Effects of genetic variation on the dynamics of neurodegeneration in Alzheimer's disease

Abstract

Although many genetic markers are identified as being associated with Alzheimer's disease (AD), not much is known about their association with the structural changes that happen as the disease progresses. In this study, we investigate the genetic etiology of neurodegeneration in AD by associating genetic markers with atrophy profiles obtained using patient data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. The atrophy profiles were quantified using a linear least-squares regression model over the span of patient enrollment, and used as imaging features throughout the analysis. A subset of the imaging features were selected for genetic association based on their ability to discriminate between healthy individuals and AD patients in a Support Vector Machines (SVM) classifier. Each imaging feature was associated with single-nucleotide polymorphisms (SNPs) using a linear model that included age and cognitive impairment scores as covariates to correct for normal disease progression. After false discovery rate correction, we observed 53 significant associations between SNPs and our imaging features, including associations of ventricular enlargement with SNPs on estrogen receptor 1 (ESR1) and sortilin-related VPS10 domain containing receptor 1 (SORCS1), hippocampal atrophy with SNPs on ESR1, and cerebral atrophy with SNPs on transferrin (TF) and amyloid beta precursor protein (APP). This study provides important insights into genetic predictors of specific types of neurodegeneration that could potentially be used to improve the efficacy of treatment strategies for the disease and allow the development of personalized treatment plans based on each patient's unique genetic profile.

Perceived Racial Discrimination and DNA Methylation Among African American Women in the InterGEN Study

“…The LRRN3 gene has also recently been linked with differential gene expression by age after traumatic brain injury (TBI) (Cho et al, 2016). Lastly, the Sortilin Related VPS10 Domain Containing Receptor 1 ( SORCS1 ) is a protein-coding gene that is also associated with a brain disorder, however unlike LRRN3 it is not TBI but narcolepsy and neurodegeneration in Alzheimer's (Knight et al, 2016; Printy, Verma, Cowperthwaite, Markey, & Alzheimer's Disease Neuroimaging Initiative, 2014; Scheinfeldt et al, 2015).…”

Unexpected partial correction of metabolic and behavioral phenotypes of Alzheimer’s APP/PSEN1 mice by gene targeting of diabetes/Alzheimer’s-related Sorcs1

“…Furthermore, several studies have demonstrated links between SNPs in SORCS1 and cognition. Printy et al [ 49 ] assessed atrophy profiles against genetic markers in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort, finding associations of cerebral atrophy with SNPs on APP but also ventricular enlargement with SNPs on SORCS1 . Reitz et al [ 53 ] also assessed the impact of genetic variation in SORCS1 and memory retention and found three SNPS were associated with memory retention.…”

Recent publications from the Alzheimer's Disease Neuroimaging Initiative: Reviewing progress toward improved AD clinical trials

“…A statistically significant synergistic interaction between two SNPs in an olfactory gene cluster suggested that this pathway may be involved in AD. Using a subset of imaging features able to discriminate between CN and AD subjects as quantitative phenotypes, genetic variation in a relatively small number of genes ( ESR1 , BIN1 , LDLR , SORCS1 , APP , LRAT , and TF ) was found to be associated with ventricular enlargement, hippocampal atrophy, and cortical atrophy, suggesting that these loci could have potential in diagnostic classification [213]. Another study selected neuroimaging biomarkers associated with disease state on the basis of global shape analysis and found differential associations between SNPs and regional volumes at different disease stages [214].…”