Abstract
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. 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. 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. 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.
Highlights
BACKGROUND AND PURPOSEAmong cognitively healthy older individuals, the relationship among the 2 hallmark proteins of AD (A and APOE 4) and neurodegeneration is not well-understood
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 4 primarily influences the pathology of Alzheimer disease via A-related mechanisms, and in turn, A-associated neurodegeneration occurs only in the presence of p-
The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer Disease Cooperative Study at the University of California, San Diego
Summary
We examined 107 cognitively healthy older adults who underwent longitudinal MR imaging and baseline lumbar puncture. A total of 115 cognitively healthy older individuals had undergone longitudinal MR imaging, CSF lumbar puncture, and APOE 4 genotyping. Of these individuals, we restricted our analyses to those participants (n ϭ 107) with qualityassured baseline and at least 1 follow-up MR imaging (6 months to 3.5 years; 10% with 6-month follow-up, 15% with 12-month follow-up, 34% with 23-month follow-up, and 41% with 36month follow-up) available as of December 2011. Using recently proposed CSF cutoffs,[15] we classified all participants on the basis of high (Ͼ23 pg/mL, “positive”) and low (Ͻ23 pg/ mL, “negative”) p- levels, and on low (Ͻ192 pg/mL, “positive”) and high (Ͼ192 pg/mL, “negative”) A1–42 levels (Tables 1 and 2)
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