Resilience to cognitive decline and resistance to Alzheimer's disease and related neurodegenerative diseases in individuals from Colombia with autosomal dominant dementias

导致常染色体显性遗传性阿尔茨海默病(ADAD)和相关痴呆的基因突变， 具有高的外显率，提供了一个独特的机会来表征与 神经退行性疾病。在哥伦比亚的安提奥基亚(南美洲)，我们发现有几个家庭患有 基因突变导致的早发性痴呆。我们有世界上已知的与ADAD最大的亲属 由大约6,000名在世亲属组成，包括1,200名早老素-1 E280A(PSEN1)突变携带者 (Lora等人，1997；Fuller等人，2019年)。我们也有非常大的NOTCH3突变家族导致 伴有皮质下梗塞和白质脑病的常染色体显性遗传性脑动脉病(CADASIL，早期 发病的血管性痴呆)(Schoemaker等人，2021年)，以及携带MAPT突变导致额叶痴呆的大家族。 颞叶痴呆(FTD；Ramos等人，2020年)。 我们小组最近从ADAD家族中发现了一名PSEN1突变携带者，该携带者没有出现轻微的疾病 认知障碍(MCI)直到她七十岁，也就是临床发病年龄中值三十年后。当她 在我们的研究中，她在72岁时被检查，她有早期的MCI，非常高的脑淀粉样蛋白，但有限的tau缠结 和神经退行性测量(Arboleda-Vas quez等人，自然医学，2019年)。遗传分析 她透露，她有两个副本的APOE3克赖斯特彻奇(R136S)突变，表明这个基因 VARIANT在面对高度淀粉样变性时，通过减少tau病理和神经变性来发挥保护作用。 我们与哥伦比亚家庭的合作使我们能够识别其他人，尽管他们携带 确定性突变在认知上一直没有受到损害，直到更老的时候。我们建议延长我们的工作时间 通过研究这些受保护的病例，例如APOE3克赖斯特彻奇病例，以确定潜在的保护基因 变种。我们将研究认知弹性和抵抗AD和其他疾病的潜在机制 患有ADAD、CADASIL或家族性FTD的个体中的神经退行性疾病 哥伦比亚。我们计划使用临床和认知测量以及神经成像和生物标记物方法(MRI和 调查受保护携带者大脑网络的完整性，并使用遗传分析和诱导 多能干细胞(IPS)衍生的脑有机体用于检查候选基因变体之间的机制联系 和保护性表型。我们将测试假设，我们已经发现的一些变体作为 对AD患者的保护(例如，APOE克赖斯特彻奇)也可能对其他痴呆有保护作用。我们会 还要在AD、CADASIL和FTD的其他受保护个人中搜索新的变体，并跨 疾病。我们的目标是识别疾病特异性的遗传保护因子和泛保护基因变体。 这项工作是这种资助机制的理想选择，因为它需要临床医生和 因为它关注的是一个极具挑战性的基因发现问题 大小=1。

Genetic mutations that cause autosomal dominant Alzheimer’s disease (ADAD) and related dementias, with high penetrance, provide a unique opportunity to characterize the biological abnormalities associated with neurodegenerative conditions. In Antioquia, Colombia (South America), we have identified several families with early-onset dementia caused by genetic mutations. We have the world’s largest known kindred with ADAD consisting of approximately 6,000 living relatives, including 1,200 Presenilin-1 E280A (PSEN1) mutation carriers (Lopera et al, 1997; Fuller et al., 2019). We also have very large families with NOTCH3 mutations leading to cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL, an early onset vascular dementia) (Schoemaker et al., 2021), and large families with MAPT mutations leading to fronto- temporal dementia (FTD; Ramos et al., 2020). Our group recently identified a PSEN1 mutation carrier from the ADAD kindred, who did not develop mild cognitive impairment (MCI) until her seventies, three decades after the median age of clinical onset. When she was examined in our study at the age of 72, she had early MCI, very high brain amyloid, but limited tau tangle and neurodegenerative measurements (Arboleda-Velasquez et al., Nature Medicine, 2019). Genetic analysis revealed that she had two copies of the APOE3 Christchurch (R136S) mutation, suggesting that this genetic variant exerts protection by reducing tau pathology and neurodegeneration in the face of high amyloid pathology. Our work with Colombian families has allowed to identify other individuals who despite carrying deterministic mutations have remained cognitively unimpaired until older ages. We propose to extend our work by studying these protected cases, such as the APOE3 Christchurch case, to identify potential protective gene variants. We will study underlying mechanisms of cognitive resilience and resistance to AD and other neurodegenerative diseases in individuals who belong to families with ADAD, CADASIL or familial FTD from Colombia. We plan to use clinical and cognitive measures and neuroimaging and biomarker methods (MRI and PET) to investigate the integrity of brain networks in protected carriers, and use genetic analyses and induced pluripotent stem (IPS)-derived cerebral organoids to examine mechanistic links between candidate gene variants and protective phenotypes. We will test the hypothesis that some of the variants that we have discovered as protective in AD patients (e.g. APOE Christchurch) could be also protective against other dementias. We will also search for new variants in other protected individuals from AD, CADASIL and FTD and validate across diseases. Our goal is to identify disease-specific genetic protective factors and pan-protective gene variants. This work is ideal for this funding mechanism because it requires complementary expertise of clinicians and basic scientists and because it focuses on an extremely challenging problem of genetic discovery with a sample size=1.