as well as key issues impacting the tau research community.&lt;/p&gt;&lt;p&gt;Questions about the Tau Global Conference may be sent to &lt;span&gt;[email protected]&lt;/span&gt;.&lt;/p&gt;&lt;p&gt;In early December 2024, the bipartisan BOLD Reauthorization Act was signed into law. The bill, which passed unanimously out of Congress, reauthorizes the Building Our Largest Dementia (BOLD) Infrastructure for Alzheimer's Act (P.L.115-406) and will enable public health departments to implement effective dementia interventions.&lt;/p&gt;&lt;p&gt;“In the 5 years since the initial BOLD Act was signed into law, public health departments across the country have been making a real-world impact by successfully implementing effective Alzheimer's interventions, such as increasing early detection and diagnosis and reducing risk,” said Robert Egge, Alzheimer's Impact Movement (AIM) president and Alzheimer's Association chief public policy officer. “Today's reauthorization will build on this progress and expand the law's impact further into communities.”&lt;/p&gt;&lt;p&gt;The BOLD Reauthorization Act was championed by Sens. Susan Collins (R-Maine), Catherine Cortez Masto (D-Nev.), Shelley Moore Capito (R-W. Va.), and Tim Kaine (D-Va.) in the Senate, and Reps. Brett Guthrie (R-Ky.), Paul Tonko (D-N.Y.), Chris Smith (R-N.J.), and Maxine Waters (D-Calif.) in the House.&lt;/p&gt;&lt;p&gt;“We are grateful to the bill's sponsors for their tremendous bipartisan leadership in introducing the bipartisan BOLD Reauthorization Act, and their steadfast commitment to the Alzheimer's and dementia community,” continued Egge.&lt;/p&gt;&lt;p&gt;The BOLD Act has been essential to creating and growing a public health infrastructure for dementia across the country. Through the law, the Centers for Disease Control and Prevention (CDC) has provided funding to state, local, and tribal public health departments to help them improve brain health in their communities. Since 2018, the CDC has made 66 awards to 45 state, local, and tribal publi","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 3","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.14554","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143698709","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":"Blood DNA methylation signature for incident dementia: Evidence from longitudinal cohorts","authors":"Wei Zhang,&nbsp;Juan I. Young,&nbsp;Lissette Gomez,&nbsp;Michael A. Schmidt,&nbsp;David Lukacsovich,&nbsp;Brian W. Kunkle,&nbsp;X. Steven Chen,&nbsp;Eden R. Martin,&nbsp;Lily Wang","doi":"10.1002/alz.14496","DOIUrl":"https://doi.org/10.1002/alz.14496","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Distinguishing between molecular changes that precede dementia onset and those resulting from the disease is challenging with cross-sectional studies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>We studied blood DNA methylation (DNAm) differences and incident dementia in two large longitudinal cohorts: the Offspring cohort of the Framingham Heart Study (FHS) and the Alzheimer's Disease Neuroimaging Initiative (ADNI) study. We analyzed blood DNAm samples from &gt; 1000 cognitively unimpaired subjects.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>Meta-analysis identified 44 CpGs and 44 differentially methylated regions consistently associated with time to dementia in both cohorts. Our integrative analysis identified early processes in dementia, such as immune responses and metabolic dysfunction. Furthermore, we developed a methylation-based risk score, which successfully predicted future cognitive decline in an independent validation set, even after accounting for age, sex, apolipoprotein E ε4, years of education, baseline diagnosis, and baseline Mini-Mental State Examination score.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>DNAm offers a promising source as a biomarker for dementia risk assessment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Blood DNA methylation (DNAm) differences at individual CpGs and differentially methylated regions are significantly associated with incident dementia.</li>\u0000 \u0000 <li>Pathway analysis revealed DNAm differences associated with incident dementia are significantly enriched in biological pathways involved in immune responses and metabolic processes.</li>\u0000 \u0000 <li>Out-of-sample validation analysis demonstrated that a methylation-based risk score successfully predicted future cognitive decline in an independent dataset, even after accounting for age, sex, apolipoprotein E ε4, years of education, baseline diagnosis, and baseline Mini-Mental State Examination score.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 3","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.14496","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143698710","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}