APOE ε4–associated heterogeneity of neuroimaging biomarkers across the Alzheimer’s disease continuum

22 8月 2025
Author :  
APOE ε4–associated heterogeneity of neuroimaging biomarkers across the Alzheimer’s disease continuum

Jason Mares1,2 Gautam Kumar1,3,4 Anurag Sharma1,3 Sheina Emrani5 Laura Beth McIntire6 Jia Guo7,8 Vilas Menon1,2 Tal Nuriel1,3 for the Alzheimer’s Disease Neuroimaging Initiative

1 Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University, New York, New York, USA

2 Department of Neurology, Columbia University, New York, New York, USA

3 Department of Pathology and Cell Biology, Columbia University, New York, New York, USA

4 Department of Neurobiology, University of Maryland, Baltimore, Maryland, USA

5 Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

6 Lipidomics and Biomarker Discovery Lab, Brain Health Imaging Institute, Department of Radiology, Weill Cornell Medicine, New York, New York, USA

7 Department of Psychiatry, Columbia University, New York, New York, USA

8 Zuckerman Institute, Columbia University, New York, New York, USA

Correspondence

Tal Nuriel, Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University, 630 W. 168th St., P&S 12-420E, New York, NY 10032, USA. Email: 该Email地址已收到反垃圾邮件插件保护。要显示它您需要在浏览器中启用JavaScript。 The Alzheimer’s Disease Neuroimaging Initiative: Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data, but did not participate in analysis or writing of this report.

Funding information

NIA, Grant/Award Numbers: K01 AG061264, R01 AG070202, R01 AG078800, R01 AG066831, U19 AG024904 This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

© 2025 The Author(s). Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association

Abstract

INTRODUCTION: While the role of apolipoprotein E (APOE) ε4 in Alzheimer’s dis ease (AD) susceptibility has been studied extensively, much less is known about the differences in disease presentation in APOE ε4 carriers versus non-carriers.

METHODS: To help elucidate these differences, we performed a broad analysis com paring the regional levels of six different neuroimaging biomarkers in the brains of APOE ε4 carriers versus non-carriers who participated in the Alzheimer’s Disease Neuroimaging Initiative (ADNI).

RESULTS:We observed significant APOE ε4–associated heterogeneity in regional amy loid beta deposition, tau accumulation, glucose uptake, brain volume, cerebral blood flow, and white matter hyperintensities within each AD diagnostic group. We also observed important APOE ε4–associated differences in cognitively unimpaired indi viduals who converted to mild cognitive impairment/AD versus those who did not

DISCUSSION: This observed heterogeneity in neuroimaging biomarkers between APOE ε4 carriers versus non-carriers may have important implications regarding the prevention, diagnosis, and treatment of AD in different subpopulations.

KEYWORDS

Alzheimer’s disease, Alzheimer’s Disease Neuroimaging Initiative, apolipoprotein E, biomarkers, heterogeneity, neuroimaging

Highlights

∙ An extensive study was performed on the apolipoprotein E (APOE) ε4–associated heterogeneity in neuroimaging biomarkers from the Alzheimer’s Disease Neu roimaging Initiative.

∙ Robust APOE ε4–associated increases in amyloid beta (Aβ) deposition throughout the brain, in every diagnostic group, were observed.

∙ APOE ε4–associated increases in tau pathology, decreases in glucose uptake, and increases in brain atrophy, which expand in regional scope and magnitude with disease progression, were observed.

∙ Significant sex- and age-related differences in APOE ε4–associated neuroimaging biomarker heterogeneity, with overall increases in pathological presentation in female APOE ε4 carriers, were observed.

∙ Regional differences in Aβ deposition, tau accumulation, glucose uptake, ventricle size, and white matter hyperintensities were observed in cognitively normal partic ipants who converted to mild cognitive impairment/Alzheimer’s disease, which may hold potential predictive value.

 

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-

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