Clinically normal older adults harboring amyloid burden show disruption of functional connectivity that cannot be accounted for by increased age or structural atrophy. Decreases in spontaneous functional correlations among regions within the default network were observed using a priori defined regions in both group analyses and in analyses treating amyloid burden as a continuous measure. Whole-brain analyses further demonstrated decreased functional correlations with the hippocampal formation. Taken collectively, these results suggest the broad network comprising components of the default network linked to the hippocampal formation is disrupted in the preclinical phase of AD.
These results build upon previous observations that the functional integrity of the default network is reduced in AD (Greicius et al., 2004
) and MCI (Sorg et al., 2007
) and further demonstrate that the presence of amyloid is sufficient to predict functional disruption before clinical symptoms emerge. Recent observations in clinically normal individuals (CDR 0) associate amyloid burden with whole-brain atrophy (Fotenos et al., 2008
), atrophy of the hippocampal formation (Mormino et al., 2008
), cortical thinning in default network regions (Dickerson et al., 2009
), and aberrant task-induced activity decreases within the posterior cingulate/precuneus (Sperling et al., 2009
). The present results reveal that disruption associated with amyloid burden involves interactions between the widespread cortical regions that comprise the default network and the hippocampal formation.
Consistent with earlier reports (Aizenstein et al., 2008
; Jack et al., 2008
; Mormino et al., 2008
; but see Pike et al., 2007
), amyloid burden was not associated with detectable differences in neuropsychological test performance, suggesting that functional disruption can occur either absent cognitive impairment or with impairment so mild as to be below threshold on standard tests. One possibility is that compensatory processes can mitigate behavioral decline for a period of time when amyloid is present in the brain and associated with functional consequences.
There are multiple implications of the observation that amyloid burden is associated with functional differences in clinically normal individuals. First, consistent with models that place amyloid-beta as an important protein product initiating or correlated with synaptic toxicity in AD (Mattson, 2004
; Walsh and Selkoe, 2004
), the present results show the presence of amyloid deposition is correlated with physiological differences in normal older adults. The results are inconsistent with models that suggest amyloid-beta is unrelated to dysfunction in AD, although the results do not directly speak to whether amyloid-beta is causal to the toxic cascade.
Second, the results suggest functional disruption in AD may be present years prior to the onset of clinical symptoms. While the results do not yet include longitudinal follow-up to firmly establish that the observed disruption is prodromal AD, the observation that amyloid deposition is linked to mild forms of cortical dysfunction that are observed in MCI and AD (e.g., Greicius et al., 2004
; Sorg et al., 2007
) suggests that the effects may reflect an endophenotype of AD. Disruptions of functional connectivity, used in conjunction with other markers and in the presence of amyloid deposition or CSF markers of amyloid levels, may eventually allow the targeting of at-risk individuals for early diagnosis and interventional therapies.
Third, these results hold an important implication for the study of normal aging – namely, that a substantial fraction of clinically normal individuals harbor amyloid burden that is linked to functional disruption. Normal aging, independent of amyloid burden, is associated with nonspecific network disruption that includes but extends beyond the default network (Andrews-Hanna et al., 2007
; Damoiseaux et al., 2008
). Molecular markers of amyloid burden will be important to clarify the relationship between normal and pathological aging given the prevalence of amyloid burden in the clinically normal population.
Finally, the observation from our whole-brain analyses that network disruption includes the hippocampal formation and, specifically, its correlation with the posterior cingulate is consistent with the possibility that memory network failure may be an early consequence of amyloid burden. The default network consists of multiple distributed regions including the posterior cingulate cortex/retrosplenial cortex, the ventromedial prefrontal cortex, and the inferior lateral parietal cortex, and can be subdivided into at least two interacting subsystems – one involving the medial temporal lobe and the other involving the dorsomedial prefrontal cortex (Buckner, et al., 2008
; Greicius, et al., 2009
). Our exploratory whole-brain analyses indicate that the subsystem correlating with the hippocampal formation is disrupted. Future work will be required to determine whether the medial temporal lobe subsystem is preferentially associated with disruption in the earliest preclinical stages of AD or whether the broader network of cortical regions is affected earliest owing to its high baseline metabolism and activity fluctuations (e.g., Buckner et al., 2005
). A possibility that will need to be considered is that functional correlations may be impacted by amyloid burden in remote regions if such regions modulate or interact with the correlated regions under investigation.
It remains to be determined whether the early effects of amyloid burden are associated with declines in cognitive capacities such as memory, which are defining symptoms of AD, and whether longitudinal studies will reveal a predictive effect of amyloid burden on eventual progression from normal cognitive status to MCI or AD. The detection of network disruptions among those clinically normal older adults with substantial amyloid burden indicates that amyloid does associate with a detrimental neurophysiological effect even before cognitive consequences are observed on standard neuropsychological tests. Further research is needed to definitively attribute a neuronal source to these network disruptions, as opposed to physiological influences on neurovascular coupling. Further exploration of cognitive performance on more sensitive tests of memory and also the exploration of mediating influences, such as cognitive reserve, may reveal cognitive correlates of the functional disruption observed here.