Valla J, Yaari R, Wolf AB, Kusne Y, Beach TG, Roher AE, Corneveaux JJ, Huentelman MJ, Caselli RJ, Reiman EM. Reduced posterior cingulate mitochondrial activity in expired young adult carriers of the APOE ε4 allele, the major late-onset Alzheimer's susceptibility gene. J Alzheimers Dis. 2010;22(1):307-13. PubMed.
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Gladstone Institute of Neurological Disease, UCSF
The ε4 allele of apolipoprotein (Apo) E is the major susceptibility gene for late-onset Alzheimer’s disease (AD). In most clinical studies, ApoE4 carriers account for 65-80 percent of all late-onset AD cases (1), highlighting the importance of ApoE4 in AD pathogenesis. A long-standing question about ApoE4 and AD is whether ApoE4 is solely a modifier of amyloid-β (Aβ) pathology or an independent causative factor for AD.
One way of addressing this question is to determine the earliest brain changes associated with ApoE4 and their relationship with Aβ pathology. Toward this goal, previous studies have shown in young adults (age 20-35) that ApoE4 carriers have significantly decreased glucose metabolism and significantly increased regional coactivation in brain areas later vulnerable to AD (2,3). Thus, the effects of ApoE4 in human brains occur several decades before possible onset of dementia. The current paper by Valla et al. adds another important observation showing that young adult (age 21-40) carriers of ApoE4 also have significantly reduced mitochondrial activity in the same brain area. Valla’s study is important and has significant implications.
First, it shows that the detrimental effect of ApoE4 on mitochondrial function in the posterior cingulate cortex occurs not only at young ages, but also before any evidence of Aβ or tau pathology. Thus, this study provides for the first time evidence in humans that ApoE4-driven mitochondrial impairment precedes Aβ pathology in a brain area later vulnerable to AD.
Second, it supports the notion that ApoE4 could be an independent causative factor for AD (4). We and others have previously demonstrated in vivo and in vitro that ApoE4 undergoes neuron-specific proteolysis, generating toxic fragments that cause cellular and mitochondrial dysfunction in the absence of Aβ accumulation (5,6), including direct binding to electron transport complex III and IV subunits leading to decreased enzyme activities (7). Importantly, ApoE4 is more susceptible than ApoE3 to the cleavage, and ApoE4 carriers have more fragments in their brains than non-carriers (8).
Valla’s study also raises new questions for further investigation. Does ApoE4 affect mitochondrial function in other regions of the brain? Could ApoE4 impair mitochondrial function in all classes or subclasses of neurons? Does ApoE4-associated mitochondrial impairment directly initiate AD pathogenesis or predispose the affected brain areas to other AD-causative factors? Answering these questions should shed light on the mechanisms underlying ApoE4’s contribution to AD and on drug development targeting ApoE4’s detrimental effects in early stages of AD.
References:
Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, Myers RH, Pericak-Vance MA, Risch N, van Duijn CM. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA. 1997 Oct 22-29;278(16):1349-56. PubMed.
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Nakamura T, Watanabe A, Fujino T, Hosono T, Michikawa M. Apolipoprotein E4 (1-272) fragment is associated with mitochondrial proteins and affects mitochondrial function in neuronal cells. Mol Neurodegener. 2009;4:35. PubMed.
Harris FM, Brecht WJ, Xu Q, Tesseur I, Kekonius L, Wyss-Coray T, Fish JD, Masliah E, Hopkins PC, Scearce-Levie K, Weisgraber KH, Mucke L, Mahley RW, Huang Y. Carboxyl-terminal-truncated apolipoprotein E4 causes Alzheimer's disease-like neurodegeneration and behavioral deficits in transgenic mice. Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):10966-71. PubMed.
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