A Foreshadowing? ApoE4 Disrupts Brain Connectivity in Absence of Aβ

Pressing to uncover what goes awry in cognitively normal people before they get Alzheimer’s disease, scientists have found red flags in seniors with high brain amyloid. Now, however, a study in the December 15 Journal of Neuroscience suggests that people at genetic risk for AD can show the same warning signs—i.e., disrupted functional connections in the default-mode network—even without much detectable brain amyloid. Reported by Yvette Sheline and colleagues at Washington University School of Medicine in St. Louis, Missouri, the findings add to the evidence that ApoE4, the major genetic risk factor for sporadic AD, may have functional consequences in the brain independent of amyloid pathology, or perhaps prior to amyloid pathology. The findings may help scientists and clinicians come up with an earlier diagnosis.

Washington University colleague Mark Mintun got the ball rolling on the project before handing the reins to first author Sheline as he transitioned into a new role at Avid Radiopharmaceuticals, Inc., Philadelphia, Pennsylvania. In a previous study, Sheline and Mintun had analyzed cognitively normal elderly with functional magnetic resonance imaging (fMRI), and found that in those with abnormally high brain amyloid, resting-state connectivity was disrupted in the same default-mode regions that fade in AD (Sheline et al., 2010). Others have published similar findings (e.g., see Hedden et al., 2009 and ARF HAI conference report). “That motivated me to ask whether you could see this even in people without brain amyloid,” Sheline told ARF.

A small fMRI study of non-demented seniors had found default-mode signal differences in ApoE4 carriers, compared with non-carriers (Fleisher et al., 2009), suggesting that ApoE4 contributes to AD-like brain abnormalities. However, because that study did not assess brain amyloid load, it was unclear whether the ApoE4 effects occurred before, along with, of after Aβ deposition. Another study strengthened the possibility that ApoE4 has amyloid-independent effects by uncovering distinct patterns of default-mode activity in ApoE4 carriers who were so young that they most likely had little to no amyloid in their brains (Filippini et al., 2009 and ARF related news story). Along similar lines, recent work shows that young ApoE4 carriers had mitochondrial abnormalities in the absence of detectable Aβ pathology, again suggesting that ApoE4 effects may precede Aβ changes (Valla et al., 2010). Cognitively normal E4 carriers also show brain glucose hypometabolism (see Reiman et al., 2005 and Langbaum et al., 2010).

In the present study, Sheline and colleagues analyzed 100 cognitively normal elderly enrolled in ongoing longitudinal studies of memory and aging at Washington University. All were amyloid-negative by Pittsburgh Compound B (PIB) binding. Compared with the ApoE4 non-carrier group, the 38 ApoE4 carriers had clear abnormalities in functional connectivity by resting-state fMRI. The changes appeared in nine predefined brain regions known to have abnormal connectivity to the precuneus in AD patients. Five of these brain areas—left hippocampus, left parahippocampus, dorsal anterior cingulate, dorsal occipital cortex, and middle temporal cortex—remained significant in post-hoc analysis on the 70 of 100 participants who, besides being PIB-negative, also had cerebrospinal fluid Aβ42 levels falling above the “abnormal” cutoff (see Morris et al., 2010). Beyond these pre-specified regions of interest, several additional areas showed fMRI alterations in unbiased, exploratory whole-brain analyses. The whole-brain findings suggest there might be “some ApoE4 signature for how the brain connects a little differently, independent of AD,” Sheline said, noting these data are preliminary and need confirmation in an independent sample.

“I think it’s a really interesting paper,” said Reisa Sperling of Brigham and Women’s Hospital in Boston. “It’s important to have a large enough sample of ApoE4 carriers who have relatively low levels of amyloid to ask these questions. I think this study adds to the evidence that there are ApoE4 effects on function that are somewhat independent of amyloid.” Sperling did mention one caveat—the possibility that ApoE4-positive participants had slightly more brain amyloid than did ApoE4 non-carriers. Though the absolute values for these measurements were small, the p value for comparing amyloid load between the two groups was 0.06, trending toward a significant difference. Instead of only analyzing ApoE4-positive and ApoE4-negative groups in a binary fashion, Sperling suggested, the data could have been solidified by also showing correlation between fMRI connectivity with amyloid burden, even among the ApoE4 non-carriers.

