The National Institute of Neurological Disorders and Stroke (NINDS) announces the first round of awards for the new NINDS Collaborative Opportunities for Multidisciplinary, Bold, and Innovative Neuroscience (COMBINE) program. This program enables multidisciplinary research teams to pursue critically important research goals that could not be met by individual or parallel efforts.
We are delighted to announce that Yakeel Quiroz, PHD, Director of the Familial Dementia Neuroimaging Lab and the Multicultural Alzheimer’s Prevention Program (MAPP), at Mass General Hospital, and co-investigators Joseph Arboleda-Velasquez, MD, PhD and Francisco Lopera, MD, have been granted one of the six awards from NINDS.
This funding will allow Dr. Quiroz and her colleagues to continue their research of individuals belonging to the world’s largest family with autosomal-dominant Alzheimer’s disease.
The six awards total approximately $50 million from NINDS over five years. The awards support multidisciplinary teams that seek to cross technical and conceptual boundaries through interdisciplinary collaboration to achieve a single, focused, and transformative goal. The projects span basic, translational, and neurological disease topics, including approaches that cross multiple species, scales, and disciplines. The NINDS COMBINE program emphasizes a team science approach to achieving transformative science through integration of diverse scientific disciplines, approaches, expertise, and personnel.
Resilience to cognitive decline and resistance to Alzheimer’s disease and related neurodegenerative diseases in individuals from Colombia with autosomal dominant dementias
Abstract: 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.
We will study underlying mechanisms of cognitive resilience and resistance to early-onset dementia in protected individuals who carry PSEN1, NOTCH3 and MAPT mutations. We plan to use clinical and cognitive measures, as well as neuroimaging and biomarker methods 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 and also search for new variants in other protected individuals from AD, CADASIL and FTD and validate across diseases.
