In the context of this review, we define hyperactivation as higher blood oxygenation level-dependent (BOLD) signal on functional MRI (fMRI) in a single individual or a group of individuals either with biomarkers supportive of Alzheimer's disease (i.e. Aβ and tau) or at risk of developing Alzheimer’s disease dementia [e.g. mild cognitive impairment (MCI), APOE4 carriership] (see Fig. 1). The gene discussed is APOE; the disease is early-onset autosomal dominant Alzheimer disease.