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...  Read more

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:
1. Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, Myers RH, Pericak-Vance MA, Risch N, van Duijn CM (1997) Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. J. Am. Med. Assoc. 278, 1349-1356. Abstract

2. Reiman EM, Chen K, Alexander GE, Caselli RJ, Bandy D, Osborne D, Saunders AM, Hardy J (2004) Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's dementia. Proc. Natl. Acad. Sci. USA. 101:284-289. Abstract

3. Filippini N, MacIntosh BJ, Hough MG, Goodwin GM, Frisoni GB, Smith SM, Matthews PM, Bechmann CF, Mackay CE (2009) Distinct patterns of brain activity in young carriers of the APOE-epsilon4 allele. Proc. Natl. Acad. Sci. USA. 106:7209-7214. Abstract

4. Huang, Y (2010) Abeta-independent roles of apolipoprotein E4 in the pathogenesis of Alzheimer's disease. Trends Mol. Med. 16:287-294. Abstract

5. Brecht WJ, Harris FM, Chang S, Tesseur I, Yu GQ, Xu Q, Wyss-Coray T, Buttini M, Mucke L, Mahley RW, and Huang Y (2004) Neuron-specific apolipoprotein E4 proteolysis is associated with increased tau phosphorylation in brains of transgenic mice. J. Neurosci. 24:2527-2534. Abstract

6. Chang S, Ma TR, Miranda RD, Balestra ME, Mahley RW, and Huang Y (2005) Lipid-and receptor-binding regions of apolipoprotein E4 fragments act in concert to cause mitochondrial dysfunction and neurotoxicity. Proc. Natl. Acad. Sci. USA. 102:18694-18699. Abstract

7. Nakamura T, Watanake A, Fujino T, Hosono T, Michikawa M (2009) Apolipoprotein E4 (1-272) fragment is associated with mitochondrial proteins and affects mitochondrial function in neuronal cells. Mol. Neurodegener. 4:35-46. Abstract

8. Harris FM, Walter JB, Xu Q, Tesseur I, Kekonius L, Wyss-Coray T, Fish JD, Masliah E, Hopkins PC, Scearce-Levie K, Weisgraber KH, Mucke L, Mahley RW, and Huang Y (2003). Carboxyl-terminal-truncated apolipoprotein E4 causes Alzheimer’s disease-like neurodegeneration and behavioral deficits in transgenic mice. Proc. Natl. Acad. Sci. USA. 100:10966-10971. Abstract

View all comments by Yadong Huang

These are intriguing findings.

It is clear from animal and human studies that ApoE4 has a major effect on Aβ aggregation in the brain, via affecting Aβ clearance and the process of Aβ aggregation itself.

ApoE may have a variety of other actions in the central nervous system (CNS). The intriguing results here suggest that ApoE4 may be influencing brain glucose metabolism independently of its effect on Aβ aggregation.

Since the results were all obtained in relatively old individuals (mean age in their seventies), it will be both interesting and important in future studies to determine in large numbers of humans at different ages, especially young adults, whether similar findings are also present. Some studies that are quoted in the discussion of the paper suggest that there are ApoE isoform-related differences in brain activity/metabolism in young adults. It will also be important to verify this in larger sample sets. If there are differences proved early in life, this would provide important insights into how ApoE influences AD and potentially other CNS diseases.

View all comments by David Holtzman

I daresay, "most intriguing" (referring to the famous Belgian Janssen twins). This could add weight to the Tomm40 implication in AD—but also to "cognitive ageing"?

References:
Davies G, Harris SE, Reynolds CA, Payton A, Knight HM, Liewald DC, Lopez LM, Luciano M, Gow AJ, Corley J, Henderson R, Murray C, Pattie A, Fox HC, Redmond P, Lutz MW, Chiba-Falek O, Linnertz C, Saith S, Haggarty P, McNeill G, Ke X, Ollier W, Horan M, Roses AD, Ponting CP, Porteous DJ, Tenesa A, Pickles A, Starr JM, Whalley LJ, Pedersen NL, Pendleton N, Visscher PM, Deary IJ. A genome-wide association study implicates the APOE locus in nonpathological cognitive ageing. Mol Psychiatry. 2012 Dec 4. Abstract

View all comments by Fred Van Leuven

There is strong evidence that ApoE interacts with β amyloid to affect its aggregation and clearance, and this may be a major component of ApoE’s role in AD. That said, a number of other potential mechanisms may be involved in ApoE’s contribution to AD, including effects on neurodevelopment and synaptic plasticity. Of the most interest to us has been ApoE's effects on brain energy metabolism, more broadly defined as neuroenergetics.

