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The influence of midlife morbidity clusters on dementia risk: The ARIC study 中年发病群对痴呆风险的影响:ARIC研究
IF 11.1 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2026-02-09 DOI: 10.1002/alz.71110
Elise Kinyanjui, Renee C. Groechel, Valerie Morrill, Keenan A. Walker, Anna M. Kucharska-Newton, Thomas H. Mosley, Silvia Koton, David S. Knopman, Jordan Weiss, Rebecca F. Gottesman, Marco Egle

INTRODUCTION

Understanding comorbidities’ combined impacts on dementia risk may offer a more comprehensive understanding of individuals’ risk. Using machine-learning, we grouped individuals with similar midlife risk profiles into clusters and explored associations with dementia risk.

METHODS

Participants without dementia at baseline (1987–1989) from the prospective Atherosclerosis Risk in Communities (ARIC) study were included (ages 45–64 years; N = 15,250). Using unsupervised hierarchical cluster analysis, nine clusters were created and defined based on 14 midlife morbidities. The associations with incident dementia (N = 3272 cases, median follow-up 25 years) and deaths (N = 9099) were evaluated using time-to-event regression models.

RESULTS

Compared with the healthiest cluster (Cluster 1), Clusters 2 (smoking) (hazard ratio [HR](95% confidence interval [CI]) = 1.62 (1.08, 2.43)), 5 (obesity, diabetes, hypertension, and hypertriglyceridemia) (HR(95%CI) = 1.91 (1.35,2.70)), and 7/8 (atrial fibrillation/heart failure) (HR(95%CI) = 2.69 (1.59,4.57)) were associated with dementia. Accounting for competing risk of death in the Fine-Gray subdistribution model negated the cluster-dementia association.

DISCUSSION

Midlife morbidity clusters are important for dementia and mortality risk.

了解合并症对痴呆风险的综合影响可以更全面地了解个体的风险。使用机器学习,我们将具有相似中年风险概况的个体分组,并探索与痴呆风险的关联。
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引用次数: 0
Community perspectives on epigenetic dementia risk testing: Willingness, implementation preferences, and reasons for not testing in midlife and older adults 社区对表观遗传痴呆风险检测的看法:在中年和老年人中不进行检测的意愿、实施偏好和原因
IF 14 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2026-02-06 DOI: 10.1002/alz.71094
Deirdre M. O'Shea, Devi Dhanekula, Swati Kumar, Lily Wang, Lisa Wiese, Tatjana Rundek, James E. Galvin
INTRODUCTION Epigenetic assays may support non‐invasive dementia risk stratification; community views on willingness and implementation remain under‐characterized. METHODS In a survey of 425 adults ≥50 years old, we assessed the willingness for a hypothetical epigenetic test, implementation preferences, reactions to a high‐risk result, behavior‐change intentions, and reasons for not testing using multivariable models. RESULTS Overall, 82.1% showed a willingness. Health literacy (odds ratio [OR] = 2.61) and Alzheimer's disease (AD) concern (OR = 2.06) increased that willingness; doctor dependence decreased it (OR = 0.62). The top drivers were perceived to be accuracy and speed. The preferred modality was a combination of biomarker and cognitive over biomarker‐only. Intended changes prioritized alcohol reduction, then diet, exercise, cognitive activity. Risk worry and insurance concerns exceeded stigma; higher literacy related to lower stigma, and epigenetics familiarity and AD worry related to higher insurance concern. The reasons for not testing were data privacy/accuracy concerns, logistics/costs, and needles. DISCUSSION Findings support emphasizing test accuracy, turnaround, and governance/legal information when implementing DNAm testing for dementia risk.
表观遗传学分析可能支持非侵入性痴呆风险分层;社区对意愿和实施的看法仍不明确。方法在一项对425名≥50岁的成年人的调查中,我们评估了假设表观遗传测试的意愿、实施偏好、对高风险结果的反应、行为改变意图以及不使用多变量模型进行测试的原因。结果总体而言,82.1%的受访者表示愿意。健康素养(比值比[OR] = 2.61)和对阿尔茨海默病(AD)的关注(OR = 2.06)增加了这种意愿;对医生的依赖使其降低(OR = 0.62)。人们认为最重要的驱动因素是准确性和速度。首选的方式是生物标志物和认知的结合,而不是仅仅生物标志物。预期的改变首先是减少饮酒,然后是饮食、锻炼和认知活动。风险担忧和保险担忧超过了耻辱;较高的文化素养与较低的耻辱感有关,而表观遗传学熟悉度和阿尔茨海默病担忧与较高的保险担忧有关。不测试的原因是数据隐私/准确性问题、物流/成本和针头。研究结果支持在实施痴呆症风险的DNAm测试时强调测试准确性、周转时间和治理/法律信息。
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引用次数: 0
Proteomics reveals three molecular subtypes of Alzheimer's disease with distinct progression patterns 蛋白质组学揭示了阿尔茨海默病具有不同进展模式的三种分子亚型
IF 14 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2026-02-06 DOI: 10.1002/alz.71106
Xiao-He Hou, Wei Zhang, Kairan Kang, Yifei Jin, Peng Ren, Linbo Wang, Zeyu Li, Yuzhu Li, Jia You, Bei Zhang, Qing Ma, , Fang Xie, Jin-Tai Yu, Jian-Feng Feng, Wei Cheng
Alzheimer's disease (AD) shows marked molecular heterogeneity. Defining biological subtypes may refine diagnosis and treatment.
阿尔茨海默病(AD)表现出明显的分子异质性。确定生物学亚型可以改善诊断和治疗。
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引用次数: 0
Correction to “The microbiota-gut-brain axis in mild cognitive impairment and Alzheimer's disease: A scoping review of human studies” 更正“轻度认知障碍和阿尔茨海默病中的微生物-肠道-脑轴:对人类研究的范围审查”。
IF 11.1 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2026-02-06 DOI: 10.1002/alz.71221

