Functional magnetic resonance imaging (fMRI) has uncovered differences between cognitively normal ApoE4 carriers and non-carriers in the default-mode network—a set of brain areas that fire up when the mind is adrift, and tone down during goal-oriented activity. ApoE4 carriers in their late fifties and early sixties show default-mode abnormalities when their minds are resting (ARF related news story on Sheline et al., 2010) and while they focus on cognitive tasks (Fleisher et al., 2005). Even young ApoE4 carriers between the ages 20 to 35 show default-mode connectivity changes (ARF related news story on Filippini et al., 2009), suggesting that the E4 variant somehow causes this network to falter years before initial signs of memory loss.

In the online Archives of Neurology report, first author Mary Machulda and colleagues used task-free fMRI to analyze 56 E4 carriers and an equal number of age-, education-, and gender-matched non-carriers, all at least 63 years old (median age 79) and cognitively normal. The researchers not only examined connectivity in default-mode areas, which lie toward the back of the brain, but also in the salience network. This is a set of frontal structures that activate when the mind is focused and disengage during daydreaming—just the opposite of the default-mode network. In AD patients, the salience network becomes inappropriately active and default-mode activity wanes when the mind is at rest; the opposite happens in people with frontotemporal dementia (FTD).

Relative to non-carriers, ApoE4 carriers in the current study showed increased connectivity in the salience network and decreased connectivity in the default-mode network. The default mode overlaps with the brain areas that become hypometabolic and accumulate amyloid in AD (see ARF related news story on Buckner et al., 2005); hence, the low connectivity in this network makes sense, Jack told ARF. “It’s a direct manifestation of deinnervation in those areas.”

Why connectivity increases in the salience network of E4 carriers is harder to explain. Jack proposed two ideas. According to one theory, the phenomenon might be beneficial—the frontal areas become more interconnected to compensate for early local pathology. Alternatively, the increased frontal connectivity in E4 carriers could reflect their impaired ability to appropriately switch between default-mode and salience activation, leading to a decoupling of these networks. (For more on decoupling, see ARF conference story on multimodal imaging.)

“This is a very solid…paper that shores up our understanding of where and when ApoE4 begins to exert its susceptibility to Alzheimer’s disease,” Michael Greicius of Stanford University, Palo Alto, California, e-mailed to ARF (see full comment below). In his view, the report’s most important finding was the lack of differences in gray matter density between E4 and non-E4 groups. These data suggest that “resting-state functional connectivity may be a more sensitive measure of preclinical disease than structural MRI,” he wrote.

Adam Fleisher of the Banner Alzheimer’s Institute, Phoenix, Arizona, agreed that the findings suggest fMRI measures might prove useful as an AD biomarker. However, “a lot of work has to be done to see if these will be reasonable outcome measures for clinical trials,” he told ARF in a phone interview. “We need longitudinal data to really understand how these networks are changing over time, and in relationship to disease.”

At a mechanistic level, how does ApoE4 cause default-mode areas to lose connectivity? David Holtzman of Washington University in St. Louis, Missouri, thinks it is because a much larger proportion of ApoE4-positive seniors have high brain amyloid, relative to age-matched E4 non-carriers (see Morris et al., 2010). “ApoE4 is driving earlier Aβ deposition,” Holtzman wrote. “This occurs first in the default-mode network, and I would hypothesize that something associated with this process leads to dysfunction,” he wrote in an e-mail to ARF. “Thus, dysfunction in connectivity is seen first there.”

The current paper does not report participants’ brain amyloid levels. However, in Jack’s view, “it’s a certainty that our E4 carriers had, on average, higher Aβ burden than the non-carriers. So, to some extent, the effects we’re seeing are indeed related to increased amyloid deposition in ApoE4 carriers,” he said. However, Jack noted that past fMRI studies uncovering functional connectivity changes in this subgroup only looked at seniors without brain Aβ (Sheline et al., 2010), or examined young people who were highly unlikely to have appreciable brain amyloid (Filippini et al., 2009). These studies indicate that “over and above ApoE4’s effect on increasing amyloid deposition in the brain, E4 has independent effects on functional connectivity,” Jack said.

Given that Aβ contributes to ApoE4’s effect on network connectivity, a key question becomes, Why do E4 allele carriers have higher Aβ burden? The Journal of Neuroscience paper may offer a potential explanation. In this study, Heneka and colleagues reduced brain amyloid levels in AD transgenic mice (APP23) using a compound that binds and activates liver X receptors (LXRs), which regulate inflammation and cholesterol metabolism. The findings jibe with previous work showing that LXR agonists enhance Aβ clearance in cultured cells and AD mouse models (see ARF related news story on Jiang et al., 2008), and that knocking out LXRα or LXRβ intensifies plaque load in APP/PS1 mice (see ARF related news story on Zelcer et al., 2007). The present study went further, demonstrating that “microglial Aβ phagocytosis is under the control of astrocytes,” Heneka said. Led by first author Dick Terwel, the researchers showed that LXR agonist-treated astrocytes encouraged brain phagocytes to gobble up fibrillar Aβ, but not if the astrocytes came from ApoE- or LXRα-deficient mice. They conclude that microglial Aβ clearance relies on astrocytic LXRα activation and astrocytic ApoE.

In collaboration with Philip Verghese in the Holtzman lab, the University of Bonn researchers showed that ApoE lipidation in astrocytes is mediated by LXRα. These data, coupled with previous work suggesting that lipidated ApoE3 binds Aβ better than lipidated E4 (Tokuda et al., 2000), argue that “E4 carriers have lipidated ApoE with decreased affinity toward Aβ, and therefore decreased microglial clearance of pathological Aβ peptides,” Heneka said.

Extending similar reasoning to tau, Jack wondered if people with certain ApoE variants may be less effective than non-carriers at resisting the effects of toxic tau proteins. If true, this may agree with a genotype analysis by Carlo Masullo and colleagues at Catholic University School of Medicine in Rome, Italy. As reported in this month’s Archives of Neurology, first author Davide Seripa and colleagues genotyped 86 people with sporadic FTD (of whom 32 patients had primary progressive aphasia [PPA]), and 99 non-demented controls. The FTD and PPA groups had a three- to fourfold higher proportion of ApoE3/E4 participants compared with the control group. The PPA group also had a 12-fold overrepresentation of the ApoE2/E4 genotype. In addition, the researchers found several polymorphisms at the ApoE promoter region associating with both diseases. Links to ApoE have turned up in a few studies of Parkinson’s disease, as well (Blázquez et al., 2006; Buchanan et al., 2007; see others in PDGene). And for those still hungry for more on ApoE, the New York Academy of Sciences is hosting a one-day conference on May 24.—Esther Landhuis.

References:
Machulda MM, Jones DT, Vemuri P, McDade E, Avula R, Przybelski S, Boeve BF, Knopman DS, Petersen RC, Jack CR. Effect of APOE epsilon4 status on intrinsic network connectivity in cognitively normal elderly subjects. Arch Neurol. 9 May 2011. Abstract

Terwel D, Steffensen KR, Verghese PB, Kummer MP, Gustafsson J, Holtzman DM, Heneka MT. Critical role of astroglial apolipoprotein E and liver X receptor-alpha expression for microglial Aβ phagocytosis. J. Neurosci. 11 May 2011;31(19):7049-7059. Abstract

Seripa D, Bizzarro A, Panza F, Acciarri A, Pellegrini F, Pilotto A, Masullo C. The APOE gene locus in frontotemporal dementia and primary progressive aphasia. Arch Neurol. May 2011;68(5):622-628. Abstract