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Does ApoE4 Lower Brain Metabolism Independently of Aβ?
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14 Dec 2012. Chalk another one up for the “not-all-about-amyloid” camp. Analyzing cognitively normal elderly, researchers led by William Jagust and Susan Landau at the University of California, Berkeley, find that apolipoprotein E4 carriers have reduced brain metabolism compared to non-carriers, yet their hypometabolism did not correlate with brain amyloid deposition. “Every way we looked at the data, we found that ApoE4 explained what was going on with glucose metabolism, but brain Aβ did not,” Jagust told Alzforum. The findings were reported in the December 12 Journal of Neuroscience. The results strengthen the idea that ApoE4, the top risk gene for sporadic AD, can impair brain function by mechanisms independent of Aβ.
In cultured cells, AD mice, longitudinal cohorts, and human postmortem brain, ApoE4 correlates with increased aggregation (Rebeck et al., 1993; Rowe et al., 2010; Ma et al., 1994) and impaired clearance (Castellano et al., 2011) of brain Aβ. Meanwhile, other research shows that asymptomatic ApoE4 carriers have reduced glucose metabolism (Reiman et al., 1996; Small et al., 2000)—even adults in their twenties and thirties, decades before the age of expected AD pathology (Reiman et al., 2004). While ApoE4 clearly has a major effect on brain Aβ aggregation, it may also act in the central nervous system in other ways, noted David Holtzman of Washington University School of Medicine, St. Louis, Missouri (see full comment below).
In the current study, Jagust and Landau asked if ApoE4 status or brain amyloid drives hypometabolism. To address this, the researchers took data on amyloid load and glucose metabolism using positron emission tomography (PET) brain scans of 175 non-demented seniors enrolled in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Fifty people had amyloid-positive florbetapir scans. Forty were ApoE4 carriers—half of them amyloid-positive.
ApoE4 carriers had lower glucose metabolism than did non-carriers. However, florbetapir PET showed no association between amyloid burden and glucose metabolism. These findings held whether the scientists analyzed metabolism in prespecified, AD-relevant brain regions or used a whole-brain approach.
“I think this is an important clinical study,” said Yadong Huang of the Gladstone Institute for Neurological Disease, San Francisco, California. “It supports the notion that ApoE4 has Aβ-independent effects on neuronal function, which I believe contribute to AD pathogenesis.”
The present ADNI data jibe with other brain imaging studies suggesting lack of correlation between metabolism and Aβ burden. Functional magnetic resonance imaging (fMRI) reveals disrupted resting-state connectivity in young ApoE4 carriers between 20 and 35 years of age (see ARF related news story on Filippini et al., 2009), and in elderly ApoE4 carriers without Aβ plaques and with normal cerebrospinal fluid Aβ42 (see ARF related news story on Sheline et al., 2010). Moreover, other research links the ApoE4 allele with entorhinal cortical thinning in children (Shaw et al., 2007), and with reduced brain mitochondrial activity in young adults (Valla et al., 2010). Even in ApoE4-positive AD patients, neuroimaging reveals distinct anatomical patterns of atrophy, hypometabolism, and amyloid deposition, with the last distribution differing markedly from the other two measures (see ARF related news story on La Joie et al., 2012). All of this points to Aβ-independent effects of ApoE4 in the brain.
Together with this body of data, the current findings suggest that existing models of AD biomarker changes may warrant modification. In the scenario proposed by Cliff Jack of the Mayo Clinic, Rochester, Minnesota, and colleagues, amyloid changes precede hypometabolism (Jack et al., 2010; see also ARF Webinar ). However, “I think [the current data] give evidence that synaptic function may decline before you see amyloid,” Jagust said.
Jack agrees, but notes that it remains unclear whether the early metabolic abnormalities definitively lead to AD. “We don’t have the longitudinal data to prove that someone with glucose metabolism changes prior to amyloid deposition will develop AD,” he said.
In a broader view, the present findings point “to the idea that there is no single way to get AD,” Jagust said. “What ApoE4 may be doing is producing a metabolic stress on the brain that puts you at risk for AD. It also increases the amount of amyloid in the brain. These two things may be a particularly nasty combination. But there may be other things that produce metabolic stress in a similar way and that also increase your risk of AD.” (For a review, see Jagust and Mormino, 2011.)
Functional MRI studies suggest that the brain of an ApoE4 carrier may work harder and consume more energy than non-carriers doing the same mental task (Bookheimer et al., 2000; Filippini et al., 2011). ApoE carriers show greater hippocampal hyperactivation during a memory task than non-carriers (Dickerson et al., 2005). To explore the mechanisms, Jagust would like to examine more people who are very young to see what is happening in their brains functionally and metabolically. He is interested in how hypometabolism stresses their brains and what goes on while they are thinking.—Esther Landhuis.
Reference:
Jagust WJ and Landau SM for the Alzheimer’s Disease Neuroimaging Initiative. Apolipoprotein E, Not Fibrillar β-Amyloid, Reduces Cerebral Glucose Metabolism in Normal Aging. J Neurosci. 12 Dec 2012;32(50):18227-18233. Abstract
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Comment by: David Holtzman
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Submitted 14 December 2012
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Posted 14 December 2012
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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 |
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Comment by: Fred Van Leuven (Disclosure)
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Submitted 17 December 2012
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Posted 17 December 2012
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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 |
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Comment by: Jon Valla, Andrew Wolf
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Submitted 17 December 2012
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Posted 19 December 2012
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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...
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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 |
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Comment by: Sanjay W. Pimplikar
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Submitted 17 December 2012
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Posted 19 December 2012
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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...
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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 |
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