Neural mechanisms of cognitive reserve in Alzheimer's disease

Alzheimer’s disease (AD) is the most common cause of age-related dementia, where neuropathological changes develop gradually over years before the onset of dementia symptoms. Yet, despite the progression of AD pathology, the decline in cognitive abilities such as episodic memory can be relatively slow. A slower decline of cognition and delayed onset of dementia relative to the progression of neuropathology has been associated with particular intellectual and lifestyle factors such as more years of education and IQ. Thus education and IQ are seen as protective factors that are associated with an increased ability to cope with brain pathology, i.e. cognitive reserve. While numerous studies showed that education, IQ and other lifestyle factors are associated with relatively high cognitive abilities in AD, little is known about the underlying brain mechanisms of reserve. Most previous studies tested the association between protective factors such as education or IQ and differences in brain structure and function in order to identify brain mechanisms underlying reserve. Since such protective factors are global in nature and unspecific with regard to reserve, the results were highly variable. So far, there is a lack of knowledge of brain features that are associated with a higher ability to maintain cognition in the face of AD pathology. The overall aim of this dissertation was to test a priori selected functional network features that may underlie cognitive reserve. We focused on resting-state functional networks, and in particular the fronto-parietal control network as correlate of cognitive reserve. Such functional networks are thought to be composed of brain regions that are co-activated during a particular task, where the interaction between brain regions may be critical to support cognitive function. During task-free resting-state periods, the different and often distant brain regions of such network show correlated activity, i.e. functional connectivity. For the fronto-parietal control network, and in particular its globally connected hub in the left frontal cortex (LFC), higher resting-state connectivity has been previously shown to be associated with higher cognitive abilities as well as higher education and IQ, i.e. protective factors associated with reserve. Since that network and its LFC hub are relatively spared in AD, in contrast to more posterior parietal networks, we investigated whether higher connectivity of the fronto-parietal control network is associated with higher reserve in AD. We argued that the fronto-parietal control network is relatively stable during the initial stages of AD and may thus be well posited to subserve reserve in AD. In contrast, networks like the default mode network (DMN) that cover midline brain structures including the medial frontal lobe and the posterior cingulate may be highly vulnerable to AD pathology, given the previous observations of altered DMN connectivity and posterior parietal FDG-PET hypometabolism in AD. In particular, the resting-state connectivity between the DMN and the dorsal attention network (DAN) may be predictive of lower episodic memory in AD. Both networks interact in a competitive (i.e. anti-correlated) way during task and resting-state, which is critical for cognitive processes such as episodic memory. In a first step, we tested whether the resting-state connectivity between the DMN and theDAN (i.e. anti-correlated activity) is associated with lower episodic memory in subjects with amnestic mild cognitive impairment (MCI), i.e. subjects at increased risk to convertto AD dementia. Furthermore, we tested whether protective factors such as higher education moderate the association between the DMN-DAN anti-correlation andcognition. Here, the DMN-DAN anti-correlation was a measure of AD relatedpathological change rather than a substrate of reserve.We could show in two independent samples of patients at risk of AD dementia that a weaker DMN-DAN anti-correlation was associated with lower episodic memory, where the decrements in episodic memory were however weaker in subjects with higher education or IQ (interaction DMN-DAN x education/IQ). These results suggest that MCI subjects with higher protective factors (education, IQ) maintain episodic memory relatively well at a given level of AD-related brain changes. In the second step, we sought to identify those network differences that support cognitive reserve, i.e. that may explain the association between higher education and milder cognitive impairment in AD. Here, we could show that greater resting-state fMRI assessed global connectivity of the LFC, i.e. a key hub of the fronto-parietal control network, was associated with greater education and attenuated effects of neurodegeneration (measured by parietal FDG-PET hypometabolism) on memory in prodromal AD. Together, these results support the idea that global connectivity of a fronto-parietal control network hub supports cognitive reserve in AD. Based on this finding, we developed a novel restingstate fMRI index of fronto-parietal control network connectivity as a functional imaging marker of cognitive reserve. This marker is highly correlated with education and may thus be used as an imaging-based index of cognitive reserve. Together, our results provide for the first time evidence that cognitive reserve in AD is supported by higher functional connectivity of the fronto-parietal control network, in particular its LFC hub.