A quadratic function of activation in individuals at risk of Alzheimer's disease

Introduction: Brain activation is hypothesized to form an inverse U-shape in prodromal Alzheimer's disease (AD), with hyperactivation in the early phase, followed by hypoactivation.

Methods: Using task-related functional magnetic resonance imaging (fMRI), we tested the inverse U-shape hypothesis with polynomial regressions and between-group comparisons in individuals with subjective cognitive decline plus (SCD⁺; smaller hippocampal volumes compared to a group of healthy controls without SCD and/or apolipoprotein E [APOE] ε4 allele) or mild cognitive impairment (MCI).

Results: A quadratic function modeled the relationship between proxies of disease severity (neurodegeneration, memory performance) and left superior parietal activation. Linear negative functions modeled the relationship between neurodegeneration and left hippocampal/right inferior temporal activation. Group comparison indicated presence of hyperactivation in SCD⁺ and hypoactivation in MCI in the left superior parietal lobule, relative to healthy controls.

Discussion: These findings support the presence of an inverse U-shape model of activation and suggest that hyperactivation might represent a biomarker of the early AD stages.