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

项目总结 阿尔茨海默病和阿尔茨海默病相关痴呆(AD/ADRD)的负担随着 全球人口老龄化。符合老年科学的新模型，临床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，在该过程中，遗传易感性， 环境侮辱和生活方式因素相互作用，推动了病理。事实上，AD/ADRD的许多风险因素是 可在临床检测前几十年在儿童和中年进行测量。这种关于衰老的寿命观， 再加上晚年AD/ADRD预防试验令人失望的结果，表明有希望 有机会设计针对中年高危人群的干预措施，在此之前减缓衰老过程 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， 这带来了一项重大挑战：确定干预的可行结果。在典型的临床试验中，发病率 AD/ADRD是干预目标，也是测量结果。虽然在方法上是合理的，但这 将设计输出到中年将是一个挑战，因为它将需要持续20年或更长时间的试用才能使用 以65岁以前少见的AD/ADRD诊断为结果。另一种策略是找到中年 指示亚临床生物学和认知变化的替代生物标记物 AD/ADRD。中年生物学和认知方面的这种病前变化可能进一步帮助识别病因疾病 机械装置。在这个相互竞争的续订申请中，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记物：已知的大脑结构完整性的MRI测量 在以后的生活中与AD/ADRD联系在一起。具体地说，我们建议在52岁时对一个人口进行跟踪- 一年内在一个城市出生并进行全面研究的1037名婴儿的代表性队列： 达尼丁研究。通过我们之前的奖项(R01AG049789)，我们成功地收集了高质量、可靠的MRI 93%的在世和参与研究的成员在45岁时测量大脑结构的完整性(N=875)。 拟议的第二波磁共振成像数据收集将在52岁时允许量化个人 高危大脑结构变化的差异(例如，WMH增加更多，皮质变薄，和海马体变薄 萎缩)年龄在45岁到52岁之间。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。我们还将绘制高危中年结构性大脑的个体差异图 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测试 在具有代表性的大样本中，没有年龄和/或队列影响的相关性。最重要的 低自然减员和无自然减员偏见进一步提供了检查整个范围内的关联的机会 包括低功能和高功能个体的认知。这些功能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的研究结果。

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.