Alzheimer's & Dementia最新文献

{"title":"Dementia in a resource-constrained sub-Saharan African setting: A comprehensive retrospective analysis of prevalence, risk factors, and management at the only neuropsychiatric facility in Northeastern Nigeria","authors":"Ibrahim Abdu Wakawa,&nbsp;Umar Baba Musami,&nbsp;Suleiman Hamidu Kwairanga,&nbsp;Placidus Nwankuba Ogualili,&nbsp;Mohammed Yusuf Mahmood,&nbsp;Muhammad Abba Fugu,&nbsp;Mohammed Mala Gimba,&nbsp;Muktar Mohammed Allamin,&nbsp;Zaharadeen Umar Abbas,&nbsp;Muhammad Kawu Sunkani,&nbsp;Zainab Bukar Yaganami,&nbsp;Fatima Mustapha Kadau,&nbsp;Nasir Muhammad Sani,&nbsp;Peter Danmallam,&nbsp;Luka Nanjul,&nbsp;Larema Babazau,&nbsp;Zaid Muhammad,&nbsp;Baba Waru Goni,&nbsp;Babagana Kundi Machina,&nbsp;Celeste M. Karch,&nbsp;Chinedu Udeh-Momoh,&nbsp;Thomas K. Karikari,&nbsp;Chiadi U. Onyike,&nbsp;Mahmoud Bukar Maina","doi":"10.1002/alz.14538","DOIUrl":"10.1002/alz.14538","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Dementia prevalence is increasing in sub-Saharan Africa, potentially due to population growth and aging. Resource-constrained settings such as Northeastern Nigeria face challenges in dementia management.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>We assessed dementia burden and management at the Federal Neuropsychiatric Hospital Maiduguri, the only neuropsychiatric facility in Northeastern Nigeria. This retrospective analysis included patient records from 1999 to 2023 for individuals 60 year of age and older with a dementia diagnosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>Of the 1216 cases reported, Alzheimer's disease (60.5%) was the most common subtype, followed by vascular dementia (24.5%). Hypertension (41.6%) was the most frequent comorbidity. Memory loss was present in all cases, whereas behavioral symptoms like agitation presented in some cases. Treatments included cognitive enhancers (donepezil), supplements (gingko biloba), and non-drug therapies (psychoeducation).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>The increasing burden of dementia at this sole facility highlights the urgent need for targeted interventions and further research to understand the underlying factors contributing to dementia in this population.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Dementia trends and management in a neuropsychiatric facility serving over 26 million people in Northeastern Nigeria.</li>\u0000 \u0000 <li>Alzheimer's disease accounted for 60.5% of the dementia cases reported, with hypertension as the leading comorbidity.</li>\u0000 \u0000 <li>There is an urgent need for improved diagnostic tools and health care infrastructure to address dementia in resource-constrained settings.</li>\u0000 \u0000 <li>The findings lay the foundation for developing a dementia cohort as part of the Northern Nigeria Dementia Research Group.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 3","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.14538","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143660312","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":"Fibrillar tau alters cerebral endothelial cell metabolism, vascular inflammatory activation, and barrier function in vitro and in vivo","authors":"Roberto Guzmán-Hernández,&nbsp;Silvia Fossati","doi":"10.1002/alz.70077","DOIUrl":"10.1002/alz.70077","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>The presence of tau aggregates in and around the brain vasculature in Alzheimer's disease (AD) and tauopathies suggests its possible pathogenicity to cerebral endothelial cells (ECs).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>We used an in vitro model of the blood–brain barrier (BBB) to understand the mechanisms of fibrillar tau–mediated cerebral EC and BBB pathology, confirming our findings in 3-month-old P301S mice brains and extracted microvessels.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>Protofibrillar and fibrillar tau species induce endothelial barrier permeability through an increase in glycolysis, which activates ECs toward a pro-inflammatory phenotype, inducing loss of junction protein expression and localization. The Warburg-like metabolic shift toward glycolysis and increased vascular pathological phenotypes are also present in young P301S mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>In sum, our work reveals that fibrillar tau species, by enhancing endothelial glycolytic metabolism, promote vascular inflammatory phenotypes and loss of BBB function, highlighting the importance of addressing and targeting early tau-mediated neurovascular damage in AD and tauopathies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>We improve the understanding of the mechanisms of vascular pathology in tauopathies.</li>\u0000 \u0000 <li>Fibrillar tau mediates vascular metabolic changes, inflammation, and blood–brain barrier (BBB) dysfunction.</li>\u0000 \u0000 <li>These events are replicated at early stages in a tauopathy mouse model.</li>\u0000 \u0000 <li>Inhibiting altered glycolysis reduces BBB permeability and endothelial activation.