Tau pathology and neurodegeneration contribute to cognitive impairment in Alzheimer’s disease

Abstract

Neuropathological and in vivo studies have revealed a tight relationship between tau pathology and cognitive impairment across the Alzheimer's disease spectrum. However, tau pathology is also intimately associated with neurodegeneration and amyloid pathology. The aim of the present study was therefore to assess whether grey matter atrophy and amyloid pathology contribute to the relationship between tau pathology, as measured with 18F-AV-1451-PET imaging, and cognitive deficits in Alzheimer's disease. We included 40 amyloid-positive patients meeting criteria for mild cognitive impairment due to Alzheimer's disease (n = 5) or probable Alzheimer's disease dementia (n = 35). Twelve patients additionally fulfilled the diagnostic criteria for posterior cortical atrophy and eight for logopenic variant primary progressive aphasia. All participants underwent 3 T magnetic resonance imaging, amyloid (11C-PiB) positron emission tomography and tau (18F-AV-1451) positron emission tomography, and episodic and semantic memory, language, executive and visuospatial 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 binding and each cognitive domain, and we used the Biological Parametric Mapping toolbox to further control for local grey matter volumes, 11C-PiB uptake, or both. Partial correlations and causal mediation analyses (mediation R package) were then performed in brain regions showing an association between cognition and both 18F-AV-1451 uptake and grey matter volume. Our results showed that decreased cognitive performance in each domain was related to increased 18F-AV-1451 binding in specific brain regions conforming to established brain-behaviour relationships (i.e. episodic memory: medial temporal lobe and angular gyrus; semantic memory: left anterior temporal regions; language: left posterior superior temporal lobe and supramarginal gyrus; executive functions: bilateral frontoparietal regions; visuospatial functions: right more than left occipitotemporal regions). This pattern of regional associations remained essentially unchanged-although less spatially extended-when grey matter volume or 11C-PiB uptake maps were added as covariates. Mediation analyses revealed both direct and grey matter-mediated effects of 18F-AV-1451 uptake on cognitive performance. Together, these results show that tau pathology is related in a region-specific manner to cognitive impairment in Alzheimer's disease. These regional relationships are weakly related to amyloid burden, but are in part mediated by grey matter volumes. This suggests that tau pathology may lead to cognitive deficits through a variety of mechanisms, including, but not restricted to, grey matter loss. These results might have implications for future therapeutic trials targeting tau pathology.

Longitudinal tau accumulation and atrophy in aging and alzheimer disease

“…10,26 Briefly, BACS subjects undergo testing to measure performance on global cognitive (eg, MMSE) and specific cognitive tasks including those related to verbal and visual memory, working memory, processing speed, executive function, language, and attention. 10,26 Briefly, BACS subjects undergo testing to measure performance on global cognitive (eg, MMSE) and specific cognitive tasks including those related to verbal and visual memory, working memory, processing speed, executive function, language, and attention.…”

“…4 Since the recent advent of tau-PET imaging, several cross-sectional studies have shown that FTP retention in vivo reveals patterns consistent with the known neuropathological topology of NFTs. [5][6][7][8][9][10] Very few studies, however, have examined longitudinal FTP imaging. [5][6][7][8][9][10] Very few studies, however, have examined longitudinal FTP imaging.…”

“…Importantly, optimal methods for quantification of cross-sectional and longitudinal PET data are not necessarily in agreement, especially in reference region selection. 10,21 Normal aging is accompanied by a stereotyped pattern of cortical thinning but, similar to the accumulation and spread of tau, there is an acceleration of this process manifesting as frank neurodegeneration in AD. 19,20 Imaging studies reveal a strong relationship between FTP binding and atrophy in cross-sectional cohorts, which indicates that these pathologies likely interact over time.…”

Data-driven approaches for Tau-PET imaging biomarkers in Alzheimer’s disease

“…While amyloid-β may be present decades prior to symptom onset 3 , the presence of neocortical tau is temporally more closely related to current cognitive status and degree of neurodegeneration, as convincingly demonstrated by studies utilizing post-mortem tissue, animal models, cerebrospinal fluid and, more recently, the positron emission tomography (PET) tracer [ 18 F]AV1451 [4][5][6][7][8][9] .…”

“…Furthermore, regional [ 18 F]AV1451 retention co-localizes with sites of brain atrophy or hypometabolism 7,18 and has been associated with impairments in specific cognitive domains [7][8][9] .…”