TaubCONNECT Research Perspectives

AN NIA-FUNDED ALZHEIMER'S DISEASE RESEARCH CENTER

Columbia University
Irving Medical Center
Neurological Institute

710 West 168th Street, 3rd floor
(212) 305-1818

TaubCONNECT Research Perspective:
May 2025

View 2025 - 2021 Archive || 2020 Archive || 2019 Archive || 2018 Archive || 2017 and Earlier Archive

1: CLU Alleviates Alzheimer's Disease-Relevant Processes by Modulating Astrocyte Reactivity and Microglia-Dependent Synaptic Density

2: Selective Removal of Astrocytic PERK Protects Against Glymphatic Impairment and Decreases Toxic Aggregation of β-Amyloid and Tau

3: APOE ε4-Associated Heterogeneity of Neuroimaging Biomarkers Across the Alzheimer's Disease Continuum

CLU Alleviates Alzheimer's Disease-Relevant Processes by Modulating Astrocyte Reactivity and Microglia-Dependent Synaptic Density


Vilas Menon, PhD	Philip L. De Jager, MD, PhD

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Vilas Menon, PhD
Assistant Professor of Neurological Sciences (in Neurology and the Taub Institute)
vm2545@cumc.columbia.edu

Philip L. De Jager, MD, PhD
Weil-Granat Professor of Neurology(in The Taub Institute)
pld2115@cumc.columbia.edu

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Selective Removal of Astrocytic PERK Protects Against Glymphatic Impairment and Decreases Toxic Aggregation of β-Amyloid and Tau


Kai Chen, PhD		Tal Nuriel, PhD		Osama Al Dalahmah, MD, PhD

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Kai Chen, PhD
Associate Research Scientist in the Department of Anesthesiology
kc3378@cumc.columbia.edu

Tal Nuriel, PhD
Assistant Professor of Pathology and Cell Biology (in the Taub Institute) at CUMC
tn2283@cumc.columbia.edu

Osama Al Dalahmah, MD, PhD
Assistant Professor in Pathology and Cell Biology
oa2298@cumc.columbia.edu

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APOE4-Associated Heterogeneity of Neuroimaging Biomarkers Across the Alzheimer's Disease Continuum


Tal Nuriel, PhD		Osama Al Dalahmah, MD, PhD

Figure 1. APOE ε4–associated differences by diagnostic group. We performed linear mixed‐effects analyses comparing regional neuroimaging biomarker levels between APOE ε4 carriers versus non‐carriers, classified into one of three diagnostic groups: CN, MCI, or AD participants. Regions with significantly different biomarker levels (p ‹ 0.05) between the APOE ε4 carriers and non‐carriers in each diagnostic group were graphed onto box plots with two of the top regions labeled (A). We also rendered the regions onto a human brain template (displayed axially, coronally, and sagittally) using different shades of red (upregulated in APOE ε4 carriers) or blue (downregulated in APOE ε4 carriers) that corresponds to the magnitude of their statistical difference (beta) between APOE ε4 carrier groups (B)–(F). We show the rendered biomarker differences from each analysis that resulted in at least one statistically different region, which in this diagnostic group–level comparison included Aβ PET results (B), tau PET results (C), FDG PET results (D), structural MRI results (E), and FLAIR MRI WMH results (F). Aβ, amyloid beta; AD, Alzheimer's disease; APOE, apolipoprotein E; ASL, arterial spin labeling; CBF, cerebral blood flow; CN, cognitively normal; FDG, fluorodeoxyglucose; FLAIR, fluid‐attenuated inversion recovery; MCI, mild cognitive impairment; MRI, magnetic resonance imaging; PET, positron emission tomography; WMH, white matter hyperintensity

Apoliprotein E ε4 (APOE4) is the primary genetic risk factor for the late-onset, sporadic form of Alzheimer’s disease (AD). As such, researchers have extensively investigated the reasons why APOE4 increases an individual’s susceptibility to AD. However, much less research has been conducted to identify the differences in disease presentation that occur between APOE4 carriers vs. non-carriers. To help address this topic, we performed a comprehensive analysis of neuroimaging biomarkers in the brains of APOE4 carriers vs. non-carriers who participated in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Specifically, we processed ADNI data from six neuroimaging biomarkers: florbetapir positron emission tomography (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). Furthermore, we compared the regional levels of each of these biomarkers in APOE4 carriers vs. non-carriers at three separate ADNI-determined diagnostic stages: cognitively normal (CN), mild cognitive impairment (MCI), and AD. The analysis was conducted under my supervision and primarily performed by Jason Mares, a highly skilled bioinformatician in Dr. Vilas Menon’s group.

Overall, we observed extensive heterogeneity in how these neuroimaging biomarkers present in the brains of APOE4 carriers vs. non-carriers. In particular, we observed robust APOE4–associated increases in Aβ deposition throughout the brain, in all three diagnostic groups. We also observed APOE4–associated increases in tau pathology, decreases in glucose uptake, and increases in brain atrophy, which expanded in regional scope and magnitude with disease progression. Significant sex‐ and age‐related differences in APOE4–associated neuroimaging biomarker heterogeneity were also observed, with female APOE4 carriers displaying notable increases in pathological presentation for a variety of biomarkers. Lastly, specific regional differences in Aβ deposition, tau accumulation, glucose uptake, ventricle size, and white matter hyperintensities were observed in CN participants who converted to MCI/AD during their participation in ADNI, which we showed may hold potential predictive value for determining the likelihood of MCI/AD conversion among cognitively unimpaired individuals.

Our study highlights the need for genotype-specific approaches in AD diagnostics and interventions, given the clear biological heterogeneity associated with an individual’s APOE4 status.

Tal Nuriel, PhD
Assistant Professor of Pathology and Cell Biology (in the Taub Institute) at CUMC
tn2283@cumc.columbia.edu

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Columbia University Irving Medical Center Neurological Institute

TaubCONNECT Research Perspective: May 2025