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 3","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.70077","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143660621","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 of neighborhood disadvantage with cognitive function and cortical disorganization in an unimpaired cohort: An exploratory study","authors":"Apoorva Safai,&nbsp;William R Buckingham,&nbsp;Erin M Jonaitis,&nbsp;Rebecca E Langhough,&nbsp;Sterling C. Johnson,&nbsp;W. Ryan Powell,&nbsp;Amy J. Kind,&nbsp;Barbara B. Bendlin,&nbsp;Pallavi Tiwari","doi":"10.1002/alz.70095","DOIUrl":"10.1002/alz.70095","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;Neighborhood disadvantage has been shown to impact health and cognitive outcomes, while morphological similarity network (MSN) can elucidate structural morphological patterns underlying cognitive functions. We hypothesized MSNs could provide cortical patterns linked with neighborhood disadvantage and cognitive function, explaining the potential risk of cognitive impairment in disadvantaged neighborhoods.&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;For cognitively unimpaired participants from the Wisconsin Alzheimer's Disease Research Center or Wisconsin Registry for Alzheimer's Prevention (&lt;i&gt;n&lt;/i&gt; = 524), and the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort (&lt;i&gt;n&lt;/i&gt; = 100), neighborhood disadvantage was obtained using Area Deprivation Index (ADI) and its association with cognitive performance and MSN features was analyzed using linear regression and mediation analysis.&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;Neighborhood disadvantage was associated with worse cognitive performance on memory, executive function, processing speed, and preclinical Alzheimer's tests on both datasets. Local morphological organization of predominantly the frontal and temporal regions showed association trends with ADI.&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;Morphological patterns associated with ADI, in-part, may explain the risk for poor cognitive functioning in a neighborhood disadvantaged population.&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;Social determinants of health such as neighborhood context can be studied using ADI.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;High neighborhood disadvantage was related to worse performance on category fluency, implicit learning speed, story recall memory and pre-clinical Alzheimer's cognitive composite.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;In this exploratory study, using morphological brain networks that indicate similarity in distribution of cortical thickness between regions, we observed that centrality of predominantly frontal and temporal regions was marginally linked with neighborhood disadvantage status and also partially mediated its association with preclinical Alzheimer's composite test.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;There is a potential role for considering neighborhood status in early screening of cognitive impairment ","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 3","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.70095","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143660306","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":"Distinct medical and substance use histories associate with cognitive decline in Alzheimer's disease","authors":"Clayton Mansel,&nbsp;Diego R. Mazzotti,&nbsp;Ryan Townley,&nbsp;Mihaela E. Sardiu,&nbsp;Russell H. Swerdlow,&nbsp;Robyn A. Honea,&nbsp;Olivia J. Veatch","doi":"10.1002/alz.70017","DOIUrl":"10.1002/alz.70017","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Phenotype clustering reduces patient heterogeneity and could be useful when designing precision clinical trials. We hypothesized that the onset of early cognitive decline in patients would exhibit variance predicated on the clinical history documented prior to an Alzheimer's disease (AD) diagnosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>Self-reported medical and substance use history (i.e., problem history) was used to cluster participants from the National Alzheimer's Coordinating Center (NACC) into distinct subtypes. Linear mixed effects modeling was used to determine the effect of problem history subtype on cognitive decline over 2 years.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>Two thousand seven hundred fifty-four individuals were partitioned into three subtypes: minimal (<i>n</i> = 1380), substance use (<i>n</i> = 1038), and cardiovascular (<i>n</i> = 336). The cardiovascular problem history subtype had significantly worse cognitive decline over a 2 year follow-up period (<i>p</i> = 0.013).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>Our study highlights the need to account for problem history to reduce heterogeneity of outcomes in AD clinical trials.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Clinical data were used to identify subtypes of patients with Alzheimer's disease (AD) in the National Alzheimer's Coordinating Center dataset.</li>\u0000 \u0000 <li>Three problem history subtypes were found: minimal, substance use, and cardiovascular.</li>\u0000 \u0000 <li>The mean change in Clinical Dementia Rating Sum of Boxes (CDR-SB) was assessed over a 2 year follow-up.</li>\u0000 \u0000 <li>The cardiovascular subtype was associated with the worst cognitive decline.</li>\u0000 \u0000 <li>The magnitude of change in CDR-SB was similar to recent AD clinical trials.