Late-onset Alzheimer’s disease (LOAD) susceptibility genes are good candidates for association with cognitive decline, as the pathological features of LOAD progress to varying degrees in individuals without dementia or cognitive impairment. However, to date, studies investigating the role of AD risk loci in cognitive decline have been characterized by a lack of consensus. I investigated the role of known genetic variants associated with LOAD in cognitive function. This research improved upon previous studies by using a large well-characterized cohort with 12 years of follow-up, and with participants undergoing a comprehensive neuropsychological battery. It was observed that a subset of the AD risk loci were associated with cognitive function, however, the effect sizes were small, and when demographic and lifestyle factors are taken into account, neither individual SNPs nor a genetic risk score explained a meaningful proportion of the variance in cognitive decline in our sample. Additionally, in a systematic review of the literature (currently under review), we do not support a consistent association between individual non-APOE LOAD risk and cognitive performance or decline. However, evidence suggests that aggregate LOAD genetic risk exerts deleterious effects on decline in episodic memory and global cognition. This research indicates that individual AD-related genetic markers may have limited utility in identifying individuals at risk of cognitive decline. In contrast, genetic risk scores may offer more utility in predicting cognitive decline and impairment.

Selected Publications:

1. Andrews SJ, Das D, Cherbuin N, Anstey KJ, Easteal S. (2016). Association of genetic risk factors with cognitive decline: The PATH through life project. Neurobiology of Aging. 41: 150-158. PubMed PMID: 27103528
2. Andrews SJ, Das D, Anstey KJ, Easteal S. (2017). Association of AKAP6 and MIR2113 with cognitive performance in a population based sample of older adults. Genes, Brain and Behavior. 16(4): 472-478. PubMed PMID: 28067462
3. Andrews SJ, Das D, Anstey KJ, Easteal S (2017). Late Onset Alzheimer’s disease risk variants in cognitive decline: The PATH Through Life Study. Journal of Alzheimer’s disease. 57:423-436. PubMed PMID: 28269768

Accurate risk assessment for cognitive impairment and dementia is increasingly important given the current lack of effective disease-modifying treatments for AD and other dementias. Validated risk assessment tools that can be administered at very low cost provide methods for low-income countries and regions to assess dementia risk and apply prevention strategies. Given current projections of increasing dementia prevalence, there is an urgent need for validated risk assessment tools that have been evaluated on well-characterized samples, over long time periods. To address this important issue, I investigated the association of an AD genetic risk score and a risk score comprised of lifestyle, medical, and demographic factors (the ANU-ADRI) with the risk of progression from normal cognition to Mild Cognitive Impairment (MCI) or Dementia. I observed that a higher score (indicating greater risk) on the ANU-ADRI was predictive of progression from normal cognition to MCI/Dementia, while the genetic risk score was not. Secondly, I investigated the association of the ANU-ADRI and GRS with two latent factors representing general cognitive availability and dementia severity. I observed that a higher ANU-ADRI was associated with both general cognitive ability and dementia severity, however, it was associated with a larger deleterious effect on dementia severity. In contrast, the GRS was only associated with a deleterious effect on dementia severity. These results complement previous evidence that the ANU-ADRI is predictive of AD and dementia. This also provides further support for using the ANU-ADRI for individual patient assessment and for informing intervention and treatment strategies aimed at delaying or preventing dementia.

Selected Publications:

1. Andrews SJ, Eramudugolla R, Velez JI, Cherbuin N, Easteal S, Anstey KJ. (2017). Validating the role of the Australian National University Alzheimer’s Disease Risk Index (ANU-ADRI) and a genetic risk score in progression to cognitive impairment in a population-based cohort of older adults followed for 12 years. Alzheimer’s Research & Therapy. 9:1-16. PubMed PMID: 28259165
2. Andrew SJ, McFall G, Dixon R, Cherbuin N, Eramudugolla R, Anstey K. (2018). Alzheimer’s environmental and genetic risk scores are differentially associated with general cognitive ability and dementia severity. Alzheimer Disease & Associated Disorders. 33(2):95-103. PubMed PMID: 30681434.

The central nervous system is particularly vulnerable to impaired mitochondrial metabolism because of its high-energy demands. Increasing evidence links mitochondrial dysfunction to neurodegenerative diseases such as AD. Each mitochondrion possesses its own 16,569 base pair circular genome (mtDNA) that encodes 37 genes. We quantified brain-derived mtDNA abundance in postmortem brain tissue and evaluated the association of mtDNA abundance with AD neuropathology. Reduced brain-derived mtDNA abundance was associated with increased AD neuropathology and worse cognitive performance. Mediation analysis further indicated that 30% of the effect of mtDNAcn on global cognition was mediated by tau pathology or global AD pathology. These results indicate that changes in mitochondrial function resulting from altered mtDNA genome abundance levels may initiate or mediate AD neuropathology or the cellular response to AD neuropathology. We have also demonstrated that interactions between genetic variation on the mitochondrial genome and nuclear genome influence AD risk.

Selected Publications:

1. McInerney WT, Fulton-Howard B, Patterson C, Paliwal D, Jermiin LS, Patel HR, Swerdlow RH, Pa J, Goate A, Easteal S, Andrews SJ. (2021). A globally diverse reference alignment and panel for imputation of mitochondrial DNA variants. BMC Bioinformatics. 22(417). PubMed PMID: 34470617.
2. Paliwal D, McInerney WT, Pa J, Swerdlow RH, Easteal S, Andrews SJ. (2021). Mitochondrial pathway polygenic risk scores are associated with Alzheimer’s Disease. Neurobiology of Aging. 108, 213–222. PubMed PMID: 34521561
3. Harerimana NV, Paliwal D, Romero Molina C, Bennet D, Pa J, Goate A, Swerdlow RH, Andrews SJ. (2023) The Role of Mitochondrial genome abundance in Alzheimer’s Disease. Alzheimer’s & Dementia. 5(19):2069-2083

The coronavirus disease 2019 (COVID-19) pandemic, caused by infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in enormous health and economic burden worldwide. Host genetics can contribute to susceptibility and response to viral infection and the identification of host- specific genetic factors can indicate biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. As part of the COVID-19 Host Genetic Initiative, a global network of researchers investigating the human genetics of SARS- COV-2 infection and COVID-19 severity, I led the Mendelian randomization working group that aimed to identify causal modifiable risk factors for SARS-CoV-2 infection and outcomes. We first investigated the genetic correlations between a set of 38 disease, health and neuropsychiatric phenotypes as potential COVID-19 risk factors based on their putative relevance to the disease susceptibility, severity, or mortality with SARS-CoV-2 infection, COVID-19 hospitalization and COVID-19 critical illness. Genetic correlations were observed between BMI, smoking, risk tolerance, ADHD, coronary artery disease diabetes, ischemic stroke and lupus and COVID-19 outcomes. Using Mendelian randomization, it was found that BMI, smoking, height, and red blood cell count were robustly causally associated with SARS-CoV-2 infection or COVID-19 severity.

Selected Publications:

1. The COVID-19 Host Genetic Initiative. (2021). Mapping the human genetic architecture of COVID-19. Nature. 600,472-477. PubMed PMID: 34237774
2. Fadista, J. Kraven L, Karajalainen J, Andrews SJ, Geller F. (2021). Shared genetic etiology between idiopathic pulmonary fibrosis and COVID-19 severity. Ebiomedicine 65, 103277. PubMed PMID: 33714028
3. The COVID-19 Host Genetic Initiative. (2022). A first update on mapping the human genetic architecture of COVID-19. Nature 608, E1–E10. PubMed PMID: 35922517