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

哥伦比亚常染色体显性痴呆患者对认知能力下降的抵抗力以及对阿尔茨海默病和相关神经退行性疾病的抵抗力

• 批准号: 10721433
• 负责人: Joseph Arboleda-Velasquez
• 金额: $ 382.16万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10721433
• 关键词: Age; Alzheimer' s Disease; Alzheimer' s disease related dementia; Amyloid; Arterial Disorder; Atrophic; Biological; Biological Markers; Boston; Brain; CADASIL; Candidate Disease Gene; Cerebrum; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Cognitive; Colombia; Colombian; DNA Sequence Alteration; Dementia; Disease; Ear; Etiology; Eye; Family; Frontotemporal Dementia; Functional Magnetic Resonance Imaging; Funding Mechanisms; General Hospitals; Genetic; Genetic Induction; Goals; Hippocampus; Image; Impaired cognition; Individual; Link; Magnetic Resonance Imaging; Measurement; Measures; Medicine; Memory; Methods; Molecular; Mutation; NOTCH3 gene; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Organoids; Parietal; Pathology; Patients; Pattern; Penetrance; Phenotype; Plasma; Positron-Emission Tomography; Publishing; Research Institute; Resistance; Sample Size; Scientist; Site; South America; Subcortical Infarctions; Subcortical Leukoencephalopathy; System; Testing; Validation; Variant; Vascular Dementia; Work; amyloid pathology; apolipoprotein E-3; autosomal dominant Alzheimer' s disease; autosome; candidate identification; cognitive performance; comparison control; early onset; genetic analysis; genetic association; genetic variant; genome sequencing; human old age (65+); kindred; mild cognitive impairment; mutation carrier; neural; neuroimaging; presenilin-1; protective factors; rare variant; resilience; stem; tau Proteins; white matter; whole genome

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.

引起常染色体显性阿尔茨海默氏病（ADAD）和相关痴呆症的基因突变， 具有较高的外观，提供了一个独特的机会来表征与之相关的生物学异常 神经退行性条件。在哥伦比亚（南美）的Antioquia，我们确定了几个家庭 基因突变引起的早期发作痴呆。我们拥有世界上最大的已知亲属ADAD 由大约6,000个亲戚组成，包括1,200个Presenilin-1 E280A（PSEN1）突变载体 （Lopera等，1997； Fuller等，2019）。我们也有很大的家庭具有Notch3突变的原因 脑常染色体显性动脉炎和皮质下的小动脉病和白细胞症（Cadasil，早期 发作血管性痴呆）（Schoemaker等，2021），具有MAPT突变的大家庭导致额叶 临时痴呆（FTD； Ramos等，2020）。 我们的小组最近确定了Adad Kindred的PSEN1突变载体 认知障碍（MCI）直到她的七十多岁，是临床发作中位年龄的三十年。当她 在我们72岁的研究中检查了她的早期MCI，大脑淀粉样蛋白很高，但Tau Tangle有限 和神经退行性测量（Arboleta-Velasquez等人，自然医学，2019年）。遗传分析 揭示她有两份APOE3基督城（R136）突变的副本，这表明这种遗传 面对高淀粉样蛋白病理学，变体通过减少tau病理和神经退行性的影响来施加保护。 我们与哥伦比亚家庭的合作允许确定其他载有载的人 确定性的突变一直在认知上一直保持不变，直到年龄较大。我们建议扩大我们的工作 通过研究这些受保护的病例，例如APOE3基督城案例，以识别潜在的受保护基因 变体。我们将研究认知弹性和对AD和其他其他的抵抗力的潜在机制 属于Adad，Cadasil或家庭FTD家庭的神经退行性疾病 哥伦比亚。我们计划使用临床和认知措施以及神经影像学和生物标志物方法（MRI和 PET）研究受保护载体中大脑网络的完整性，并使用遗传分析并诱导 多能茎（IPS）衍生的大脑器官检查候选基因变体之间的机械联系 和受保护的表型。我们将检验以下假设，即我们发现的一些变体 AD患者（例如Apoe Christchurch）的保护性也可以保护其他痴呆症。我们将 还搜索来自AD，Cadasil和FTD的其他受保护个体的新变体，并验证 疾病。我们的目标是鉴定疾病特异性的遗传保护因子和泛保护基因变异。 这项工作是这种资金机制的理想选择，因为它需要临床医生和 基本科学家，因为它专注于一个样本的遗传发现的极其挑战的问题 尺寸= 1。