The current finding of decreased precuneus resting state functional connectivity with hippocampus, parahippocampus, anterior cingulate, dorsal anterior cingulate, gyrus rectus, and superior precuneus extends findings of disruptions in AD, and highlights the importance of integrity of the default network (3
), since all these regions fall within the default mode network. We show here that even prior to cognitive impairment, cognitively normal individuals with cerebral Aβ deposits had clear-cut abnormalities in resting state functional connectivity in key regions, suggesting that Aβ deposition is associated with a disrupted functional connectivity within the DMN, even in the absence of a task. Altered resting state functional connectivity between the posterior and anterior portions of the default mode network has been described in AD (3
). Most fMRI studies in AD to date have examined task-based fMRI responses (13
), the interpretation of which is confounded by differences in task performance. In the current study the same regions showed altered resting state functional connectivity in presumptive preclinical AD. Specifically, connectivity between precuneus and hippocampus was significantly lower in individuals with amyloid plaques vs. those without evidence of brain A β plaques, indicating that resting state functional disconnection already had occurred in nondemented aging with Aβ plaques. Because there are extensive anatomical connections between posterior cortical regions and hippocampus and parahippocampus (which includes the entorhinal cortex) (14
), it is possible that even without observable Aβ deposits in the hippocampus, the Aβ deposits in the precuneus may alter hippocampal function. The precuneus is known to have very early involvement in PIB deposition (2
) and may play a critical role in memory function. Here, decreased resting state hippocampal functional connectivity may explain early disruptions in memory despite minimal early amyloid deposition in AD. Another critically important region for cognitive control, the anterior cingulate, is affected early in the course of PIB deposition (2
). Here we also found significant reductions in connectivity in PIB+ vs PIB− subjects in the same regions as in very mild AD.
In contrast, the connectivity between the precuneus and visual cortex was significantly higher in PIB+ non-demented individuals and AD subjects; we note that this region is involved in sensory processing. We speculate that since one role of default mode network appears to be vigilance and modulation of attention across the sensory domain (15
), disruptions to this network may result in dysregulation of the normal functional control of sensory processing. Speculatively, regions with increased connectivity following amyloid deposition may reflect impaired function in other involved region(s) that provide inhibitory input or a compensatory effect.
It is likely that these changes indicate a preclinical stage of AD. The “amyloid hypothesis” (16
) states that the “accumulation of Aβ in the brain is the primary influence driving AD pathogenesis.” Studies from our group strongly support the concept of pre-clinical AD (17
). We now extend this observation to brain activity abnormalities in pre-clinical disease, in individuals with no apparent cognitive abnormalities, but with Aβ plaque deposition associated with resting state differences. How long Aβ pathology needs to be present before disruption of brain circuitry occurs is unknown but is an important topic for future investigation. Using the decreased functional connectivity within the DMN as markers, longitudinal studies will be important in order to determine the time-course of neuronal dysfunction and damage to help plan the optimal timing for potential interventional studies in individuals at risk for symptomatic AD.