The role of apolipoprotein E (APOE) genotype in early mild cognitive impairment (E-MCI)

Shannon Risacher

doi:10.3389/fnagi.2013.00011

Abstract

Objective: Our goal was to evaluate the association of APOE with amyloid deposition, cerebrospinal fluid levels (CSF) of Aβ, tau, and p-tau, brain atrophy, cognition and cognitive complaints in E-MCI patients and cognitively healthy older adults (HC) in the ADNI-2 cohort.Methods: Two-hundred and nine E-MCI and 123 HC participants from the ADNI-2 cohort were included. We evaluated the impact of diagnostic status (E-MCI vs. HC) and APOE ε4 status (ε4 positive vs. ε4 negative) on cortical amyloid deposition (AV-45/Florbetapir SUVR PET scans), brain atrophy (structural MRI scans processed using voxel-based morphometry and Freesurfer version 5.1), CSF levels of Aβ, tau, and p-tau, and cognitive performance and complaints.Results: E-MCI participants showed significantly impaired cognition, higher levels of cognitive complaints, greater levels of tau and p-tau, and subcortical and cortical atrophy relative to HC participants (p < 0.05). Cortical amyloid deposition and CSF levels of Aβ were significantly associated with APOE ε4 status but not E-MCI diagnosis, with ε4 positive participants showing more amyloid deposition and lower levels of CSF Aβ than ε4 negative participants. Other effects of APOE ε4 status on cognition and CSF tau levels were also observed.Conclusions: APOE ε4 status is associated with amyloid accumulation and lower CSF Aβ, as well as increased CSF tau levels in early prodromal stages of AD (E-MCI) and HC. Alternatively, neurodegeneration, cognitive impairment, and increased complaints are primarily associated with a diagnosis of E-MCI. These findings underscore the importance of considering APOE genotype when evaluating biomarkers in early stages of disease.

Highlights

Alzheimer’s disease (AD) is the most common age-related neurodegenerative disease, featuring cognitive decline, accumulation of amyloid plaques and neurofibrillary tangles, and extensive neurodegeneration (Alzheimer’s Association, 2011; McKhann et al, 2011)
We evaluated the impact of diagnostic status (E-mild cognitive impairment (MCI) vs. HC) and apolipoprotein E (APOE) ε4 status (ε4 positive vs. ε4 negative) on cortical amyloid deposition (AV-45/Florbetapir SUVR positron emission tomography (PET) scans), brain atrophy, cerebrospinal fluid (CSF) levels of Aβ, tau, and p-tau, and cognitive performance and complaints
Cortical amyloid deposition and CSF levels of Aβ were significantly associated with APOE ε4 status but not early MCI (E-MCI) diagnosis, with ε4 positive participants showing more amyloid deposition and lower levels of CSF Aβ than ε4 negative participants

Summary

Introduction

Alzheimer’s disease (AD) is the most common age-related neurodegenerative disease, featuring cognitive decline, accumulation of amyloid plaques and neurofibrillary tangles, and extensive neurodegeneration (Alzheimer’s Association, 2011; McKhann et al, 2011). The specificity of these diagnostic criteria has yet to be determined and may be lower than the L-MCI cut-offs, allowing participants with more diverse causal factors of cognitive decline (other than prodromal AD) to be included in this diagnostic category Future studies examining these clinical criteria and clinical and pathological outcomes of identified E-MCI patients relative to L-MCI patients will be important for understanding the cognitive changes observed in these patients. These new guidelines provide an opportunity to evaluate the role of AD biomarkers and other potential disease-causing factors in a very early clinical stage. A recent study demonstrated increased amyloid binding measured using [18F]Florbetapir positron emission tomography (PET) in patients with E-MCI relative to HC, but no alterations in metabolism as assessed using [18F]FDG PET (Wu et al, 2012)

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