On the whole, though, the data seem to “indicate that reduced functional connectivity may actually be a precursor rather than a consequence of amyloid pathology in the brain,” commented Alexander Drzezga of the Technical University in Munich, Germany. It could also be that ApoE4 carriers have early amyloid pathology (e.g., soluble Aβ oligomers not detected by PIB imaging) that contributes to synaptic dysfunction and/or reduced connectivity, he noted in an e-mail to ARF (see full comment below). “This study has contributed some very important new insights and strongly encourages further work on the causal interaction between different pathologies involved in the disease, particularly in early or asymptomatic stages.” If further evidence like this comes to light, and not only in ApoE4 carriers, then the staggered curves in biomarker staging diagrams for preclinical AD so frequently cited at conferences (see ARF Webinar and Perrin et al., 2009) might have to shift to the right and accommodate a new connectivity curve as an even earlier marker on their left.—Esther Landhuis

Comments

  1. This is a highly interesting study on the association between the ApoE4-genotype (which encodes for an elevated risk to develop Alzheimer’s disease) and changes in functional connectivity in the brain. In healthy subjects carrying the ApoE4-genotype, the authors were able to demonstrate subtle abnormalities of functional connectivity in the brain in a similar regional pattern as observed in patients with mild cognitive impairment and in manifest Alzheimer’s disease (AD). These findings complement results from several recent studies which were able to demonstrate abnormalities in different neuroimaging measures in healthy ApoE4-positive subjects without cognitive symptoms. This includes regional hypometabolism (with [18F]FDG-PET) or minor amyloid-deposition (with [11C]PIB) (1,2). Also, reduced functional connectivity has been previously demonstrated in amyloid-positive healthy controls (3). Most of these studies had in common that the detected abnormalities in ApoE4-positives were similar to findings in manifest Alzheimer’s disease, although less pronounced.

    A particularly intriguing finding of the current study is that the authors were able to demonstrate abnormalities in healthy subjects which were negative for amyloid-deposition in the brain. This finding raises a number of questions with regard to the order and, thus, the causal association of pathologies.

    This result indicates that reduced functional connectivity may actually be a precursor rather than a consequence of amyloid pathology in the brain. This somewhat counterintuitive finding is indeed of very high relevance regarding the pathophysiological hypothesis of Alzheimer’s disease. In the amyloid hypothesis, it has been assumed that amyloid pathology is the leading pathologic entity in AD, and that most other pathologies occur downstream and potentially as causal consequences (4). The current study offers three possible conclusions: 1) changes of neuronal communication, i.e., functional changes, may precede or even lead to amyloid pathology in the brain; 2) early amyloid pathology (in particular, soluble oligomers of β amyloid), which has not been tangible with (11C)PIB-PET imaging, may have been present in the examined ApoE4-positive population and lead to synaptic dysfunction with the consequence of reduced connectivity. “PIB-measurable” amyloid-deposition in the form of amyloid plaques may be a later phenomenon following these early changes in connectivity; 3) functional changes in the brain occur independently from amyloid pathology. In this context, other recent findings appear in a new light: It has been demonstrated that cerebral hypometabolic abnormalities as a measure of neuronal dysfunction increase and regionally expand continuously even in later stages of AD, whereas amyloid deposition appears to reach a relative plateau at some point (5). Additionally, amyloid deposition, as measured with PIB-PET, does not show strong correlation with cognitive decrease.

    Finally, it cannot be excluded that the abnormalities in functional connectivity detected in the ApoE4-positive subjects in the current study do not represent actual early AD pathology, but rather reflect constitutional differences between ApoE4-positives and negatives, which may predispose for but not necessarily result in AD. This seems less probable, regarding the fact that similar but more pronounced abnormalities have also been documented in manifest AD (6,7).

    In summary, this study has contributed some very important new insights, and it strongly encourages further work into the causal interaction between different pathologies involved in this disease, particularly in early, or asymptomatic, stages.

    References:

    Reiman EM, Caselli RJ, Yun LS, Chen K, Bandy D, Minoshima S, Thibodeau SN, Osborne D. 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.

    Reiman EM, Chen K, Liu X, Bandy D, Yu M, Lee W, Ayutyanont N, Keppler J, Reeder SA, Langbaum JB, Alexander GE, Klunk WE, Mathis CA, Price JC, Aizenstein HJ, Dekosky ST, Caselli RJ. Fibrillar amyloid-beta burden in cognitively normal people at 3 levels of genetic risk for Alzheimer's disease. Proc Natl Acad Sci U S A. 2009 Apr 21;106(16):6820-5. PubMed.