Warren A, Wynia Z, Corr PG, et al. The microbiota-gut-brain axis in mild cognitive impairment and Alzheimer's disease: A scoping review of human studies. Alzheimers Dement. 2026;22(1):e71023. doi:10.1002/alz.71023

The online version and final PDF have italicized phyla-level taxa in the Abstract and Highlights, which should not be italicized: Pseudomonadota and Actinomycetota.

We apologize for this error.

Warren A, Wynia Z, Corr PG,等。轻度认知障碍和阿尔茨海默病中的微生物-肠-脑轴:对人类研究的范围回顾。阿尔茨海默病杂志,2016;22(1):71023。doi: 10.1002 / alz。71023在线版本和最终PDF在摘要和概要中已斜体化门级分类群,不应斜体化:假单胞菌和放线菌。我们为这个错误道歉。
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引用次数: 0
Spatial heterogeneity in microglia-complement crosstalk: Implications for synaptic pruning in Alzheimer's disease 小胶质-补体串扰的空间异质性:阿尔茨海默病突触修剪的含义
IF 11.1 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2026-02-05 DOI: 10.1002/alz.71185
Qiuyan Ye, Wei Gao, Jiaping Feng, Xue Li, Jianhui Li, Fengge Yang, Linqing Li, Mingsheng Zi, Xinkai Wu, Hainan Gao, Honglin Li

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by synaptic loss, as a key pathological feature in its early stages. Recent studies have highlighted the central role of microglia–complement interactions in synaptic pruning. This interaction exhibits significant spatial heterogeneity in AD, with activation patterns and functional manifestations varying across different brain regions and stages of disease. Therefore, this article systematically reviews the synergistic mechanisms of microglia and the complement system in physiological synaptic pruning. Additionally, the dynamic evolution of the complement–immune network during disease progression is analyzed, and the amplifying effect of genetic factors on the spatial heterogeneity of synaptic pruning is explored. Furthermore, current treatment strategies from both Western medicine and traditional Chinese medicine are discussed, emphasizing the potential value of combining these approaches for intervening in synaptic loss in AD.

阿尔茨海默病(AD)是一种以突触丧失为特征的神经退行性疾病,是其早期的一个关键病理特征。最近的研究强调了小胶质细胞-补体相互作用在突触修剪中的核心作用。这种相互作用在阿尔茨海默病中表现出显著的空间异质性,在不同的大脑区域和疾病阶段,激活模式和功能表现各不相同。因此,本文就小胶质细胞与补体系统在生理突触修剪中的协同作用机制作一系统综述。此外,还分析了补体-免疫网络在疾病进展过程中的动态演化,并探讨了遗传因素对突触修剪空间异质性的放大效应。此外,本文还讨论了目前西医和中医的治疗策略,强调了结合这些方法干预阿尔茨海默病突触丧失的潜在价值。
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引用次数: 0
Generation and characterization of iPSC-derived microglia for in vitro modeling of stimuli-specific neuroimmune responses ipsc衍生的小胶质细胞的生成和表征用于刺激特异性神经免疫反应的体外建模。
IF 11.1 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2026-02-04 DOI: 10.1002/alz.71117
Angela K. Haskell, Joshua A. Kulas, William E. Carter, June Javens-Wolfe, Raven Dance Hinkel, Mustapha Moussaif, Jacob S. Smiley, Olivia Lazaro, Sylvia Robertson, Alan D. Palkowitz, Bruce T. Lamb, Timothy I. Richardson, Jeffrey L. Dage, Shaoyou Chu, Travis Johnson, Louis F. Stancato, Abdul Qadir Syed

