As is usually the case with work from Buckner, Sperling, and Johnson, this is very interesting and innovative work. It’s similar in some respects to the 2005 J. Neurosci paper comparing the topography of the default mode network to amyloid deposition. Indeed, many of the hubs lie in this region, and hub activity may be at the root of default mode activity and, in turn, may exacerbate Aβ deposition. It’s not completely clear to me whether this hub-vulnerability is simply a function of activity level (of any type) or whether it’s more a function of some form of connectivity and activity that is unique to hubs and may be less dependent on the actual level of activity (as might be measured by fMRI or FDG, for example).

The implications to this work appear rather ominous to me. If there is this arrangement of hubs, it’s highly likely that this architecture and its normal functioning are essential to normal cognition. Therefore, it may be very difficult to affect the hub network without bad consequences. However, it may be that some people have hyperactive hubs and they may...  Read more

As is usually the case with work from Buckner, Sperling, and Johnson, this is very interesting and innovative work. It’s similar in some respects to the 2005 J. Neurosci paper comparing the topography of the default mode network to amyloid deposition. Indeed, many of the hubs lie in this region, and hub activity may be at the root of default mode activity and, in turn, may exacerbate Aβ deposition. It’s not completely clear to me whether this hub-vulnerability is simply a function of activity level (of any type) or whether it’s more a function of some form of connectivity and activity that is unique to hubs and may be less dependent on the actual level of activity (as might be measured by fMRI or FDG, for example).

The implications to this work appear rather ominous to me. If there is this arrangement of hubs, it’s highly likely that this architecture and its normal functioning are essential to normal cognition. Therefore, it may be very difficult to affect the hub network without bad consequences. However, it may be that some people have hyperactive hubs and they may benefit from some downregulation without noticing any untoward effects.

One thing is sure: this is an elegant and innovative hypothesis and could suggest novel avenues of treatment that would be most welcome in our current efforts against AD.

View all comments by William Klunk

This paper takes the previous associations between brain function and β amyloid deposition a step further. These investigators have previously noted the interesting similarity between regions of β amyloid deposition and the default mode network. Using a different computational approach they defined hubs as brain regions with unusually high connectivity, and they find that it is these areas that are particularly predisposed to β amyloid accumulation. The idea essentially parallels molecular studies that have shown how neural activity stimulates Aβ production.

So basically, the idea is that persistent, high levels of neural activity may be responsible for Aβ deposition. This is an attractive argument as it explains not only why β amyloid tends to occur in some regions but not others, and also because it might explain age-dependence of the disease and its ubiquity. On the other hand, it is somewhat difficult to reconcile with epidemiological data showing that cognitive activity reduces the risk of AD. The data do not also seem to fully correspond to the deposition of β amyloid...  Read more

This paper takes the previous associations between brain function and β amyloid deposition a step further. These investigators have previously noted the interesting similarity between regions of β amyloid deposition and the default mode network. Using a different computational approach they defined hubs as brain regions with unusually high connectivity, and they find that it is these areas that are particularly predisposed to β amyloid accumulation. The idea essentially parallels molecular studies that have shown how neural activity stimulates Aβ production.

So basically, the idea is that persistent, high levels of neural activity may be responsible for Aβ deposition. This is an attractive argument as it explains not only why β amyloid tends to occur in some regions but not others, and also because it might explain age-dependence of the disease and its ubiquity. On the other hand, it is somewhat difficult to reconcile with epidemiological data showing that cognitive activity reduces the risk of AD. The data do not also seem to fully correspond to the deposition of β amyloid in subcortical structures and to some regions of prefrontal cortex. Nevertheless, as the authors point out, these data provide further testable approaches to exploring the pathogenesis of AD.

View all comments by William Jagust

This is another very interesting paper from David Holtzman's lab, continuing a very interesting theme that suggests neural function (or dysfunction, in this case) affects Aβ deposition. Previous work (a nice paper by in Nature Neuroscience last year, Bero et al., 2011) showed that neural activity was related to subsequent development of plaques in transgenic animals. This paper breaks new ground by applying a method this lab developed that uses optical imaging to measure functional connectivity. It's motivated by studies in humans with fMRI that show disruption of functional connectivity in normal older people with Aβ deposition. In this case, through the use of transgenic animals, the authors were able to demonstrate regional loss of connectivity in young animals, prior to Aβ deposition.

This is quite a novel finding, and extends the theme that the lab has been working on relating neural activity to Aβ to include measures of functional connectivity. The functional connectivity measures in this paper are especially interesting...  Read more

This is another very interesting paper from David Holtzman's lab, continuing a very interesting theme that suggests neural function (or dysfunction, in this case) affects Aβ deposition. Previous work (a nice paper by in Nature Neuroscience last year, Bero et al., 2011) showed that neural activity was related to subsequent development of plaques in transgenic animals. This paper breaks new ground by applying a method this lab developed that uses optical imaging to measure functional connectivity. It's motivated by studies in humans with fMRI that show disruption of functional connectivity in normal older people with Aβ deposition. In this case, through the use of transgenic animals, the authors were able to demonstrate regional loss of connectivity in young animals, prior to Aβ deposition.

This is quite a novel finding, and extends the theme that the lab has been working on relating neural activity to Aβ to include measures of functional connectivity. The functional connectivity measures in this paper are especially interesting because of their relevance to similar human functional connectivity data.

View all comments by William Jagust