KLOTHO and Resilience to Synaptic Dysfunction in Preclinical AD

项目摘要/摘要 阿尔茨海默病(AD)是一种进行性和衰弱的老年神经系统疾病， 临床上以记忆力减退为特征，神经病理学上以Aβ斑块和 神经原纤维缠绕在大脑中。突触功能障碍最近出现为另一种早期 阿尔茨海默病的关键特征；有证据表明，在临床前，突触密度下降了30% AD的分期与认知障碍的相关性比Aβ病理更密切。虽然年龄很大 是患阿尔茨海默病的单一最大风险因素，观察到即使是处于基因水平的个体 患阿尔茨海默病或患有阿尔茨海默病神经病变的风险能够保持认知正常，随着年龄的增长 重新调整研究的重点，不再关注风险，并强调有必要调查 赋予复原力，希望减少残疾和疾病发生率。Klotho被称为 抗衰老和长寿基因，并在细胞代谢、中枢神经系统中发挥关键作用 成熟和突触可塑性。这项提议的关键是，KLOTHO似乎也 增强突触的完整性，防止神经退化。因此，这种综合性的、临床上的 相关项目将严格调查KLOTHO 1)是否具有抗衰老能力- 和AD相关的突触功能障碍，以及2)修改这些功能障碍之间的关系 而认知能力在横向和纵向上都有所下降。拟议的研究将是 嵌入在强健的框架内，该框架具有良好的特性并纵向遵循 约2,000名高危中年成年人的队列(威斯康星州阿尔茨海默氏症登记处 预防[WRAP]和威斯康星州阿尔茨海默病研究中心[WADRC])。全 参与者已经进行了KLOTHO基因分型，并在认知表型方面进行了长达 在WRAP/WADRC工作了20年。R01将为这些参与者中的一部分提供资源 (n=150)接受多模式生物标志物评估([11C]UCB-J PET成像、脑脊液和 以血液为基础的生物标志物)在基线和2年随访。完成这项研究后， 有潜力为预防大脑/认知障碍提供宝贵的见解和可下药的靶点 随着年龄的增加或AD病理负担的加重而恶化。

PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD), a progressive and debilitating neurological disorder of old age, is clinically hallmarked by memory loss and neuropathologically by accumulation of Aβ plaques and neurofibrillary tangles in the brain. Synaptic dysfunction has recently emerged as another early key feature of AD; evidence suggests that synaptic density decreases up to 30% in preclinical stages of AD and correlates more closely with cognitive deficits than Aβ pathology. Although age is the single biggest risk factor for developing AD, the observation that even individuals at genetic risk for AD or harboring AD neuropathology are able to remain cognitively normal as they age has refocused research away from risk and underscored the need for investigations of the factors that confer resilience in hopes of reducing disability and disease incidence. KLOTHO is dubbed an anti-aging and longevity gene, and plays a key role in cellular metabolism, central nervous system maturation, and synaptic plasticity. Critical to this proposal is that KLOTHO also seems to enhance synaptic integrity and protects from neurodegeneration. Thus, this integrative, clinically relevant project will rigorously investigate whether KLOTHO 1) confers resilience against age- and AD-related synaptic dysfunction, and 2) modifies the relationship between such dysfunction and cognitive decline both cross-sectionally and longitudinally. The proposed study will be embedded within the robust framework of two well-characterized and longitudinally followed cohorts of ~2,000 at-risk, late-middle-aged adults (the Wisconsin Registry for Alzheimer’s Prevention [WRAP] and the Wisconsin Alzheimer’s Disease Research Center [WADRC]). All participants are already genotyped for KLOTHO and have been cognitively phenotyped for up to 20 years under WRAP/WADRC. The R01 will provide resources for a subset of these participants (N=150) to undergo multimodal biomarker assessment ([11C]UCB-J PET imaging, CSF and blood-based biomarkers) at baseline and 2-year follow-up. Completion of this study has the potential to provide invaluable insights and druggable targets for forestalling brain/cognitive deterioration with advancing age or AD pathological burden.