TAU PATHOLOGY AND GRAY MATTER ATROPHY CONTRIBUTE TO COGNITIVE IMPAIRMENT IN ALZHEIMER’S DISEASE

Abstract

Neuropathological and in vivo studies have revealed a close relationship between tau pathology and cognitive impairment across the Alzheimer's disease (AD) spectrum. However, tau pathology is also intimately associated with neurodegeneration. We therefore assessed in a heterogeneous sample of AD patients whether the relationship between tau pathology, as measured with 18F-AV1451-PET imaging, and cognition remained significant after controlling for local gray matter atrophy and amyloid pathology. We also performed causal mediation analyses to further examine the potential intermediary role of gray matter atrophy. Forty Aβ-PET+ patients with heterogeneous AD phenotypes (Table 1) underwent 3T MRI, 11C-PiB-PET and 18F-AV1451-PET, and episodic and semantic memory, language, executive and visuo-spatial functions assessment. Raw cognitive scores were converted to age-adjusted Z-scores (W-scores) and averaged to compute composite scores for each cognitive domain. Independent regressions were performed between 18F-AV-1451 SUVR and each cognitive domain and Biological Parametric Mapping (BPM) was used to further control for local gray matter volumes, PIB-DVR, or both. Partial correlations and mediation analyses (mediation R package) were performed in brain regions showing an association between cognition and both 18F-AV-1451 SUVR and gray matter volume. The average direct effect (ADE) and average causal mediation effect (ACME), reflecting direct and indirect effects 18F-AV-1451 on cognition, were computed using the mediation R package (non-parametric bootstrapping, 5000 simulations). Decreased cognitive performance in each domain was related to increased 18F-AV-1451 SUVR in specific brain regions conforming to established brain-behavior relationships (Figure 1). This pattern of regional associations remained essentially unchanged – although less spatially extended – when gray matter volume or 11C-PiB uptake maps were added as covariates (Figure 2). Mediation analyses revealed both direct and gray matter-mediated effects of 18F-AV-1451 uptake on cognitive performance (Figure 3). Tau pathology is related in a region-specific manner to cognitive impairment in AD. These regional relationships are weakly related to amyloid burden, but are in part mediated by gray matter volumes. These results suggest that tau pathology may lead to cognitive deficits through a variety of mechanisms, including, but not restricted, to neuronal loss. Voxel-wise results and scatter plots of the independent regressions between 18F-AV-1451 SUVR and each cognitive domain score. (SPM, p<0.001 - k>500 mm3). Voxel-wise results of the multiple regressions between 18F-AV-1451 SUVR and each cognitive domain score controlling for local grey matter volume and/or local 11C-PiB DVR. (Biological Parametric Mapping, p<0.001 - k>500 mm3) Partial correlations and mediation analyses in the brain areas where both 18F-AV-1451 SUVR and gray matter volume were related to cognitive domain scores.