INTRODUCTION

Microglia are macrophage-like brain resident immune cells known to express numerous Alzheimer's disease risk genes. Here we generated a human induced pluripotent stem cell (iPSC) derived microglia cell culture model for use in neuroimmune modeling and therapeutic testing.

METHODS

We generated iPSC lines using episomal reprogramming for subsequent stepwise differentiation of iPSC-derived microglia (iMG) without commercial kits. We characterized the responses of this model to immunogenic stimuli and recombinant TREM2 antibodies.

RESULTS

The iMG expressed several key microglia signature genes and are morphologically and transcriptionally dynamic. iMG rapidly phagocytosed myelin debris and strongly changed expression of lipid homeostasis genes. iMG expressed TREM2 and increased TREM2 levels in response to IL-4. Recombinant TREM2 antibody treatment impaired iMG myelin phagocytosis and upregulated chemokines.

DISCUSSION

We validated our iMG model system for the evaluation of biological responses of human microglia-like cells to stimuli and pharmacological agents for their transcriptional and functional impacts.

小胶质细胞是巨噬细胞样的大脑常驻免疫细胞,已知表达许多阿尔茨海默病风险基因。在这里,我们建立了一个人类诱导多能干细胞(iPSC)衍生的小胶质细胞培养模型,用于神经免疫建模和治疗试验。方法:我们使用episomal重编程生成iPSC系,用于iPSC衍生的小胶质细胞(iMG)的后续逐步分化,没有商业试剂盒。我们描述了该模型对免疫原性刺激和重组TREM2抗体的反应。结果:iMG表达了几个关键的小胶质细胞特征基因,并且在形态和转录上是动态的。iMG迅速吞噬髓磷脂碎片并强烈改变脂质稳态基因的表达。iMG表达TREM2,并增加TREM2水平响应IL-4。重组TREM2抗体治疗损伤iMG髓磷脂吞噬和上调趋化因子。讨论:我们验证了我们的iMG模型系统,用于评估人类小胶质样细胞对刺激和药物的生物学反应,以及它们的转录和功能影响。
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引用次数: 0
Temporal dynamics of white matter hyperintensities related to Alzheimer's disease in adults with Down syndrome 成年唐氏综合症患者与阿尔茨海默病相关的白质高强度的时间动态
IF 11.1 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2026-02-04 DOI: 10.1002/alz.71157
Alejandra O. Morcillo-Nieto, Mateus Rozalem-Aranha, Lucia Maure-Blesa, Íñigo Rodríguez-Baz, José Enrique Arriola-Infante, Maria Franquesa-Mullerat, Sara E. Zsadanyi, Lídia Vaqué-Alcázar, José Allende Parra, Zili Zhao, Javier Arranz, Laura Videla, Isabel Barroeta, Laura Del Hoyo Soriano, Bessy Benejam, Susana Fernández, Aida Sanjuan Hernandez, Lucia Pertierra, Sandra Giménez, Daniel Alcolea, Olivia Belbin, Alberto Lleó, María Carmona-Iragui, Juan Fortea, Alexandre Bejanin

INTRODUCTION

White matter hyperintensities (WMH) are common in Down syndrome (DS), yet their longitudinal evolution and associations with Alzheimer's disease (AD) remain unclear.

METHODS

Longitudinal MRI study, including 80 DS adults and 53 euploid controls. WMH were segmented on serial FLAIR using a longitudinal pipeline. We assessed the effects of demographic, genetic factors, AD clinical stage, AD-related fluid, and cerebrovascular biomarkers on annual WMH volume changes.

RESULTS

In DS, annual WMH changes were relatively stable until age 40, and then exhibited fluctuations, with a significant decrease at the group level. Declines were larger in symptomatic cases, particularly in periventricular and fronto-parieto-occipital regions. Higher baseline WMH and microbleeds presence related to greater WMH reduction. Visual ratings and adjustment for white matter volume supported the robustness of the results.

DISCUSSION

WMH trajectories were heterogeneous in DS and declined over time with AD symptoms. This unexpected reduction may reflect different underlying pathological processes, including neurodegeneration or neuroinflammation.