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 3","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.70017","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143660324","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":"The impact of arteriolosclerosis on cognitive impairment in decedents without severe dementia from the National Alzheimer's Coordinating Center","authors":"Cellas A. Hayes,&nbsp;Christina B. Young,&nbsp;Carla Abdelnour,&nbsp;Alexis Reeves,&nbsp;Michelle C. Odden,&nbsp;Jeffrey Nirschl,&nbsp;Paul K. Crane,&nbsp;Kathleen L. Poston,&nbsp;Elizabeth C. Mormino,&nbsp;Kyan Younes","doi":"10.1002/alz.70059","DOIUrl":"10.1002/alz.70059","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Alzheimer's disease neuropathologic change (ADNC), Lewy body disease (LBD), and vascular neuropathologies occur together. Previous studies have been limited by a large majority of participants with severe dementia or advanced stages of pathologies, which limits the detectability of cognitive effects from vascular neuropathologies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>Using neuropathology data from the National Alzheimer's Coordinating Center, we examined the association of vascular neuropathologies with cognitive scores in participants without severe dementia (<i>N</i> = 1526) using multivariable linear regression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>Controlling for age, sex, education, LBD, and ADNC, arteriolosclerosis was associated with lower memory (<i>β</i> = −0.16 ± 0.06, <i>p</i> &lt; 0.001), executive function (<i>β</i> = −0.25 ± 0.05, <i>p</i> &lt; 0.001), and language scores (<i>β</i> = −0.20 ± 0.05, <i>p</i> &lt; 0.001). The effects of arteriolosclerosis remained when controlling for vascular risk factors.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>Vascular neuropathologies exhibit distinct relationships with cognition. Arteriolosclerosis is an independent contributor to cognition. Further research should be conducted on whether arteriolosclerosis can serve as a surrogate marker for cognitive decline in early disease stages.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>In individuals who do not have severe dementia, vascular neuropathologies are common, and the combination of pathologies is heterogeneous in a convenience sample from the Alzheimer's Disease Research Center that reported all the neuropathology data elements for this investigation.</li>\u0000 \u0000 <li>Arteriolosclerosis is associated with several cognitive domain scores, including memory, executive function, and language when controlling for the effects of Alzheimer's disease neuropathologic change and Lewy body disease.</li>\u0000 \u0000 <li>These results reinforce the importance of vascular pathology for cognition among people along the Alzheimer's disease spectrum.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 3","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.70059","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143660543","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":"Connectome-based predictive modeling of brain pathology and cognition in autosomal dominant Alzheimer's disease","authors":"Vaibhav Tripathi,&nbsp;Joshua Fox-Fuller,&nbsp;Vincent Malotaux,&nbsp;Ana Baena,&nbsp;Nikole Bonillas Felix,&nbsp;Sergio Alvarez,&nbsp;David Aguillon,&nbsp;Francisco Lopera,&nbsp;David C. Somers,&nbsp;Yakeel T. Quiroz","doi":"10.1002/alz.70061","DOIUrl":"10.1002/alz.70061","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Autosomal dominant Alzheimer's disease (ADAD) through genetic mutations can result in near complete expression of the disease. Tracking AD pathology development in an ADAD cohort of Presenilin-1 (<i>PSEN1)</i> E280A carriers’ mutation has allowed us to observe incipient tau tangles accumulation as early as 6 years prior to symptom onset.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>Resting-state functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) scans were acquired in a group of <i>PSEN1</i> carriers (<i>n</i> = 32) and non-carrier family members (<i>n</i> = 35). We applied connectome-based predictive modeling (CPM) to examine the relationship between the participant's functional connectome and their respective tau/amyloid-β levels and cognitive scores (word list recall).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>CPM models strongly predicted tau concentrations and cognitive scores within the carrier group. The connectivity patterns between the temporal cortex, default mode network, and other memory networks were the most informative of tau burden.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>These results indicate that resting-state functional magnetic resonance imaging (fMRI) methods can complement PET methods in early detection and monitoring of disease progression in ADAD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Connectivity-based predictive modeling of tau and amyloid-β in ADAD carriers.</li>\u0000 \u0000 <li>Strong predictions for tau deposition; weaker predictions for amyloid-β.</li>\u0000 \u0000 <li>Cognitive scores for memory and mental state are predicted strongly.</li>\u0000 \u0000 <li>Connectivity between IPL, DAN, DMN, temporal cortex most predictive.