1 BACKGROUND
Possession of the apolipoprotein E (APOE) ε4 allele is the primary genetic risk factor for the late-onset form of Alzheimer’s disease (AD). While there have been numerous investigations into the mechanism(s) responsible for this increased risk of AD among APOE ε4 carriers, far less research has been performed to understand the specific differ ences in AD-related pathology that occur in the brains of APOE ε4 carriers versus non-carriers. This information is critical, however, as we enter a new era of AD research and treatment, in which different subpopulations of patients and at-risk individuals may require different approaches for preventing, diagnosing, and treating the disease. Fortunately, large cohort studies on human subjects have provided AD researchers with significant amounts of publicly available data, which can be utilized to interrogate the APOE ε4–associated differ ences in AD development and presentation. One such cohort is the Alzheimer’s Disease Neuroimaging Initiative (ADNI), which has been collecting neuroimaging data from elderly individuals (participants range from 55 to 90 years old at the start of the study) for the past two decades. For this study, we used six previously compiled neuroimaging datasets available from ADNI: florbetapir positron emission tomogra phy (PET) measurements of amyloid beta (Aβ) deposition, flortaucipir PET measurements of tau accumulation, fluorodeoxyglucose (FDG) PET measurements of glucose uptake, structural magnetic resonance imaging (MRI) measurements of brain volume, arterial spin labeling (ASL) MRI measurements of cerebral blood flow (CBF), and fluid attenuated inversion recovery (FLAIR) MRI measurements of white matter hyperintensities (WMHs). Each of these neuroimaging biomarkers represent an important pathological manifestation that has been reported either in mild cogni tive impairment (MCI)/AD patients, or in cognitively unimpaired APOE ε4 carriers prior to the development of AD (or in both). Amyloid and tau are well known as the two primary hallmarks of AD pathology, which were first observed in the brain of Auguste Deter by Dr. Alois Alzheimer in the early 1900s.1 Structural MRI measurement of brain atrophy/neurodegeneration is now recognized as an equally important biomarker of AD, with the A/T/N classification scheme adding neurode generation (N) as an essential component for tracking the pathogenesis of AD, along with Aβ (A) and tau (T).2 Decreased glucose uptake, as measured by FDG PET, was also discovered early on as an important phenomenon that occurs in the AD brain, as well as in young/middle aged APOE ε4 carriers long before the development of AD;3–5 in both scenarios, the decreased glucose uptake primarily occurs in regions associated with the default mode network (DMN), which includes the posterior cingulate cortex/precuneus, the medial prefrontal cortex, and the angular gyrus.6 Dysregulated neuronal excitability is another phenotype that has been reported during early AD pathogenesis and in cognitively unimpaired APOE ε4 carriers. While this dysregulated excitability has most commonly been reported during task-based blood oxygenation level dependent (BOLD) MRI studies,7–15 other AD and APOE ε4 studies have used ASL MRI measurements of resting-state CBF levels (see review by Zhang et al.16), which is correlated with brain activity. Finally, numerous investigations have also reported increased detection ofWMHs in the brains of AD patients,17–19 which is generally hypothesized to be an indicator of vascular impairments,20 although alternative explanations exist as well.21 For our analyses, we performed separate comparisons of each neuroimaging biomarker in the brains of APOE ε4 carriers versus non carriers. First, we measured the overall differences within each of the three diagnostic groups classified by ADNI (cognitively normal [CN], MCI, and AD), controlling for sex and age between the APOE ε4 carrier and non-carrier groups. Then, we performed separate analyses strati-
