Spatial patterns of tau deposition are associated with amyloid, ApoE, sex, and cognitive decline in older adults

Abstract

Purpose: The abnormal deposition of tau begins before the onset of clinical symptoms and seems to target specific brain networks. The aim of this study is to identify the spatial patterns of tau deposition in cognitively normal older adults and assess whether they are related to amyloid-β (Aβ), APOE, sex, and longitudinal cognitive decline.

Methods: We included 114 older adults with cross-sectional flortaucipir (FTP) and Pittsburgh Compound-B PET in addition to longitudinal cognitive testing. A voxel-wise independent component analysis was applied to FTP images to identify the spatial patterns of tau deposition. We then assessed whether tau within these patterns differed by Aβ status, APOE genotype, and sex. Linear mixed effects models were built to test whether tau in each component predicted cognitive decline. Finally, we ordered the spatial components based on the frequency of high tau deposition to model tau spread.

Results: We found 10 biologically plausible tau patterns in the whole sample. There was greater tau in medial temporal, occipital, and orbitofrontal components in Aβ-positive compared with Aβ-negative individuals; in the parahippocampal component in ε3ε3 compared with ε2ε3 carriers; and in temporo-parietal and anterior frontal components in women compared with men. Higher tau in temporal and frontal components predicted longitudinal cognitive decline in memory and executive functions, respectively. Tau deposition was most frequently observed in medial temporal and ventral cortical areas, followed by lateral and primary areas.

Conclusions: These findings suggest that the spatial patterns of tau in asymptomatic individuals are clinically meaningful and are associated with Aβ, APOE ε2ε3, sex and cognitive decline. These patterns could be used to predict the regional spread of tau and perform in vivo tau staging in older adults.

Keywords: APOE; Amyloid; Cognitive decline; Flortaucipir PET; Older adults; Sex.

Fig. 1

Spatial patterns of tau deposition in aging. We identified 10 independent components for tau in the analyses of FTP data. These components were thresholded with a Z score > 2.0

Fig. 2

Tau burden within spatial patterns differs by Aβ, APOE, and sex in older adults. We found significantly higher tau burden in some of the spatial patterns in Aβ-positive compared with Aβ-negative peers, APOE ε3ε3 compared with ε2ε3 carriers, and in women compared with men. Asterisk indicates significant differences between groups, after regressing out the effects of age, sex, education for Aβ groups; age, sex, education, and PiB DVR for APOE groups; and age, education, and PiB DVR for sex groups. All results were corrected for multiple comparisons using FDR (q < 0.05)

Fig. 3

Progression of tau pathology across different spatial patterns. We used the means and standard deviations of Aβ− individuals with entorhinal tau < 1.2 to identify individuals with high tau in the different spatial patterns. The patterns that were determined to show increased binding in a greater number of participants were considered to be regions of early tau deposition. Using this approach, we found a spreading order of tau across the spatial patterns from limbic and ventral areas, to lateral and medial posterior regions, and frontal and sensorimotor cortices. Patterns colored in light red correspond to a newly added stage, whereas patterns colored in dark red correspond to previous stage