    Hedden T, Van Dijk KR, Becker JA, Mehta A, Sperling RA, Johnson KA, Buckner RL. Disruption of functional connectivity in clinically normal older adults harboring amyloid burden. J Neurosci. 2009 Oct 7;29(40):12686-94. PubMed.

    Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science. 2002 Jul 19;297(5580):353-6. PubMed.

    Engler H, Forsberg A, Almkvist O, Blomquist G, Larsson E, Savitcheva I, Wall A, Ringheim A, Långström B, Nordberg A. Two-year follow-up of amyloid deposition in patients with Alzheimer's disease. Brain. 2006 Nov;129(Pt 11):2856-66. PubMed.

    Sorg C, Riedl V, Mühlau M, Calhoun VD, Eichele T, Läer L, Drzezga A, Förstl H, Kurz A, Zimmer C, Wohlschläger AM. Selective changes of resting-state networks in individuals at risk for Alzheimer's disease. Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18760-5. PubMed.

    Greicius MD, Srivastava G, Reiss AL, Menon V. Default-mode network activity distinguishes Alzheimer's disease from healthy aging: evidence from functional MRI. Proc Natl Acad Sci U S A. 2004 Mar 30;101(13):4637-42. PubMed.

    View all comments by Alexander Drzezga

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References

News Citations

  1. Toronto: Human Amyloid Imaging Conference Showcases a Maturing Field
  2. ApoE4 Linked to Default Network Differences in Young Adults

Webinar Citations

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

Paper Citations

  1. Sheline YI, Raichle ME, Snyder AZ, Morris JC, Head D, Wang S, Mintun MA. Amyloid plaques disrupt resting state default mode network connectivity in cognitively normal elderly. Biol Psychiatry. 2010 Mar 15;67(6):584-7. PubMed.
  2. Hedden T, Van Dijk KR, Becker JA, Mehta A, Sperling RA, Johnson KA, Buckner RL. Disruption of functional connectivity in clinically normal older adults harboring amyloid burden. J Neurosci. 2009 Oct 7;29(40):12686-94. PubMed.
  3. Fleisher AS, Sherzai A, Taylor C, Langbaum JB, Chen K, Buxton RB. Resting-state BOLD networks versus task-associated functional MRI for distinguishing Alzheimer's disease risk groups. Neuroimage. 2009 Oct 1;47(4):1678-90. PubMed.
  4. 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. PubMed.
  5. 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.
  6. Reiman EM, Chen K, Alexander GE, Caselli RJ, Bandy D, Osborne D, Saunders AM, Hardy J. Correlations between apolipoprotein E epsilon4 gene dose and brain-imaging measurements of regional hypometabolism. Proc Natl Acad Sci U S A. 2005 Jun 7;102(23):8299-302. PubMed.
  7. Langbaum JB, Chen K, Caselli RJ, Lee W, Reschke C, Bandy D, Alexander GE, Burns CM, Kaszniak AW, Reeder SA, Corneveaux JJ, Allen AN, Pruzin J, Huentelman MJ, Fleisher AS, Reiman EM. Hypometabolism in Alzheimer-affected brain regions in cognitively healthy Latino individuals carrying the apolipoprotein E epsilon4 allele. Arch Neurol. 2010 Apr;67(4):462-8. PubMed.
  8. Morris JC, Roe CM, Xiong C, Fagan AM, Goate AM, Holtzman DM, Mintun MA. APOE predicts amyloid-beta but not tau Alzheimer pathology in cognitively normal aging. Ann Neurol. 2010 Jan;67(1):122-31. PubMed.
  9. Perrin RJ, Fagan AM, Holtzman DM. Multimodal techniques for diagnosis and prognosis of Alzheimer's disease. Nature. 2009 Oct 15;461(7266):916-22. PubMed.

Further Reading

Papers

  1. 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.
  2. Langbaum JB, Chen K, Caselli RJ, Lee W, Reschke C, Bandy D, Alexander GE, Burns CM, Kaszniak AW, Reeder SA, Corneveaux JJ, Allen AN, Pruzin J, Huentelman MJ, Fleisher AS, Reiman EM. Hypometabolism in Alzheimer-affected brain regions in cognitively healthy Latino individuals carrying the apolipoprotein E epsilon4 allele. Arch Neurol. 2010 Apr;67(4):462-8. PubMed.

Primary Papers

  1. Sheline YI, Morris JC, Snyder AZ, Price JL, Yan Z, D'Angelo G, Liu C, Dixit S, Benzinger T, Fagan A, Goate A, Mintun MA. 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.

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