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

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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.