白质高强度(WMH)在唐氏综合征(DS)中很常见,但其纵向进化及其与阿尔茨海默病(AD)的关系尚不清楚。方法:纵向MRI研究,包括80名DS成人和53名整倍体对照。使用纵向管道在串行FLAIR上对WMH进行分段。我们评估了人口统计学、遗传因素、阿尔茨海默病临床分期、阿尔茨海默病相关液体和脑血管生物标志物对年WMH体积变化的影响。结果:DS患者在40岁之前,WMH的年变化相对稳定,之后出现波动,在组水平上明显下降。在有症状的病例中下降更大,特别是在脑室周围和额顶枕区。较高的基线WMH和微出血的存在与更大的WMH降低有关。视觉评分和白质体积的调整支持了结果的稳健性。讨论:WMH轨迹在退行性椎体滑移中是异质的,并且随着时间的推移随着AD症状而下降。这种意想不到的减少可能反映了不同的潜在病理过程,包括神经变性或神经炎症。
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引用次数: 0
Care preferences for persons with cognitive impairment: A discrete choice experiment 认知障碍患者的护理偏好:一个离散选择实验。
IF 11.1 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2026-02-03 DOI: 10.1002/alz.71107
Dean A. Regier, Jean O. Taylor, Astoria Ho, Soo Borson, Anne M. Turner

INTRODUCTION

Evidence is limited on preferences of persons with cognitive decline and their care partners (CPs) regarding care. Our aim was to identify preferences and preference evolution for transitions in supportive care.

METHODS

We conducted a discrete choice experiment (DCE) (repeated measures baseline, 6-months) with older adults with mild cognitive impairment or mild to moderate dementia and CPs. Tasks were anchored to health states describing progressive memory and function decline. Split-sample mixed logit models estimated part-worth utilities.

RESULTS

Baseline DCEs were completed by 131 cognitively impaired older adults and 137 CPs; 118 and 132 completed 6-month DCEs. At both timepoints, respondents preferred in-home care with moderate support when considering moderate or severe cognitive impairment. As impairment worsened, the acceptability of assisted living increased, especially among CPs.

DISCUSSION

Persons with cognitive decline engaged in future-oriented decisions. Preferences were stable across time for both samples, and assisted living was more acceptable for CPs.

关于认知衰退患者及其护理伙伴(CPs)对护理的偏好的证据有限。我们的目的是确定支持治疗过渡的偏好和偏好演变。方法:我们对患有轻度认知障碍或轻中度痴呆和CPs的老年人进行了离散选择实验(DCE)(重复测量基线,6个月)。任务被固定在描述渐进记忆和功能衰退的健康状态上。分样本混合logit模型估计部分价值公用事业。结果:131名认知障碍老年人和137名CPs完成了基线dce;118和132完成了6个月的dce。在这两个时间点,当考虑到中度或重度认知障碍时,受访者更倾向于有中等支持的家庭护理。随着损伤的恶化,辅助生活的可接受性增加,特别是在CPs中。讨论:认知能力下降的人从事面向未来的决策。随着时间的推移,两个样本的偏好都是稳定的,CPs更容易接受辅助生活。
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引用次数: 0
An MRI-based macro- and microstructural neuroimaging-wide association study of subsequent cognitive impairment 一项基于mri的宏观和微观结构神经成像与继发性认知障碍的关联研究。
IF 11.1 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2026-02-03 DOI: 10.1002/alz.71135
Tugce Duran, Murat Bilgel, Yang An, Sridhar Kandala, Christos Davatzikos, Bennett A. Landman, Guray Erus, Abhay Moghekar, Luigi Ferrucci, Keenan A. Walker, Susan M. Resnick

INTRODUCTION

This study longitudinally examined 154 magnetic resonance imaging (MRI) biomarkers in cognitively normal (CN) individuals to identify structural brain changes most strongly associated with subsequent cognitive impairment (SI).

METHODS

We analyzed 509 Baltimore Longitudinal Study of Aging participants (age ≥ 50, CN at baseline) with longitudinal cognitive and 3T MRI (T1/T2-weighted scans and diffusion tensor imaging) data. MRI biomarker associations with SI status were analyzed, adjusting for confounders and stratifying by sex and amyloid beta (Aβ) status.

RESULTS

Participants who developed SI over 4.6 years’ follow-up showed greater longitudinal changes in white matter (WM) integrity, particularly in the corpus callosum, cingulum bundle, and inferior fronto-occipital fasciculus, compared to CN-stable. To a lesser degree, we also observed temporal thinning and atrophy linked to SI. These associations were amplified among males and amyloid-positive individuals.

