TY - JOUR T1 - <em>Apolipoprotein E</em> ε4 Does Not Modulate Amyloid-β–Associated Neurodegeneration in Preclinical Alzheimer Disease JF - American Journal of Neuroradiology JO - Am. J. Neuroradiol. SP - 505 LP - 510 DO - 10.3174/ajnr.A3267 VL - 34 IS - 3 AU - R.S. Desikan AU - L.K. McEvoy AU - D. Holland AU - W.K. Thompson AU - J.B. Brewer AU - P.S. Aisen AU - O.A. Andreassen AU - B.T. Hyman AU - R.A. Sperling AU - A.M. Dale AU - for the Alzheimer's Disease Neuroimaging Initiative Y1 - 2013/03/01 UR - http://www.ajnr.org/content/34/3/505.abstract N2 - 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 Aβ1–42, CSF p-τ and CSF Aβ1–42, 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 Aβ1–42 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 Aβ1–42 on entorhinal cortex atrophy rate, indicating elevated atrophy with time in individuals with increased CSF p-τ and decreased CSF Aβ1–42. The APOE ε4 genotype was significantly and specifically associated with CSF Aβ1–42. However, the interaction between the APOE ε4 genotype and either CSF Aβ1–42 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. Aβamyloid-βADAlzheimer diseaseAPOE ε4ε4 allele of apolipoprotein EHChealthy controlsp-τphospho-τ181pSEstandard error of the mean ER -