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AJNR Am J Neuroradiol. 2013 Mar;34(3):505-10. doi: 10.3174/ajnr.A3267. Epub 2012 Sep 13.

Apolipoprotein E epsilon4 does not modulate amyloid-β-associated neurodegeneration in preclinical Alzheimer disease.

Author information

1
Department of Radiology, University of California, San Diego, La Jolla, California 92037-0841, USA. rdesikan@ucsd.edu

Abstract

BACKGROUND AND PURPOSE:

Among cognitively healthy older individuals, the relationship among the 2 hallmark proteins of AD (Aβ and τ APOE ε4) and neurodegeneration is not well-understood. Here, we investigated the relationship between Aβ, p-τ, and APOE ε4 on longitudinal brain atrophy in preclinical AD.

MATERIALS AND METHODS:

We examined 107 cognitively healthy older adults who underwent longitudinal MR imaging and baseline lumbar puncture. Within the same linear mixed-effects model, we concurrently investigated main and interactive effects between the APOE ε4 genotype and CSF Aβ(1-42), CSF p-τ and CSF Aβ(1-42), and the APOE ε4 genotype and CSF p-τ on entorhinal cortex atrophy rate. We also examined the relationship of APOE ε4, CSF p-τ, and CSF Aβ(1-42) on the atrophy rate of other AD-vulnerable neuroanatomic regions.

RESULTS:

The full model with main and interactive effects demonstrated a significant interaction only between CSF p-τ and CSF Aβ(1-42) on entorhinal cortex atrophy rate, indicating elevated atrophy with time in individuals with increased CSF p-τ and decreased CSF Aβ(1-42). The APOE ε4 genotype was significantly and specifically associated with CSF Aβ(1-42). However, the interaction between the APOE ε4 genotype and either CSF Aβ(1-42) or CSF p-τ on entorhinal cortex atrophy rate was not significant. We found similar results in other AD-vulnerable regions.

CONCLUSIONS:

On the basis of our findings and building on prior experimental evidence, we propose a model of the pathogenic cascade underlying preclinical AD in which APOE ε4 primarily influences the pathology of Alzheimer disease via Aβ-related mechanisms, and in turn, Aβ-associated neurodegeneration occurs only in the presence of p-τ.

PMID:
22976236
PMCID:
PMC4041629
DOI:
10.3174/ajnr.A3267
[Indexed for MEDLINE]
Free PMC Article

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