In our recent review (1), we explore the links between ApoE and neuroenergetics, drawing on a significant body of brain imaging data and experimental studies using cell culture and animal models. Notably, there are a number of cellular and molecular mechanisms for ApoE to act on energetic processes, including impacts on mitochondrial function and intracellular transport (1,2). Focusing on young adults, brain imaging studies have demonstrated that ApoE4 is associated with FDG-PET measured declines in resting-brain glucose metabolism (3), H2150 PET measured alterations in resting- and task-based cerebral blood flow (4,5), fMRI measured alterations...  Read more

There is strong evidence that ApoE interacts with β amyloid to affect its aggregation and clearance, and this may be a major component of ApoE’s role in AD. That said, a number of other potential mechanisms may be involved in ApoE’s contribution to AD, including effects on neurodevelopment and synaptic plasticity. Of the most interest to us has been ApoE's effects on brain energy metabolism, more broadly defined as neuroenergetics.

In our recent review (1), we explore the links between ApoE and neuroenergetics, drawing on a significant body of brain imaging data and experimental studies using cell culture and animal models. Notably, there are a number of cellular and molecular mechanisms for ApoE to act on energetic processes, including impacts on mitochondrial function and intracellular transport (1,2). Focusing on young adults, brain imaging studies have demonstrated that ApoE4 is associated with FDG-PET measured declines in resting-brain glucose metabolism (3), H2150 PET measured alterations in resting- and task-based cerebral blood flow (4,5), fMRI measured alterations in default-mode network activity at rest and during task activation (6-8), DTI measured reductions in functional anisotropy (9), and potential differences in brain volume measured by MRI (10-12); our earlier study indicated these may be occurring prior to any measurable change in amyloid protein level, plaque deposition, or neurofibrillary tangles (13). We agree with David Holtzman that future study over a wider age range (especially among young adults) will be important in understanding the dynamics of any ApoE effects. Elucidation of the links between ApoE and synaptic activity, brain networks, and neuroenergetics is an intriguing area of ongoing research.

References:
1. Wolf AB, Caselli RJ, Reiman EM, Valla J. APOE and neuroenergetics: an emerging paradigm in Alzheimer's disease. Neurobiol Aging. 2012 Nov 16. Abstract

2. Mahley RW, Huang Y. Apolipoprotein e sets the stage: response to injury triggers neuropathology. Neuron. 2012 Dec 6;76(5):871-85. Abstract

3. Reiman EM, Chen K, Alexander GE, Caselli RJ, Bandy D, Osborne D, Saunders AM, Hardy J. Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's dementia. Proc Natl Acad Sci U S A. 2004 Jan 6;101(1):284-9. Abstract

4. Scarmeas N, Habeck CG, Hilton J, Anderson KE, Flynn J, Park A, Stern Y. APOE related alterations in cerebral activation even at college age. J Neurol Neurosurg Psychiatry. 2005 Oct;76(10):1440-4. Abstract

5. Scarmeas N, Habeck CG, Stern Y, Anderson KE. APOE genotype and cerebral blood flow in healthy young individuals. JAMA. 2003 Sep 24;290(12):1581-2. Abstract

6. Dennis NA, Browndyke JN, Stokes J, Need A, Burke JR, Welsh-Bohmer KA, Cabeza R. Temporal lobe functional activity and connectivity in young adult APOE varepsilon4 carriers. Alzheimers Dement. 2010 Jul;6(4):303-11. Abstract

7. Filbey FM, Slack KJ, Sunderland TP, Cohen RM. Functional magnetic resonance imaging and magnetoencephalography differences associated with APOEepsilon4 in young healthy adults. Neuroreport. 2006 Oct 23;17(15):1585-90. Abstract

8. Filippini N, Macintosh BJ, Hough MG, Goodwin GM, Frisoni GB, Smith SM, Matthews PM, Beckmann CF, Mackay CE. Distinct patterns of brain activity in young carriers of the APOE-epsilon4 allele. Proc Natl Acad Sci U S A. 2009 Apr 28;106(17):7209-14. Abstract

