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.

What’s That (Blue) Spot on my MRI? Multimodal Neuroimaging of the Locus Coeruleus in Neurodegenerative Disease

“…Some of the issues with development likely arise from the necessity of tau tracers to penetrate cell membranes, since misfolded tau forms intracellular inclusions, and the numerous isoforms of misfolded tau that are often disease specific. Nevertheless, PET studies confirm previous reports of tau as a better predictor of cognitive decline and cell death in AD compared to amyloid ( Cho et al, 2016 ; Kotzbauer et al, 2017 ; Gordon et al, 2018 ; Pereira et al, 2020 ). Newer tracers are being developed, and those such as 18F-RO-948 demonstrate an inverse relationship with cortical thickness ( Spotorno et al, 2020 ), which is in agreement with older tracers ( Ossenkoppele et al, 2019 ).…”

Clinical validity of increased cortical uptake of [18F]flortaucipir on PET as a biomarker for Alzheimer’s disease in the context of a structured 5-phase biomarker development framework

“…One study in two independent cohorts of cognitively normal subjects found that in the presence of high amyloid burden, women had higher entorhinal tau load than man [13]. This observation was confirmed in a study showing higher tau retention in temporo-parietal and frontal areas in women [95]. Another study suggested that men have higher uptake mainly in the frontal and parietal white matter and thalamus than women [128], although this was hypothesized to be largely driven by non-specific binding.…”

“…Furthermore, a study in healthy controls (41.2% Aβ+) found higher tau SUVrs in the parahippocampal gyrus in ɛ3ɛ3 carriers compared to ɛ2ɛ3 carriers, after adjusting for amyloid. This potentially shows the protective effect of the ɛ2 allele, although this must be interpreted with caution since the number of ɛ2ɛ3 carriers was limited (n = 11) [95].…”

“…The presence of amyloid-β may induce tau to spread outside of the MTL [53,128], although neocortical tau was present in amyloid-negative controls [67,120]. Both cross-sectional [56,66,70,85,95,100,105,110,119,128] and antecedent amyloid accumulation [62,116] were correlated with more (extra-)MTL [ 18 F]flortaucipir in the cognitively unimpaired. In addition, longitudinal [ 18 F]flortaucipir data also showed that an antecedent rise of amyloid-β was associated with a subsequent rise of tau accumulation in the inferior temporal lobe [40].…”

Resveratrol targeting tau proteins, amyloid‐beta aggregations, and their adverse effects: An updated review

“…The aggregations of tau proteins are found in temporal, ventral, lateral, and primary cortical areas of brain. Notably, the enhanced levels of tau proteins in temporal and frontal areas have most significant impacts on the decline in the memory and brain functions (Pereira, Harrison, La Joie, Baker, & Jagust, 2020). Interestingly, accumulation of tau proteins produces a signal of “eat‐me” on living neurons.…”