Relationship between tau pathology and cognitive impairment in autosomal dominant Alzheimer's disease

常染色体显性阿尔茨海默病中 tau 蛋白病理学与认知障碍的关系

• 批准号: 10164690
• 负责人: Yakeel T. Quiroz
• 金额: $ 74.51万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10164690
• 关键词: Age; Age-Years; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease pathology; Amyloid; Antibodies; Area; Biological Markers; Brain; Clinical; Clinical Trials; Cognition; Cognitive; Colombia; Data; Dementia; Development; Disease; Evolution; Failure; Family member; Functional Magnetic Resonance Imaging; Goals; Human; Impaired cognition; Individual; Longitudinal Studies; Magnetic Resonance Imaging; Measures; Medial; Memory; Memory impairment; Mutation; Neuropsychology; Pathology; Population; Positron-Emission Tomography; Presenile Alzheimer Dementia; Prevention trial; Probability; Prognostic Marker; Randomized Clinical Trials; Rest; Risk; Role; Staging; Statistical Models; Structure; Techniques; Temporal Lobe; Time; Treatment outcome; Tweens; Visit; Work; age related; amyloid pathology; autosomal dominant Alzheimer' s disease; base; cingulate cortex; cognitive performance; design; drug development; imaging study; improved; kindred; mild cognitive impairment; mutation carrier; neocortical; network dysfunction; neuroimaging; pre-clinical; preclinical trial; prevent; success; tau Proteins; tau aggregation; treatment effect; treatment trial; trial design; virtual

PROJECT SUMMARY For the first time since Alzheimer's disease (AD) was discovered, amyloid-modifying treatments are being evaluated in clinical trials, while other anti-tau antibodies and other disease-modifying treatments are in development. These treatment hold promise to modify the course of AD, and even prevent its clinical manifestation, if administered early enough. Three urgent needs now present themselves: 1) to improve our ability to detect preclinical AD and track is progression using biomarkers, 2) to understand the temporal relationships between amyloid aggregation, tau aggregation and cognitive decline, and 3) to leverage that information to increase the efficiency and probability of success of preclinical treatment trials. In this proposal, we work with an extraordinary kindred of approximately 5,000 individuals in Antioquia, Colombia, which contains roughly 1500 carriers of the autosomal-dominant Presenilin1 (PSEN1) E280A mutation. These carriers are virtually certain to develop early onset AD, and have a well-characterized disease course, with mild cognitive impairment (MCI) occurring at a mean age of 45, and dementia at a mean age of 51. Previously we used a cross-sectional approach to characterize biomarker changes as a function of age, and in relation to the kindred's mean age of clinical onset. We are currently performing the first cross-sectional tau PET imaging study with this kindred. The addition of the longitudinal data proposed here will greatly improve our understanding of the temporal and spatial trajectories of tau and amyloid in preclinical ADAD, and their relation to subsequent cognitive decline. These data will help inform the design and analysis of prevention trials, including the ongoing Alzheimer's Prevention Initiative (API) autosomal-dominant AD (ADAD) trial. We will acquire a comprehensive set of neuroimaging and neuropsychological data at baseline, 18- and 36-months in 30 cognitively unimpaired PSEN1 mutation carriers (ages 30-45 years), 30 age-matched non-carrier family members, and 20 cognitively impaired carriers (ages 40-55 years). The hypothesis that amyloid exerts harmful effects on the brain mainly by facilitating tau aggregation has been offered, but evidence for or against it in humans is limited. We hypothesize that in preclinical ADAD, cortical amyloid pathology precedes tau pathology in the medial temporal lobe (MTL). Further, tau should correlate more strongly than amyloid with memory network disruption and with cognitive impairment. All subjects will be evaluated to accomplish the following specific aims: 1) Examine the role of tau pathology in memory network dysfunction in preclinical ADAD; 2) Determine the extent to which PET measures of amyloid and tau pathology can be used as prognostic biomarker for subsequent cognitive decline and clinical progression; and 3) Provide a biomarker profile of preclinical ADAD that can inform AD trial design.

项目总结

项目成果

Associations of category fluency clustering performance with in vivo brain pathology in autosomal dominant Alzheimer's disease.

常染色体显性阿尔茨海默病中类别流畅性聚类表现与体内脑病理学的关联。

• DOI: 10.1017/s1355617723000243
• 发表时间: 2024
• 期刊: Journal of the International Neuropsychological Society : JINS
• 作者: Yucebas,Defne;Fox-Fuller,JoshuaT;BadilloCabrera,Alex;Baena,Ana;PluimMcDowell,Celina;Aduen,Paula;Vila-Castelar,Clara;Bocanegra,Yamile;Tirado,Victoria;Sanchez,JustinS;Cronin-Golomb,Alice;Lopera,Francisco;Quiroz,YakeelT
• 通讯作者: Quiroz,YakeelT