Exploring Early Signs of Structural Brain Changes in Mid-Age Apolipoprotein E epsilon-4 Carriers

Abstract

Abstract Background: Neuronal degeneration, a key feature of Alzheimer’s disease (AD), marks a crucial preclinical phase, where a person has no apparent cognitive symptoms but show some pathophysiological changes. Several studies have explored the time course of these early changes using Cerebrospinal Fluid measures and Ionizing Imaging scans. But these methods are quite invasive, and new non-invasive approaches such as blood biomarkers and magnetic resonance imaging (MRI) offer a new pathway towards early investigations. We ask whether early pathophysiological changes are present in mid-age healthy people carrying the Apolipoprotein E epsilon-4 (APOeE4) genotype, the biggest risk factor for late onset, non- familial AD. Objectives: To assess whether APOEe4 status is associated with subtle brain changes in mid age healthy adults and whether such changes, if any, are related to fine deficits in cognition or to inflammatory markers. Methods: The study comprised three phases: Phase1 Recruitment and genotyping of mid-age adults (42-59), subsequently pseudo-randomly selected to participate in the study. Phase2 comprised a blood sample, for biomarker analysis and kidney function to confirm eligibility for the final phase, and a memory task. Phase3 comprised a 70-minute brain scan on 3T scanner, including structural acquisitions and gadolinium-based dynamic contrast-enhanced MRI. Results: Although non-significant at the conventional statistical level, subtle differences in blood-brain barrier permeability, inflammatory biomarkers and brain structure were identified in the composite profiles between healthy mid-age APOEe4 carriers and non-carriers, matched on age, education and gender. Discussion: This study demonstrated a trend towards change emerging from mid-age, with quantitative but not qualitative differences observable on a number of the measures. Results from this study have potential for impact on early diagnosis of AD and will facilitate development of early interventions to change the trajectory of decline.