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 3","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.70061","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143660602","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":"Marital status and risk of dementia over 18 years: Surprising findings from the National Alzheimer's Coordinating Center","authors":"Selin Karakose,&nbsp;Martina Luchetti,&nbsp;Yannick Stephan,&nbsp;Angelina R. Sutin,&nbsp;Antonio Terracciano","doi":"10.1002/alz.70072","DOIUrl":"10.1002/alz.70072","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;Marital status is a potential risk/protective factor for adverse health outcomes. This study tested whether marital status was associated with dementia risk in older adults.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; METHODS&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Participants (&lt;i&gt;N&lt;/i&gt; = 24,107; Mean&lt;sub&gt;age &lt;/sub&gt;= 71.79) were from the National Alzheimer's Coordinating Center. Cox regressions tested the association between baseline marital status and clinically ascertained dementia over up to 18 years of follow-up.&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;Compared to married participants, widowed (hazard ratio [HR] = 0.73, 95% confidence interval [95% CI] = 0.67–0.79), divorced (HR = 0.66, 95% CI = 0.59–0.73), and never-married participants (HR = 0.60, 95% CI = 0.52–0.71) were at lower dementia risk, including for Alzheimer's disease and Lewy body dementia. The associations for divorced and never married remained significant accounting for demographic, behavioral, clinical, genetic, referral source, participation, and diagnostic factors. The associations were slightly stronger among professional referrals, males, and relatively younger participants.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; DISCUSSION&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Unmarried individuals may have a lower risk of dementia compared to married adults. The findings could indicate delayed diagnoses among unmarried individuals or challenge the assumption that marriage protects against dementia.&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;Widowed, divorced, and never-married older adults had a lower dementia risk, compared to their married counterparts.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Unmarried older adults were also at a lower risk of Alzheimer's disease and Lewy body dementia, with a pattern of mixed findings for frontotemporal lobar degeneration, and no associations with risk of vascular dementia or mild cognitive impairment.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;All unmarried groups were at a lower risk of progression from mild cognitive impairment to dementia.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;There was some evidence of moderation by age, sex, and referral source. However, stratified analyses showed small differences between groups, and most interactions were not significant, suggesting that the role of marital status in dementia tends to be similar across individuals at different levels","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 3","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.70072","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143660620","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":"Tau degradation in Alzheimer's disease: Mechanisms and therapeutic opportunities","authors":"Lisha Wang,&nbsp;Banesh Sooram,&nbsp;Rajnish Kumar,&nbsp;Sophia Schedin-Weiss,&nbsp;Lars O. Tjernberg,&nbsp;Bengt Winblad","doi":"10.1002/alz.70048","DOIUrl":"10.1002/alz.70048","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>In Alzheimer's disease (AD), tau undergoes abnormal post-translational modifications and aggregations. Impaired intracellular degradation pathways further exacerbate the accumulation of pathological tau. A new strategy – targeted protein degradation – recently emerged as a modality in drug discovery where bifunctional molecules bring the target protein close to the degradation machinery to promote clearance. Since 2016, this strategy has been applied to tau pathologies and attracted broad interest in academia and the pharmaceutical industry. However, a systematic review of recent studies on tau degradation mechanisms is lacking. Here we review tau degradation mechanisms (the ubiquitin–proteasome system and the autophagy–lysosome pathway), their dysfunction in AD, and tau-targeted degraders, such as proteolysis-targeting chimeras and autophagy-targeting chimeras. We emphasize the need for a continuous exploration of tau degradation mechanisms and provide a future perspective for developing tau-targeted degraders, encouraging researchers to work on new treatment options for AD patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Post-translational modifications, aggregation, and mutations affect tau degradation.</li>\u0000 \u0000 <li>A vicious circle exists between impaired degradation pathways and tau pathologies.</li>\u0000 \u0000 <li>Ubiquitin plays an important role in complex degradation pathways.</li>\u0000 \u0000 <li>Tau-targeted degraders provide promising strategies for novel AD treatment.