Understanding the mechanisms linking small vessel cerebrovascular disease and Alzheimer's disease pathophysiology with neurodegeneration and cognition during midlife

项目摘要 本K99/R 00提案的总体目标是阐明小血管脑血管病变的程度， 疾病（svCBVD）和阿尔茨海默病（AD）的病理生理学在其对 神经退行性疾病和中年认知，并确定这是否在种族/民族群体中存在差异。 在尸检时，在大多数痴呆病例中观察到共病的svCBVD和AD病理学，并且在 种族/少数民族。有证据表明svCBVD对淀粉样蛋白清除和tau蛋白有不利影响。 磷酸化，其加剧AD中的神经变性和认知障碍。至关重要的是， 当考虑疾病的主要驱动因素以及神经变性和认知时，svCBVD、淀粉样蛋白和tau 当考虑到这些主要驱动因素的后果。虽然svCBVD中的初始认知障碍 在执行功能和那些在AD的记忆，两者的后果变得不那么明显 当它们同时出现时。同样重要的是，中年研究是必要的，以阐明如何svCBVD和AD 病理生理学最初发展，以及AD和svCBVD的特定混合物如何影响疾病 进展目的1（K99）确定svCBVD和淀粉样蛋白对tau蛋白的生物学影响。 相关的神经变性，并探讨这些协会的种族/民族差异。目标2（K99） 确定svCBVD和淀粉样蛋白对tau相关记忆功能障碍的认知后果， 探索这些协会中的种族/民族差异。核心假设是，在中年， svCBVD患者表现出更多的AD相关神经退行性变， 这种影响在种族/族裔少数群体中更强，因为 svCBVD。为了实现这些目标，申请人将在三个方面接受快速但必不可少的指导培训 领域：（1）tau和小血管脑血管疾病，（2）应用神经科学，（3）高级统计 建模有了这些技能，申请人将有能力独立追求目标3（R 00）， 确定基线svCBVD和淀粉样蛋白对神经变性的纵向影响， 记忆力会随着时间的推移而下降。了解单一或混合svCBVD和AD病理的后果将 告知治疗目标，并帮助确定是否需要根据种族/民族区分干预策略。 这个建议的优势包括生物标志物所代表的基础病理学的正式培训 及其与认知的联系，以及正式的统计培训，以严格执行灵活的国家统计制度， 老龄化研究所（NIA）-阿尔茨海默氏症协会推荐的研究框架，以直接解决 NIA的当前任务。对于申请人来说，这一加速培训期将促进以下方面的发展： 一个独立的研究项目，专注于AD和相关痴呆症的大规模神经影像学研究 在不同的人群中。

PROJECT SUMMARY The overall goal of this K99/R00 proposal is to elucidate the extent to which small vessel cerebrovascular disease (svCBVD) and Alzheimer’s disease (AD) pathophysiology are additive or synergistic in their effects on neurodegeneration and cognition in midlife, and to determine if that differs across racial/ethnic groups. Comorbid svCBVD and AD pathology is observed in most dementia cases at autopsy, and is more prevalent in racial/ethnic minorities. Evidence is building that svCBVD has detrimental effects on amyloid clearance and tau phosphorylation, which exacerbates neurodegeneration and cognitive impairment in AD. It is crucial to include svCBVD, amyloid, and tau when considering primary drivers of disease, and neurodegeneration and cognition when considering the consequences of those primary drivers. While initial cognitive impairments in svCBVD are in executive function and those in AD are in memory, the consequences of the two become less distinct when they co-occur. Equally as important, studies in midlife are necessary to elucidate how svCBVD and AD pathophysiology initially develop, and how a particular mixture of AD and svCBVD influences disease progression. Aim 1 (K99) determines the biological consequence that svCBVD and amyloid have on tau- related neurodegeneration, and explores racial/ethnic differences in these associations. Aim 2 (K99) determines the cognitive consequence that svCBVD and amyloid have on tau-related memory dysfunction, and explores racial/ethnic differences in these associations. The central hypothesis is that, in middle age, individuals with svCBVD demonstrate more AD-related neurodegeneration and subsequently more cognitive impairment, and that this effect will be stronger in racial/ethnic minorities due to the higher prevalence of svCBVD. To achieve these goals, the applicant will undergo quick, but essential mentored training in three areas: (1) tau and small vessel cerebrovascular disease, (2) applied neuroscience, and (3) advanced statistical modeling. With these skills, the applicant will be well equipped to independently pursue Aim 3 (R00), which determines the longitudinal consequences that baseline svCBVD and amyloid have on neurodegeneration and memory decline over time. Understanding the consequences of single or mixed svCBVD and AD pathology will inform therapeutic targets and help determine whether interventional strategies need to differ by race/ethnicity. The strengths of this proposal include formal training in the underlying pathology represented by biomarkers and its connection to cognition, as well as formal training in statistics to rigorously implement a flexible National Institute on Aging(NIA)-Alzheimer’s Association-recommended research framework to directly address the current missions of the NIA. For the applicant, this accelerated training period will facilitate the development of an independent research program focused on large-scale neuroimaging studies of AD and related dementias in diverse populations.