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

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  1. 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.

  2. 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:

    . A genome-wide association study implicates the APOE locus in nonpathological cognitive ageing. Mol Psychiatry. 2012 Dec 4; PubMed.

  3. 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.

    <p>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:

    . APOE and neuroenergetics: an emerging paradigm in Alzheimer's disease. Neurobiol Aging. 2013 Apr;34(4):1007-17. PubMed.

    . Apolipoprotein e sets the stage: response to injury triggers neuropathology. Neuron. 2012 Dec 6;76(5):871-85. PubMed.

    . 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. PubMed.

    . APOE related alterations in cerebral activation even at college age. J Neurol Neurosurg Psychiatry. 2005 Oct;76(10):1440-4. PubMed.

    . APOE genotype and cerebral blood flow in healthy young individuals. JAMA. 2003 Sep 24;290(12):1581-2. PubMed.

    . Temporal lobe functional activity and connectivity in young adult APOE varepsilon4 carriers. Alzheimers Dement. 2010 Jul;6(4):303-11. PubMed.

    . Functional magnetic resonance imaging and magnetoencephalography differences associated with APOEepsilon4 in young healthy adults. Neuroreport. 2006 Oct 23;17(15):1585-90. PubMed.

    . 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. PubMed.

    . The APOE ɛ4 allele modulates brain white matter integrity in healthy adults. Mol Psychiatry. 2011 Sep;16(9):908-16. PubMed.

    . Hippocampal volume differences between healthy young apolipoprotein E ε2 and ε4 carriers. J Alzheimers Dis. 2011;26(2):207-10. PubMed.

    . Influence of brain-derived neurotrophic-factor and apolipoprotein E genetic variants on hippocampal volume and memory performance in healthy young adults. J Neural Transm. 2011 Feb;118(2):249-57. PubMed.

    . Cortical morphology in children and adolescents with different apolipoprotein E gene polymorphisms: an observational study. Lancet Neurol. 2007 Jun;6(6):494-500. PubMed.

    . 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.

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

    <p>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).

    </p><p>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?

    </p><p>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:

    . Impact of apoE genotype on oxidative stress, inflammation and disease risk. Mol Nutr Food Res. 2008 Jan;52(1):131-45. PubMed.

    . ApoE-epsilon4 is associated with reduced memory in long-standing intractable temporal lobe epilepsy. Neurology. 2007 Feb 6;68(6):409-14. PubMed.

    . Temporal lobe functional activity and connectivity in young adult APOE varepsilon4 carriers. Alzheimers Dement. 2010 Jul;6(4):303-11. PubMed.

References

News Citations

  1. ApoE4 Linked to Default Network Differences in Young Adults
  2. A Foreshadowing? ApoE4 Disrupts Brain Connectivity in Absence of Aβ
  3. Multimodal Imaging: Structure, Function, Amyloid Not in Synch

Webinar Citations

  1. Together at Last, Top Five Biomarkers Model Stages of AD

Paper Citations

  1. . Apolipoprotein E in sporadic Alzheimer's disease: allelic variation and receptor interactions. Neuron. 1993 Oct;11(4):575-80. PubMed.
  2. . Amyloid imaging results from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging. Neurobiol Aging. 2010 Aug;31(8):1275-83. PubMed.
  3. . Amyloid-associated proteins alpha 1-antichymotrypsin and apolipoprotein E promote assembly of Alzheimer beta-protein into filaments. Nature. 1994 Nov 3;372(6501):92-4. PubMed.
  4. . Human apoE isoforms differentially regulate brain amyloid-β peptide clearance. Sci Transl Med. 2011 Jun 29;3(89):89ra57. PubMed.
  5. . Preclinical evidence of Alzheimer's disease in persons homozygous for the epsilon 4 allele for apolipoprotein E. N Engl J Med. 1996 Mar 21;334(12):752-8. PubMed.
  6. . Cerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer's disease. Proc Natl Acad Sci U S A. 2000 May 23;97(11):6037-42. PubMed.
  7. . 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. PubMed.
  8. . 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. PubMed.
  9. . APOE4 allele disrupts resting state fMRI connectivity in the absence of amyloid plaques or decreased CSF Aβ42. J Neurosci. 2010 Dec 15;30(50):17035-40. PubMed.
  10. . Cortical morphology in children and adolescents with different apolipoprotein E gene polymorphisms: an observational study. Lancet Neurol. 2007 Jun;6(6):494-500. PubMed.
  11. . 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.
  12. . Region-specific hierarchy between atrophy, hypometabolism, and β-amyloid (Aβ) load in Alzheimer's disease dementia. J Neurosci. 2012 Nov 14;32(46):16265-73. PubMed.
  13. . Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade. Lancet Neurol. 2010 Jan;9(1):119-28. PubMed.
  14. . Lifespan brain activity, β-amyloid, and Alzheimer's disease. Trends Cogn Sci. 2011 Nov;15(11):520-6. PubMed.
  15. . Patterns of brain activation in people at risk for Alzheimer's disease. N Engl J Med. 2000 Aug 17;343(7):450-6. PubMed.
  16. . Differential effects of the APOE genotype on brain function across the lifespan. Neuroimage. 2011 Jan 1;54(1):602-10. PubMed.
  17. . Increased hippocampal activation in mild cognitive impairment compared to normal aging and AD. Neurology. 2005 Aug 9;65(3):404-11. PubMed.

External Citations

  1. ApoE4
  2. Alzheimer’s Disease Neuroimaging Initiative (ADNI)

Further Reading

Papers

  1. . Preclinical evidence of Alzheimer's disease in persons homozygous for the epsilon 4 allele for apolipoprotein E. N Engl J Med. 1996 Mar 21;334(12):752-8. PubMed.
  2. . Cerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer's disease. Proc Natl Acad Sci U S A. 2000 May 23;97(11):6037-42. PubMed.
  3. . 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. PubMed.
  4. . 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. PubMed.
  5. . APOE4 allele disrupts resting state fMRI connectivity in the absence of amyloid plaques or decreased CSF Aβ42. J Neurosci. 2010 Dec 15;30(50):17035-40. PubMed.
  6. . Cortical morphology in children and adolescents with different apolipoprotein E gene polymorphisms: an observational study. Lancet Neurol. 2007 Jun;6(6):494-500. PubMed.
  7. . 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.
  8. . Region-specific hierarchy between atrophy, hypometabolism, and β-amyloid (Aβ) load in Alzheimer's disease dementia. J Neurosci. 2012 Nov 14;32(46):16265-73. PubMed.
  9. . Lipid- and receptor-binding regions of apolipoprotein E4 fragments act in concert to cause mitochondrial dysfunction and neurotoxicity. Proc Natl Acad Sci U S A. 2005 Dec 20;102(51):18694-9. PubMed.
  10. . Aβ amyloid, cognition, and APOE genotype in healthy older adults. Alzheimers Dement. 2012 Nov 14; PubMed.

Primary Papers

  1. . Apolipoprotein E, not fibrillar β-amyloid, reduces cerebral glucose metabolism in normal aging. J Neurosci. 2012 Dec 12;32(50):18227-33. PubMed.