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

项目总结 这项K99/R00提案的总体目标是阐明小血管脑血管 疾病(SvCBVD)和阿尔茨海默病(AD)的病理生理学在以下方面是相加或协同作用的 中年的神经退化和认知，并确定这种情况是否在种族/民族之间有所不同。 在尸检中观察到大多数痴呆症患者同时存在svCBVD和AD病理，并在 少数族裔。越来越多的证据表明，svCBVD对淀粉样蛋白清除和tau有不利影响 磷酸化，加剧阿尔茨海默病患者的神经退行性变和认知障碍。重要的是要包括 当考虑到疾病的主要驱动因素以及神经退行性变和认知时，svCBVD、淀粉样蛋白和tau 当考虑到这些主要驱动因素的后果时。而svCBVD的初始认知障碍 是在执行功能中，而在AD中是在记忆中，两者的后果变得不那么明显 当它们同时出现的时候。同样重要的是，中年研究对于阐明svCBVD和AD是如何发生的 病理生理学的初步发展，以及AD和svCBVD的特定混合物如何影响疾病 进步。目的1(K99)确定了svCBVD和淀粉样蛋白对tau-1的生物学影响。 相关的神经退行性变，并探索这些联系中的种族/民族差异。目标2(K99) 确定了svCBVD和淀粉样蛋白对tau相关记忆障碍的认知后果，以及 探索这些联系中的种族/民族差异。核心假设是，在中年， SvCBVD患者表现出更多与AD相关的神经变性，随后表现出更多的认知能力 这一影响在种族/族裔少数群体中将更强，因为更高的发病率 SvCBVD。为了实现这些目标，申请者将在三个月内接受快速但必要的指导培训 领域：(1)tau和小血管脑血管疾病，(2)应用神经科学，(3)高级统计学 模特儿。具备这些技能后，申请人将具备独立完成目标3(R00)的能力。 确定基线svCBVD和淀粉样蛋白对神经退行性变和 记忆力会随着时间的推移而衰退。了解单一或混合的svCBVD和AD病理的后果将 为治疗目标提供信息，并帮助确定干预策略是否需要因种族/民族而异。 这项建议的优点包括对生物标记物所代表的潜在病理进行正式培训。 及其与认知的联系，以及在统计方面的正式培训，以严格执行灵活的国家 老龄化研究所(NIA)-阿尔茨海默氏症协会-建议的研究框架，以直接解决 国家安全局目前的任务。对于申请者来说，这一加速的培训期将有助于发展 一项专注于AD和相关痴呆的大规模神经成像研究的独立研究计划 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.