DISCUSSION

Longitudinal alterations in WM microstructural integrity were most strongly associated with future impairment, highlighting the importance of early WM changes in the development of MCI and dementia.

本研究纵向检查了154个认知正常(CN)个体的磁共振成像(MRI)生物标志物,以确定与随后的认知障碍(SI)最密切相关的脑结构变化。方法:我们分析了509名巴尔的摩纵向研究老年参与者(年龄≥50岁,基线时CN)的纵向认知和3T MRI (T1/ t2加权扫描和扩散张量成像)数据。分析MRI生物标志物与SI状态的关联,调整混杂因素并按性别和β淀粉样蛋白(Aβ)状态分层。结果:在4.6年的随访中,发生SI的参与者在白质(WM)完整性方面表现出更大的纵向变化,特别是在胼胝体、扣带束和额枕下束,与cn -稳定相比。在较小程度上,我们还观察到与SI相关的颞叶变薄和萎缩。这些关联在男性和淀粉样蛋白阳性个体中更为明显。讨论:WM微结构完整性的纵向改变与未来的损伤密切相关,突出了早期WM变化在MCI和痴呆发展中的重要性。
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引用次数: 0
Deep cervical lymphatic–venous anastomosis attenuates cognitive dysfunction and biomarker abnormalities in severe Alzheimer's disease: A prospective single-arm study 颈淋巴-静脉深吻合减轻严重阿尔茨海默病的认知功能障碍和生物标志物异常:一项前瞻性单臂研究
IF 11.1 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2026-02-03 DOI: 10.1002/alz.71150
Xiaohong Fu, Jing Zhang, Qiuxia Xiao, Tingting Li, Qijun Li, Shaofu Zhang, Wen Zeng, Min Gong, Pan Cai, Zhaojian Deng, Xuan Zhang, Yuanjun Xin, Liping Su, Xiaohe Tian, Kaifeng Wu, Liulin Xiong

INTRODUCTION

This study evaluated the efficacy of deep cervical lymphatic–venous anastomosis (dcLVA) for severe Alzheimer's disease (AD).

METHODS

A total of 139 severe AD patients undergoing dcLVA were enrolled, and changes in cognitive function and biomarkers were evaluated by comparing preoperative measures with postoperative outcomes over a 6-month follow-up period.

RESULTS

Patients undergoing dcLVA showed modestly elevated Mini-Mental State Examination (MMSE) scores from 48 hour postoperatively to 6-month follow-up. At 6-month, observable changes across functional status and neuropsychiatric symptoms were documented, as demonstrated by reductions in scores on the Activities of Daily Living (ADL) scale, Neuropsychiatric Inventory (NPI), Neuropsychiatric Inventory-Caregiver Distress (NPI-D), and Sleep Disorders Inventory (SDI). Biomarker analyses revealed decreased cerebrospinal fluid (CSF) β-amyloid (Aβ) 42, Aβ40, and p-Tau levels postoperatively, along with increased plasma concentrations of these markers. No deaths or serious procedure-related adverse events occurred during 6-month follow-up.

DISCUSSION

These findings suggest that dcLVA may confer multifaceted clinical benefits in severe AD patients, including attenuation of certain neuropsychiatric dysfunctions and a potential slowing of symptom progression.

前言:本研究评价颈淋巴-静脉深吻合术(dcLVA)治疗重度阿尔茨海默病(AD)的疗效。方法:共纳入139例接受dcLVA的重度AD患者,通过比较术前和术后6个月的随访结果,评估认知功能和生物标志物的变化。结果:术后48小时至6个月随访期间,dcLVA患者的迷你精神状态检查(MMSE)评分中度升高。在6个月时,记录了可观察到的功能状态和神经精神症状的变化,如日常生活活动(ADL)量表、神经精神量表(NPI)、神经精神量表-照顾者困扰(NPI- d)和睡眠障碍量表(SDI)得分的降低。生物标志物分析显示,术后脑脊液(CSF) β-淀粉样蛋白(Aβ) 42、Aβ40和p-Tau水平下降,同时这些标志物的血浆浓度升高。在6个月的随访期间未发生死亡或严重的手术相关不良事件。讨论:这些发现表明,dcLVA可能给严重AD患者带来多方面的临床益处,包括某些神经精神功能障碍的减弱和症状进展的潜在减缓。
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引用次数: 0
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Alzheimer's & Dementia
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