9. Heise V, Filippini N, Ebmeier KP, Mackay CE. The APOE ɛ4 allele modulates brain white matter integrity in healthy adults. Mol Psychiatry. 2011 Sep;16(9):908-16. Abstract

10. Alexopoulos P, Richter-Schmidinger T, Horn M, Maus S, Reichel M, Sidiropoulos C, Rhein C, Lewczuk P, Doerfler A, Kornhuber J. Hippocampal volume differences between healthy young apolipoprotein E ε2 and ε4 carriers. J Alzheimers Dis. 2011;26(2):207-10. Abstract

11. Richter-Schmidinger, et al. (2011). Influence of brain-derived neurotrophic-factor and apolipoprotein E genetic variants on hippocampal volume and memory performance in healthy young adults. J Neural Transm, 118:249-257. Abstract

12. Shaw P, Lerch JP, Pruessner JC, Taylor KN, Rose AB, Greenstein D, Clasen L, Evans A, Rapoport JL, Giedd JN. Cortical morphology in children and adolescents with different apolipoprotein E gene polymorphisms: an observational study. Lancet Neurol. 2007 Jun;6(6):494-500. Abstract

13. 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. Abstract

View all comments by Jon Valla
View all comments by Andrew Wolf

The finding that ApoE4 carriers display Aβ-independent pathomechanisms is not really surprising.

To give a few examples of Aβ-independent effects of ApoE4, the literature shows that ApoE4 carriers also have poor outcome following traumatic brain injury, and have increased risk for HIV-associated dementia, postoperative cognitive dysfunction, and cardiovascular diseases (reviewed in 1). There is significant association between ApoE4 status and poor memory performance in patients with temporal lobe epilepsy (2). Young, healthy ApoE4 carriers display altered functional activation as well as functional connectivity of the medial temporal lobe (3).

Of course, ApoE4 can exert some effects in Aβ-dependent fashion. This raises a question: What is more important in ApoE4-mediated AD risk, Aβ-independent or Aβ-dependent pathomechanisms?

A complete understanding of AD pathomechanisms is essential before we can achieve an effective treatment. As I argued previously in the case of TREM2 findings and NSAID data, we must stop interpreting every piece of data through the amyloid...  Read more

The finding that ApoE4 carriers display Aβ-independent pathomechanisms is not really surprising.

To give a few examples of Aβ-independent effects of ApoE4, the literature shows that ApoE4 carriers also have poor outcome following traumatic brain injury, and have increased risk for HIV-associated dementia, postoperative cognitive dysfunction, and cardiovascular diseases (reviewed in 1). There is significant association between ApoE4 status and poor memory performance in patients with temporal lobe epilepsy (2). Young, healthy ApoE4 carriers display altered functional activation as well as functional connectivity of the medial temporal lobe (3).

Of course, ApoE4 can exert some effects in Aβ-dependent fashion. This raises a question: What is more important in ApoE4-mediated AD risk, Aβ-independent or Aβ-dependent pathomechanisms?

A complete understanding of AD pathomechanisms is essential before we can achieve an effective treatment. As I argued previously in the case of TREM2 findings and NSAID data, we must stop interpreting every piece of data through the amyloid lens. The evidence provided by this study further strengthens the merits of that reasoning.

References:
1. Jofre-Monseny L, Minihane AM, Rimbach G. Impact of apoE genotype on oxidative stress, inflammation and disease risk. Mol Nutr Food Res. 2008 Jan;52(1):131-45. Abstract

2. Busch RM, Lineweaver TT, Naugle RI, Kim KH, Gong Y, Tilelli CQ, Prayson RA, Bingaman W, Najm IM, Diaz-Arrastia R. ApoE-epsilon4 is associated with reduced memory in long-standing intractable temporal lobe epilepsy. Neurology. 2007 Feb 6;68(6):409-14. Abstract

3. Dennis NA, Browndyke JN, Stokes J, Need A, Burke JR, Welsh-Bohmer KA, Cabeza R. Temporal lobe functional activity and connectivity in young adult APOE varepsilon4 carriers. Alzheimers Dement. 2010 Jul;6(4):303-11. Abstract

View all comments by Sanjay W. Pimplikar