Apolipoprotein Eε4 Does Not Modulate Amyloid-β–Associated Neurodegeneration in Preclinical Alzheimer Disease

Abstract

Background and Purpose Among cognitively normal older individuals, the relationship between the two hallmark proteins of Alzheimer’s disease (AD), amyloid-β (Aβ) and tau, the ε4 allele of apolipoprotein E (APOE ε4), and neurodegeneration is not well understood. 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 APOE ε4 genotype and CSF Aβ1-42, CSF phospo-tau (p-tau181p) and CSF Aβ1-42, and APOE ε4 genotype and CSF p-tau181p on entorhinal cortex atrophy rate. We also examined the relationship between APOE ε4, CSF p-tau181p, and CSF Aβ1-42 on 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-tau181p and CSF Aβ1-42 on entorhinal cortex atrophy rate indicating elevated atrophy over time in individuals with increased CSF p-tau181p and decreased CSF Aβ1-42. APOE ε4 genotype was significantly and specifically associated with CSF Aβ1-42. However, the interaction between APOE ε4 genotype and either CSF Aβ1-42 or CSF p-tau181p on entorhinal cortex atrophy rate was not significant. We found similar results in other AD-vulnerable regions. Conclusions Based upon our findings and building upon prior experimental evidence, we propose a model of the pathogenic cascade underlying preclinical AD where APOE ε4 primarily influences Alzheimer’s pathology via Aβ-related mechanisms and in turn, Aβ-associated neurodegeneration occurs only in the presence of phospho-tau.

The Role of Clusterin in Amyloid-β–Associated Neurodegeneration

“…To determine whether the effect of clusterin on Aβ-associated neurodegeneration is independent from the previously observed effect of p-tau on Aβ-associated neurodegeneration, 11-13 we included interaction terms with CSF p-tau 181p status (for additional details see Subjects and Methods and Equation 2). These analyses on the full cohort revealed significant interactions between CSF clusterin, CSF Aβ 1-42 status, and time (β-coefficient = -0.026, SE = 0.01, p = 0.01) and CSF p-tau 181p status, CSF Aβ 1-42 status and time (β-coefficient = -0.010, SE = 0.004, p = 0.01) on entorhinal cortex atrophy indicating independent effects of CSF clusterin and CSF p-tau 181p on CSF Aβ 1-42 associated volume loss.…”

“…11-13 To test whether the effect of clusterin on Aβ-associated neurodegeneration is independent from the effect of p-tau on Aβ-associated neurodegeneration, we performed secondary analyses and fit the following linear mixed effects model:…”

Preclinical Alzheimer's disease and its outcome: a longitudinal cohort study

“…While APOE -ε4 is often found to be a good predictor for cognitive decline in unselected populations, the lack of its prognostic utility in individuals with AD pathology is consistent with previous studies. 33 …”

Nonlinear cerebral atrophy patterns across the Alzheimer's disease continuum: impact of APOE4 genotype

“…Elucidating the relationship between these three factors, CSF biomarkers, ApoE ε4, and regional brain atrophy, might provide important information about the vulnerability of the brain to AD (Desikan, et al, 2013).…”