Tau pathology and neuroinflammation are key etio-pathogenetic mediators of Alzheimer’s disease (AD). Network dysfunction has also been reported in AD and linked to cognitive impairment. However, it is unclear how tau pathology and neuroinflammation contribute to network dysfunction and cognitive deficit in AD.

I study these issues by combining: 1) positron emission tomography imaging using the [18F-AV]-1451 tracer (measuring in vivo tau pathology) or [11C]PK11195 ligand (indexing in vivo neuroinflammation), with 2) connectivity measures of resting-state functional magnetic resonance imaging.

I found increased [18F-AV]-1451 binding (reflecting tau pathology) in AD patients, relative to controls, in the medial/lateral temporal and parietal cortices. In terms of functional connectivity, more strongly connected brain regions accrued more tau pathology. Increasing tau burden was also linked to progressive weakening of the connectivity across the same regions.

I also found increased [11C]PK11195 binding (reflecting neuroinflammation) in the medial/lateral temporal and parietal cortices in AD patients, relative to controls. [11C]PK11195 binding in the cuneus/precuneus correlated with episodic memory deficits in AD patients. This pattern of neuroinflammation was linked to large-scale network’ dysfunction and cognitive deficit. AD patients with enhanced neuroinflammation showed more abnormal connectivity across the whole-brain. The expression of a stronger association between altered functional connectivity and high levels of neuroinflammation related to cognitive deficit in AD.

My studies have wide-ranging implications that include:

1. the validation of animal models of tau propagation in living patients with AD;

2. improvements in our understanding of the relationship between in vivo tau pathology and brain functioning;

3. evidence for a primary role of neuroinflammation in mediating network dysfunction in AD;

4. support to the notion that immune-therapeutic strategies targeting tau pathology and neuroinflammation may be useful in AD.