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PT  - JOURNAL ARTICLE
AU  - Desikan, R.S.
AU  - McEvoy, L.K.
AU  - Holland, D.
AU  - Thompson, W.K.
AU  - Brewer, J.B.
AU  - Aisen, P.S.
AU  - Andreassen, O.A.
AU  - Hyman, B.T.
AU  - Sperling, R.A.
AU  - Dale, A.M.
AU - for the Alzheimer's Disease Neuroimaging Initiative
TI  - &lt;em&gt;Apolipoprotein E&lt;/em&gt; ε4 Does Not Modulate Amyloid-β–Associated Neurodegeneration in Preclinical Alzheimer Disease
AID  - 10.3174/ajnr.A3267
DP  - 2013 Mar 01
TA  - American Journal of Neuroradiology
PG  - 505--510
VI  - 34
IP  - 3
4099  - http://www.ajnr.org/content/34/3/505.short
4100  - http://www.ajnr.org/content/34/3/505.full
SO  - Am. J. Neuroradiol.2013 Mar 01; 34
AB  - 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