The goal of our lab is to find and fight the causes of Alzheimer’s disease and illuminate the genetic underpinnings of psychological well-being and psychological resilience.

Understanding the molecular mechanisms behind how psychological well-being and depression modify AD risk

Psychological well-being (PWB) and depression are important factors that modify risk for Alzheimer’s disease (AD). Specifically, depression is associated with increased risk for AD while PWB with decreased risk for AD. Molecular mechanisms underlying these important associations, however, are not known. To address this knowledge gap, we will study a unique dataset of 850 human postmortem brains from the Rush Memory and Aging Project. This prospective longitudinal project annually collects data on depression, PWB, cognition, physical health, and dementia, and genomic, transcriptomic, and proteomic data from the dorsolateral prefrontal cortex (dPFC). We will identify key miRNAs, transcripts, and proteins associated with depression, and separately with PWB, and examine how they relate to cognitive change, AD dementia, and dementia-related pathologies.

Identifying new Genetic causes of Alzheimer’s Disease

  • Identifying New Genetic causes of Early-onset Alzheimer’s disease - Early-onset Alzheimer’s disease is a particularly aggressive form of the disease with higher heritability than typical late-onset AD and has several well-described genetic causes. We use next-generation sequencing to identify new genetic causes in families and individuals with this particularly aggressive form of AD.

  • A genetic study of a large pedigree with late-onset Alzheimer’s Disease - late-onset Alzheimer’s Disease, the more common form of the disease, is due to the cumulative effect of 1,000s or 10,000s of genetic changes. However, there still appear to be families that transmit the illness as an autosomal dominant trait. The Emory ADRC has collected a number of very large families and using linkage and next-generation sequencing techniques we are moving to identify high-risk alleles in these families.

A Proteogenomic Approach to Understanding Alzheimer’s Disease Genome-wide Association Study Results

Recent genome wide association studies (GWAS) of AD have identified at least >20 regions of the human genome that are linked with developing AD. Currently, it is not known why these regions are associated with AD. Our overarching hypothesis is that some AD GWAS signals are due to one or more coding variants that makes the translated protein more likely to aggregate. We are uniquely poised to address this hypothesis given the unique datasets of brain tissue and our expertise in both large-scale and targeted proteomic analyses. By combining our genetic sequencing data with cutting-edge mass spectrometry we will sequence encoded protein products of the same genes from individuals that underwent genetic sequencing. This will allow us to ask which genetic variants associate with AD and whether those genetic variants influence the abundance or aggregation potential of proteins in the brains of individuals with AD. Furthermore, we have developed a new method to detect and measure novel proteins that result from genetic sequence variants that cause a change the primary amino acid sequence. This gives us the ability to directly test whether variant containing proteins are more or less abundant or aggregation prone in carriers versus non-carriers and determine whether that contributes to AD risk.

Elucidating molecular mechanisms of psychological well-being

Psychological well-being (PWB) is a multidimensional construct that encompasses positive emotion, life satisfaction, and sense of purpose and meaning in life, and is more than the absence of negative emotional states. Many prospective longitudinal studies have shown that PWB is associated with better mental and physical health after adjusting for negative emotion and other relevant confounding factors. Indeed, PWB mitigates risks of having suicide ideation, depression, substance abuse, post-traumatic stress disorder, Alzheimer’s dementia, heart disease, diabetes, and reduces all-cause mortality. In this project we will investigate molecular mechanisms that underlie individual differences in PWB using human post-mortem brain multi-omic data.

Transgenerational effects of maternal stressors: Investigating the role of infant gene expression

Several prospective, longitudinal, mother-child cohort studies have found that children exposed to maternal psychological stress, depression, or anxiety during the prenatal period have higher risk for behavioral and emotional problems later in life, including increased fearfulness, anxiety, and depression. We will investigate molecular mechanisms underlying this association in collaboration with investigators at University of Cape Town in South Africa and at McLean Hospital.