Quantifying Individual Differences in Midlife Structural Brain Integrity Associated with Later AD/ADRD Risk

项目摘要 阿尔茨海默病和阿尔茨海默病相关痴呆（AD/ADRD）的负担随着年龄的增长而增长。 全球人口老龄化。与老年科学的新模型一致，临床上可检测到的认知障碍 和AD/ADRD被假设为代表终身衰老过程的结束， 环境侮辱和生活方式因素相互作用，推动病理。事实上，AD/ADRD的许多风险因素是 在临床检测之前的几十年，在儿童期和中年期就可以测量。这种关于衰老的寿命观， 再加上晚年AD/ADRD预防试验的令人失望的结果，表明有一个有希望的 有机会设计针对中年高危人群的干预措施，以减缓衰老过程， 使人衰弱的大脑衰退得到了巩固然而，将AD/ADRD预防研究转移到中年， 提出了一个重大挑战：确定干预的可行结果。在典型的临床试验中， AD/ADRD的发生率是干预的目标和衡量的结果。虽然从方法论上讲是合理的， 设计将具有挑战性的出口到中年，因为它将需要试验持续20年或更长时间才能使用 AD/ADRD诊断，这是罕见的65岁之前，作为结果。另一种策略是找到中年 替代生物标志物，其指示生物学和认知中的亚临床变化，所述亚临床变化指示病前 AD/ADRD。这种中年生物学和认知的发病前变化可能进一步帮助确定因果疾病 机制等在这个竞争性的更新应用中，我们建议量化中年的个体差异， 其中一组潜在的替代生物标志物：MRI测量大脑结构完整性，这是已知的 在以后的生活中与AD/ADRD相关。具体来说，我们建议在52岁时跟踪调查一个人口- 一年内在一个城市出生的1037名婴儿的代表性队列，并从那时起进行了全面研究： 达尼丁研究。通过我们之前的奖项（R 01 AG 049789），我们成功收集了高质量、可靠的MRI 在45岁时，93%的仍然活着的参与研究的成员（N=875）的结构性脑完整性的措施。 拟议的52岁时第二波MRI数据收集将允许量化个体 处于危险中的脑结构变化的差异（例如，WMH、皮质变薄和海马 萎缩）之间的年龄45和52。然后，我们将研究这些个体差异的程度， 通过AD/ADRD风险指数、认知能力下降的轨迹和生物衰老的速度预测，我们 已经追踪了50年我们还将绘制处于风险中的中年结构脑的个体差异， 血液AD/ADRD生物标志物的变化。重要的是，达尼丁研究设计允许检测 在没有年龄和/或队列效应的情况下，在大规模人群代表性样本中进行关联。一 低损耗和损耗偏差的缺乏进一步提供了检查整个范围的关联的机会 包括低功能和高功能的个体。这些特征将有助于生成新颖的翻译 对中年AD/ADRD干预和预防研究的直接影响。

PROJECT SUMMARY The burden of Alzheimer’s disease and Alzheimer’s disease related dementias (AD/ADRD) is growing as the global population ages. Consistent with a newer model of geroscience, clinically detectable cognitive impairment and AD/ADRD are hypothesized to represent the end of a lifelong aging process in which genetic predisposition, environmental insult, and lifestyle factors interact to drive pathology. In fact, many risk factors for AD/ADRD are measurable in childhood and midlife many decades before clinical detection. This lifespan view of aging, together with the disappointing results of AD/ADRD prevention trials in late life, suggest that there is a promising opportunity to design interventions that target at-risk individuals in midlife to slow the aging process before debilitating brain decline has been cemented. Shifting AD/ADRD prevention research to midlife, however, presents a significant challenge: identifying viable outcomes of intervention. In a typical clinical trial, incidence of AD/ADRD is the intervention target as well as the measured outcome. While methodologically sound, this design will be challenging to export to midlife because it will require trials to last 20 or more years to use AD/ADRD diagnosis, which is uncommon before 65, as the outcome. One alternative strategy is to find midlife surrogate biomarkers that index sub-clinical changes in biology and cognition that are indicative of premorbid AD/ADRD. Such premorbid changes in midlife biology and cognition could further help identify causal disease mechanisms. In this competing renewal application, we propose to quantify individual differences in midlife for one such group of potential surrogate biomarkers: MRI measures of structural brain integrity, which are known to be associated with AD/ADRD later in life. Specifically, we propose to follow up at age 52 a population- representative cohort of 1037 infants born in one city in one year and comprehensively studied ever since: the Dunedin Study. Through our prior award (R01AG049789), we successfully collected high-quality, reliable MRI measures of structural brain integrity at age 45 in 93% of still-alive and participating Study members (N=875). The proposed second wave of MRI data collection at age 52 will allow for the quantification of individual differences in at-risk structural brain changes (e.g., greater increase in WMH, cortical thinning, and hippocampal atrophy) between ages 45 and 52. We will then examine the extent to which these individual differences are predicted by AD/ADRD risk indexes, trajectories of cognitive decline, and the pace of biological aging, which we have tracked across five decades. We will also map individual differences in at-risk midlife structural brain changes onto blood AD/ADRD biomarkers. Importantly, the Dunedin Study design allows for testing of associations in the absence of age and/or cohort effects in a large population representative sample. The very low attrition and absence of attrition bias further afford opportunity to examine associations across the full-range of cognition including low- and high-functioning individuals. These features will help generate novel translational findings of immediate impact for midlife AD/ADRD intervention and prevention research.