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 3","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.70048","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143660319","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":"Mediterranean vs. Western diet effects on the primate cerebral cortical pre-synaptic proteome: Relationships with the transcriptome and multi-system phenotypes","authors":"Eloise Berson,&nbsp;Brett M. Frye,&nbsp;Chandresh R. Gajera,&nbsp;Geetha Saarunya,&nbsp;Amalia Perna,&nbsp;Thanaphong Phongpreecha,&nbsp;Sayane Shome,&nbsp;Jacob D. Negrey,&nbsp;Nima Aghaeepour,&nbsp;Thomas J. Montine,&nbsp;Suzanne Craft,&nbsp;Thomas C. Register,&nbsp;Carol A. Shively","doi":"10.1002/alz.70041","DOIUrl":"10.1002/alz.70041","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Diet quality mediates aging-related risks of cognitive decline, neurodegeneration, and Alzheimer's disease (AD) through poorly defined mechanisms.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>The effects of diet on the presynaptic proteome of the temporal cortex were assessed in 36 female cynomolgus macaques randomized to Mediterranean or Western diets for 31 months. Associations between the presynaptic proteome, determined by synaptometry by time-of-flight (SynTOF) mass spectrometry, adjacent cortex transcriptome, and multi-system phenotypes were assessed using a machine learning approach.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>Six presynaptic proteins (DAT, Aβ42, calreticulin, LC3B, K48-Ubiquitin, SLC6A8) were elevated in the presynaptic proteome in Mediterranean diet consumers (<i>p</i> &lt; 0.05). Transcriptomic data and multi-system phenotypes significantly predicted SynTOF markers. Selected SynTOF markers were correlated with changes in white matter volumes, hepatosteatosis, and behavioral and physiological measures of psychosocial stress.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>These observations demonstrate that diet composition drives cortical presynaptic protein composition, that transcriptional profiles strongly predict the presynaptic proteomic profile, and that presynaptic proteins were closely associated with peripheral metabolism, stress responsivity, neuroanatomy, and socio-emotional behavior.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Mediterranean and Western diets differentially altered the cortical presynaptic proteome, which is strongly associated with neurodegeneration and cognitive decline.</li>\u0000 \u0000 <li>Presynaptic proteomic markers were predicted by transcriptomic profiles in the adjacent cortex, and by multi-system anatomical, physiologic, and behavioral phenotypes.</li>\u0000 \u0000 <li>The data demonstrate that brain phenotypes and brain-body interactions are influenced by common dietary patterns, suggesting that improving diet quality may be an effective means to maintain brain health.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 3","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.70041","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143660320","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":"HDAC11 displays neuropathological alterations and offers as a novel drug target for Alzheimer's disease","authors":"Ping Bai,&nbsp;Prasenjit Mondal,&nbsp;Yan Liu,&nbsp;Ashley Gomm,&nbsp;Claire Suen,&nbsp;Liuyue Yang,&nbsp;Biyue Zhu,&nbsp;Haoqi Sun,&nbsp;Chongzhao Ran,&nbsp;Shiqian Shen,&nbsp;Rudolph E. Tanzi,&nbsp;Can Zhang,&nbsp;Changning Wang","doi":"10.1002/alz.14616","DOIUrl":"10.1002/alz.14616","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Alzheimer's disease (AD) is characterized by amyloid pathology and neuroinflammation, leading to cognitive decline. Targeting histone deacetylase-11 (HDAC11) offers a novel therapeutic strategy due to its role in immune regulation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>We conducted neuropathological analyses on human AD <i>post mortem</i> brain tissues and 5xFAD transgenic mice. We developed PB94, a brain-permeable HDAC11-selective inhibitor, and assessed its effects using live-animal imaging and behavioral studies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>HDAC11 was significantly upregulated in AD brains, correlating with amyloid pathology and neuroinflammatory markers. PB94 treatment reduced amyloid burden and neuroinflammation, improving cognitive function in 5xFAD mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>Our findings highlight HDAC11 as a promising drug target for AD. PB94's ability to reduce amyloid pathology and neuroinflammation suggests its potential as an effective therapeutic. This study supports further exploration of HDAC11 inhibition as a treatment strategy for AD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Histone deacetylase-11 (HDAC11) is significantly upregulated in Alzheimer's disease (AD) brains and colocalizes with amyloid pathology and neuroinflammatory markers.</li>\u0000 \u0000 <li>Novel brain-permeable HDAC11-selective inhibitor PB94 demonstrates promising therapeutic potential for AD treatment.</li>\u0000 \u0000 <li>PB94 treatment reduces amyloid burden and neuroinflammation in AD mouse models, confirmed by live imaging studies.</li>\u0000 \u0000 <li>HDAC11 inhibition enhances microglial phagocytosis of amyloid beta proteins and modulates inflammatory cytokine levels.</li>\u0000 \u0000 <li>PB94 treatment improves cognitive function in AD mouse models while showing favorable brain penetration and selectivity.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 3","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.14616","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143660317","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}