GXI Interactions

PROJECT SUMMARY/ABSTRACT By 2050, more than 2 billion people worldwide will be over the age of 65, with older adults outnumbering children for the first time in recorded history. This predicted major demographic shift highlights the importance of improving our understanding of factors that contribute to healthy brain aging. Currently, the biological bases of brain aging are poorly understood. Brain aging (often focused on cognitive decline) is characterized by numerous phenotypes that undoubtedly involve multiple environmental and genetic factors. Overtly pathological brain aging is seen in major neurological diseases such as Alzheimer's disease and related dementias (ADRD); the prevalence of ADRD is expected to double every 20 years. On top of this existing public health crisis, we are now experiencing a global pandemic that appears to negatively influence neurological function. Growing evidence indicates that SARS-CoV-2 infection causes neurological complications of short-term consequence including acute neuropathy, encephalopathy, anosmia, and hypoxic/ischemic brain injury, and longer-term consequences including cognitive impairment and neuropsychiatric disturbances. The interindividual variation in the neurobiological responses to SARS-CoV-2 is marked. As with most complex phenotypes, causal determinants likely include both genetic and environmental factors. However, no genetic epidemiological study has yet considered differential neurophenotypic response to infection. Thus, delineating the genetic architecture of ADRD-relevant neurophenotypic responses to SARS-CoV-2 will offer important biological insights, which in turn could provide strategies for fostering healthy brain aging in the presence of future infectious challenges. Our project will assess the genetic basis of ADRD-relevant endophenotypic response (across a two year period with three examinations) to SARS-CoV-2 infection in a set of older (>60 years of age) adults from diverse populations (Amerindians from Argentina [ n=3000], US Native Americans [n=250], Mexican Americans [n=500], Puerto Ricans [n=125], African Americans [n=125], and Africans [n=300]) using whole genome sequence (WGS) data in a case/control design (75% post-infection cases, 25% never infected controls). The data generated will enable estimating the importance of genetics in disease response and the identification of key genes involved in the response. Our specific aims are to: 1) detect genetic influences on endophenotypic responses to SARS-CoV-2 infection using WGS data through testing for genotype×infection interaction in neurocognitive measures (neurocognitive measures, neuroimaging measures, and blood-based biomarkers); 2) search for sequence variation in genes and gene pathways influencing response to SARS-CoV-2 infection; and 3) test whether between-population variation in mean responses to infection has a genetic component. This project represents the genetic component of a large, integrated U19 application to examine the effect of COVID-19 on risk for ADRD in understudied ethnicities. Through the proposed project, we will identify causal genetic factors that underly differential response in ADRD risk to COVID-19.