The Effects of the Apoe4 Allele on Cerebral Structural and Functional Connectivity- a Diffusion Tensor Imaging and Resting-State Mri Study

Alzheimer’s disease (AD) is the most common cause of dementia in the world. Although the specific pathophysiology of AD remains unclear, compelling evidence has shown that genetic factors play important roles in its occurrence. Apolipoprotein E, ε4 allele (APOE4), is the best-documented genetic risk factor for sporadic AD. Previous research identified APOE4 carriers present with more severe memory impairment, and greater reductions in regional brain volume and metabolism, in comparison to non-APOE4 carriers. Our preliminary study using n-back working memory (WM) blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) also demonstrated that during low WM load tasks (1-back > 0-back condition), the APOE4 carriers recruited significantly greater additional processing resources than the non-APOE4 carriers. During moderate and high WM load tasks (2-back > 1-back and 3-back > 2-back conditions), the APOE4 carrier group displayed lesser increased in activation than the non-APOE4 carrier group. The patterns of brain activation during different levels of WM load suggest possible subclinical impairment of WM capacity due to the existence of APOE4. These findings indicate that APOE4 is important for brain functioning, but the mechanisms by which it exerts its effects need further clarification. Our brain is a complex network of functionally and structurally interconnected regions. Examining the human brain as an integrative network of functional and structural brain regions can provide new insights about large-scale neuronal communication and a platform to examine how this organization may be altered in neurodegenerative diseases. In the past few years, novel neuroimaging techniques, especially diffusion tensor image (DTI) and resting-state fMRI, have enabled the in vivo examination of structural and functional connectivity on a whole-brain scale. DTI is a MRI technique that enables the reconstruction of white matter tracts in the human brain. Resting-state functional connectivity techniques, which rely on detecting coherent patterns of spontaneous activity by measuring the level of correlated dynamics of fMRI time-series, can describe the relationship between the neuronal activation patterns of anatomically separated brain regions, reflecting the level of functional communication between regions. Recently, a number of studies have suggested a direct association between functional and structural connectivity in the human brain by combining resting-state fMRI with structural DTI measurements. By using both techniques, a further understanding of how the extent and specific area of involvement by APOE4 polymorphism and how the involvement affects the functional and structural connectivity is expected. The specific aims of this three-year study are two-folds: First one is to prove the effects of the APOE4 allele on cerebral structural and functional connectivity and to demonstrate the possible locations or connectivity circuits on which APOE4 allele exerts. Both model-free and model-dependent methods will be used in resting-state fMRI analyses and both voxel-based and region-of-interest methods will be taken in DTI analyses. Second one is to compare the aforementioned methods to find out the most sensitive and specific technique in early detection of subclinical impairments in APOE4 carriers and to evaluate the feasibility of taking them as a biomarker in identifying individuals with potential AD risk. DTI and resting-state fMRI are powerful tools for study of both brain functions and brain network. This could be a new field of neuroscience.