Consistent genes associated with structural changes in clinical Alzheimer’s disease spectrum

157 

Abstract Submission 

Yingqi Lu¹, Shangjie Chen², Jinping Xu¹

¹Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangzhou, ²The People’s Hospital of Baoan Shenzhen, Shenzhen, Guangzhou

Yingqi Lu  
Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences
Shenzhen, Guangzhou

Shangjie Chen  
The People’s Hospital of Baoan Shenzhen
Shenzhen, Guangzhou

Jinping Xu  
Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences
Shenzhen, Guangzhou

Alzheimer's disease (AD) is considered a late-onset disease caused by a complex combination of genetic, epigenetic, and environmental factors. Previous studies have demonstrated that one of the major pathological changes in AD is widespread brain neurodegeneration, represented by irreversible gray matter volume (GMV) atrophy (Tondelli, Wilcock et al. 2012). However, the neurobiological and pathogenic substrates underlying this structural atrophy across AD spectrum remain largely understood. At present, gene-by-brain structure interactions of AD are widely studied (Nho, Corneveaux et al. 2013, Luis, Ortega-Cubero et al. 2014). Considering these, studying whether structural changes in the AD spectrum are driven by similar gene variants is important for fully understanding disease mechanisms and developing personalized therapeutics. The aim of the current study was to investigate structural atrophy across the full clinical AD spectrum and its genetic mechanism using gene expression data from the Allen Human Brain Atlas (AHBA) (Arnatkeviciute, Fulcher et al. 2019).

In this research, we obtained structural MRI imaging from the Alzheimer's Disease Neuroimaging Initiative (ADNI) datasets, including 83 early-stage mild cognitive impairments (EMCI), 83 late-stage mild cognitive impairments (LMCI), 83 AD, and 83 normal controls (NC), and gene expression data from the AHBA. Firstly, DPABI was used to obtain voxel-wise GMV differences map between EMCI, LMCI, and AD patients compared to NC. Secondly, 41 interesting genes were screened for AD risk genes intersected with background genes. Then, cross-sample non-parametric Spearman rank was performed to determine relationship between gene expression and regional GMV alterations. Lastly, functional enrichment analyses were used to understand the biological mechanism of related genes.

The results indicated that significant volume atrophy in left thalamus, left cerebellum, and bilateral middle frontal gyrus across AD spectrum (Figure 1). These structural changes were positively associated with gene expression levels of ABCA7, SORCS1, SORL1, PILRA, PFDN1, PLXNA4, TRIP4, and CD2AP, whereas were negatively associated with gene expression levels of CD33, PLCG2, APOE, and ECHDC3 across clinical AD spectrum (Figure 2). Further gene enrichment analyses revealed that these positively associated genes were mainly involved in positive regulation of cellular protein localization and negative regulation of cellular component organization, whereas the negatively associated genes were mainly involved in positive regulation of iron transport.

This exploratory study linked the structural changes to gene expression levels by assessing similarity of spatial distribution patterns. These genes were mostly involved in cellular protein localization, cellular component organization, and regulation of iron transport. Overall, these results offered a better understanding of biological mechanisms underlying structural changes in prodromal and clinical AD.

Neurodegenerative/ Late Life (eg. Parkinson’s, Alzheimer’s) ¹

Genetic Association Studies ²

Neurophysiology of Imaging Signals

Aging

Degenerative Disease

MRI

Other - gray matter volume, gene expression, mild cognitive impairments