Differential Aging Trajectories of Modulation of Activation to Cognitive Challenge in APOE ε4 Groups: Reduced Modulation Predicts Poorer Cognitive Performance.

The present study was designed to investigate the effect of a genetic risk factor for Alzheimer's disease (AD), ApolipoproteinE ε4 (APOEε4), on the ability of the brain to modulate activation in response to cognitive challenge in a lifespan sample of healthy human adults. A community-based sample of 181 cognitively intact, healthy adults were recruited from the Dallas-Fort Worth metroplex. Thirty-one APOEε4+ individuals (48% women), derived from the parent sample, were matched based on sex, age, and years of education to 31 individuals who were APOEε4-negative (APOEε4-). Ages ranged from 20 to 86 years of age. Blood oxygen level-dependent functional magnetic resonance imaging was collected during the performance of a visuospatial distance judgment task with three parametric levels of difficulty. Multiple regression was used in a whole-brain analysis with age, APOE group, and their interaction predicting functional brain modulation in response to difficulty. Results revealed an interaction between age and APOE in a large cluster localized primarily to the bilateral precuneus. APOEε4- individuals exhibited age-invariant modulation in response to task difficulty, whereas APOEε4+ individuals showed age-related reduction of modulation in response to increasing task difficulty compared with ε4- individuals. Decreased modulation in response to cognitive challenge was associated with reduced task accuracy as well as poorer name-face associative memory performance. Findings suggest that APOEε4 is associated with a reduction in the ability of the brain to dynamically modulate in response to cognitive challenge. Coupled with a significant genetic risk factor for AD, changes in modulation may provide additional information toward identifying individuals potentially at risk for cognitive decline associated with preclinical AD.SIGNIFICANCE STATEMENT Understanding how risk factors for Alzheimer's disease (AD) affect brain function and cognition in healthy adult samples may help to identify the biomarkers needed to detect nonsymptomatic, preclinical phases of the disease. Findings from the current study show that ApolipoproteinE ε4-positive (APOEε4+) individuals exhibit an altered lifespan trajectory in the ability of the brain to dynamically modulate function to cognitive challenge compared with APOEε4- individuals. This effect manifests in otherwise healthy individuals who are at increased risk for AD in the precuneus, a salient region for early AD changes. Notably, these functional alterations are detrimental to performance, and thus, the combination of a genetic risk factor and altered modulation may provide important information for identifying individuals who are at increased risk for AD.