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Apolipoprotein E epsilon4 does not modulate amyloid-β-associated neurodegeneration in preclinical Alzheimer disease.
AJNR Am J Neuroradiol. 2013 Mar; 34(3):505-10.AA

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.

Authors+Show Affiliations

Department of Radiology, University of California, San Diego, La Jolla, California 92037-0841, USA. rdesikan@ucsd.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22976236

Citation

Desikan, R S., et al. "Apolipoprotein E Epsilon4 Does Not Modulate Amyloid-β-associated Neurodegeneration in Preclinical Alzheimer Disease." AJNR. American Journal of Neuroradiology, vol. 34, no. 3, 2013, pp. 505-10.
Desikan RS, McEvoy LK, Holland D, et al. Apolipoprotein E epsilon4 does not modulate amyloid-β-associated neurodegeneration in preclinical Alzheimer disease. AJNR Am J Neuroradiol. 2013;34(3):505-10.
Desikan, R. S., McEvoy, L. K., Holland, D., Thompson, W. K., Brewer, J. B., Aisen, P. S., Andreassen, O. A., Hyman, B. T., Sperling, R. A., & Dale, A. M. (2013). Apolipoprotein E epsilon4 does not modulate amyloid-β-associated neurodegeneration in preclinical Alzheimer disease. AJNR. American Journal of Neuroradiology, 34(3), 505-10. https://doi.org/10.3174/ajnr.A3267
Desikan RS, et al. Apolipoprotein E Epsilon4 Does Not Modulate Amyloid-β-associated Neurodegeneration in Preclinical Alzheimer Disease. AJNR Am J Neuroradiol. 2013;34(3):505-10. PubMed PMID: 22976236.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Apolipoprotein E epsilon4 does not modulate amyloid-β-associated neurodegeneration in preclinical Alzheimer disease. 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 - ,, Y1 - 2012/09/13/ PY - 2012/9/15/entrez PY - 2012/9/15/pubmed PY - 2013/9/13/medline SP - 505 EP - 10 JF - AJNR. American journal of neuroradiology JO - AJNR Am J Neuroradiol VL - 34 IS - 3 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 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. SN - 1936-959X UR - https://www.unboundmedicine.com/medline/citation/22976236/Apolipoprotein_E_epsilon4_does_not_modulate_amyloid_β_associated_neurodegeneration_in_preclinical_Alzheimer_disease_ L2 - http://www.ajnr.org/cgi/pmidlookup?view=long&pmid=22976236 DB - PRIME DP - Unbound Medicine ER -