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

I think this is consistent with a theme that is gradually emerging in the literature: ApoE has effects on the brain that are not simply related to its effect on the processing of Aβ. One always has to be concerned about the issue of multiple comparisons when so many statistical tests are run, but the authors seem to have handled that appropriately.

What this paper says is that there are developmental effects of ApoE on the brain. There are a number of studies showing ApoE effects on brain structure and function in older people, but it's been difficult to tell whether this was related to early AD. There have been a small number of studies showing changes of glucose metabolism or brain activation in ApoE4 carriers who were young, and a couple of studies suggesting reduced brain volumes in ApoE4 carriers in childhood and adolescence. This work now extends those findings to an age where the only plausible explanation for brain structural change seems to be developmental. It is especially interesting that volume loss is particularly notable in the medial temporal lobe. It is also...  Read more

I think this is consistent with a theme that is gradually emerging in the literature: ApoE has effects on the brain that are not simply related to its effect on the processing of Aβ. One always has to be concerned about the issue of multiple comparisons when so many statistical tests are run, but the authors seem to have handled that appropriately.

What this paper says is that there are developmental effects of ApoE on the brain. There are a number of studies showing ApoE effects on brain structure and function in older people, but it's been difficult to tell whether this was related to early AD. There have been a small number of studies showing changes of glucose metabolism or brain activation in ApoE4 carriers who were young, and a couple of studies suggesting reduced brain volumes in ApoE4 carriers in childhood and adolescence. This work now extends those findings to an age where the only plausible explanation for brain structural change seems to be developmental. It is especially interesting that volume loss is particularly notable in the medial temporal lobe. It is also interesting that the increases in brain volume are in the parietal lobe. These are both, of course, brain regions affected by AD.

The study does not tell us precisely what these volume changes mean, or how they may relate to AD risk. I do think the results are consistent with our recent findings (Jagust et al., 2012) inasmuch as they support the idea that ApoE affects the brain in ways unrelated to Aβ. Our findings of reduced metabolism in older ApoE4 carriers regardless of fibrillar amyloid status are certainly consistent with a lifelong or developmental effect. However, the brain regions affected metabolically by ApoE in our paper were much more widespread than those reported by Knickmeyer et al. This could reflect the fact that we're measuring different things (we measured metabolism; they measured structure), or that the ages of our subjects are extremely different.

In any case, these are more data, combined with a limited number of human studies and a moderate number of animal studies, that suggest that ApoE affects the brain very early in life in ways that are independent from Aβ. How this relates to AD risk is very important and needs to be examined.

View all comments by William Jagust

This is a very interesting study looking at an incredible dataset of MRI scans from 272 infants. The size of the study is one of its great strengths, so when the researchers are analyzing ApoE genotype, they have enough individuals to make interesting comparisons (156 ApoE3/3 vs. 66 ApoE3/4). The exciting finding is that from whole brain scans, the researchers identified significant ApoE4-associated reductions in the hippocampus and other parts of the temporal lobe—areas that would be associated with early degeneration in Alzheimer's disease. The researchers found ApoE4-associated increases in other brain regions, such as parts of the parietal lobe. These findings add to a small but growing literature showing that ApoE4 affects brain structure and function in the absence of Alzheimer's-related pathological changes. The reductions in the temporal lobe, since they may persist through life, could be causally related to the increased risk of Alzheimer's disease in ApoE4 individuals. Thus, inheritance of ApoE4 may affect the risk of disease decades before amyloid plaques begin to...  Read more

This is a very interesting study looking at an incredible dataset of MRI scans from 272 infants. The size of the study is one of its great strengths, so when the researchers are analyzing ApoE genotype, they have enough individuals to make interesting comparisons (156 ApoE3/3 vs. 66 ApoE3/4). The exciting finding is that from whole brain scans, the researchers identified significant ApoE4-associated reductions in the hippocampus and other parts of the temporal lobe—areas that would be associated with early degeneration in Alzheimer's disease. The researchers found ApoE4-associated increases in other brain regions, such as parts of the parietal lobe. These findings add to a small but growing literature showing that ApoE4 affects brain structure and function in the absence of Alzheimer's-related pathological changes. The reductions in the temporal lobe, since they may persist through life, could be causally related to the increased risk of Alzheimer's disease in ApoE4 individuals. Thus, inheritance of ApoE4 may affect the risk of disease decades before amyloid plaques begin to accumulate.

View all comments by Adam Green
View all comments by G. William Rebeck

Very interesting study, and the outcome is important and worth considering seriously.

View all comments by P. Hemachandra Reddy

This work is very interesting, given the number of MRI studies conducted to obtain statistically reliable data among newborns carrying ApoE4. The work shows that the initial decrease in the volume of both the hippocampus and the temporal lobes of the brain is seen among newborn infants, and therefore occurs in utero. This raises the possibility of future AD development. According to our data, no research of this kind has ever been conducted.

The data in this paper have much in common with our research. We were able to reveal that children who descend from AD patients develop hypotrophic changes in the temporal and frontal-parietal brain regions at the ages of eight to 12; microcirculatory disorders are identified in the same regions as well (1,2).

Similar changes were observed among their parents and grandparents, and are generally specific to the development of AD in its later stages (3,4).

References:
1. Maksimovich, I. V. Polyaev, Yu. A. (2010) The Importance of Early Diagnosis of Dyscircular Angiopathy of Alzheimer's Type in the Study of Heredity of Alzheimer's Disease. J Alzheimer's & Dementia, 6, 4, Supp. e43. Article

2. Maksimovich, I.V. (2012) Certain New Aspects of Etiology and Pathogenesis of Alzheimer's Disease. Advances in Alzheimer’s Disease, Vol.1, No.3, 68-76. Article

3. Maksimovich, I.V. (2012) The Tomography Dementia Rating Scale (TDR) – the Rating Scale of Alzheimer's Disease Stages. J. Health. 4, Special Issue I, 712-719. Article

4. Maksimovich, I.V. (2012) Vascular factors in Alzheimer’s disease. J. Health. 4, Special Issue I, 735-742. Article

View all comments by Ivan Maksimovich

This interesting paper adds to the growing literature of brain imaging studies examining the effects of ApoE in young subjects. It is novel work in that it moves the imaging timepoint younger than the previous imaging studies performed mostly in young adults (reviewed in part in Wolf et al., 2012). Therefore, this paper provides support for the early nature of ApoE-associated modifications of brain structure. Prior work in ApoE mice has shown early decreases in dendritic spine density and alterations in morphology (Dumanis et al., 2010). However, human data are lacking on this issue. Further, this work lends credence to examining the impacts of ApoE on brain physiology beyond its interactions with amyloid, including potential effects on inflammation and energetics, among others, in addition to development.

References:
Dumanis SB, Tesoriero JA, Babus LW, Nguyen MT, Trotter JH, Ladu MJ, Weeber EJ, Turner RS, Xu B, Rebeck GW, Hoe H. ApoE4 Decreases Spine Density and Dendritic Complexity in Cortical Neurons In Vivo (2010). J Neurosci, 29: 15317-22. Abstract

Wolf AB, Caselli RJ, Reiman EM, Valla J. APOE and neuroenergetics: an emerging paradigm in Alzheimer's disease (2012). Neurobiol Aging. 2012 Nov 16. pii: S0197-4580(12)00522-2. Abstract

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