Distinct and joint effects of low and high levels of Aβ and tau deposition on cortical thickness

Alzheimer's disease (AD) is defined by the presence of Amyloid-β (Aβ), tau, and neurodegeneration (ATN framework) in the human cerebral cortex. Yet, prior studies have suggested that Aβ deposition can be associated with both cortical thinning and thickening. These contradictory results are attributed to small sample sizes, the presence versus absence of tau, and limited detectability in the earliest phase of protein deposition, which may begin in young adulthood and cannot be captured in studies enrolling only older subjects. In this study, we aimed to find the distinct and joint effects of Aβ and tau on neurodegeneration during the progression from normal to abnormal stages of pathologies that remain elusive. We used (18)F-MK6240 and (18)F-Florbetaben/(18)F-Florbetapir positron emission tomography (PET) and magnetic resonance imaging (MRI) to quantify tau, Aβ, and cortical thickness in 590 participants ranging in age from 20 to 90. We performed multiple regression analyses to assess the distinct and joint effects of Aβ and tau on cortical thickness using 590 healthy control (HC) and mild cognitive impairment (MCI) participants (141 young, 394 HC elderlies, 52 MCI). We showed that in participants with normal levels of global Aβ deposition, Aβ uptake was significantly associated with increased cortical thickness regardless of tau (e.g., left entorhinal cortex with t > 3.241, p < 0.0013). The relationship between tau deposition and neurodegeneration was more complex: in participants with abnormal levels of global tau, tau uptake was associated with cortical thinning in several regions of the brain (e.g., left entorhinal with t < -2.80, p < 0.0096 and left insula with t-value < -4.284, p < 0.0001), as reported on prior neuroimaging and neuropathological studies. Surprisingly, in participants with normal levels of global tau, tau was found to be associated with cortical thickening. Moreover, in participants with abnormal levels of global Aβ and tau, the resonance between them, defined as their correlation throughout the cortex, was associated strongly with cortical thinning even when controlling for a direct linear effect. We confirm prior findings of an association between Aβ deposition and cortical thickening and suggest this may also be the case in the earliest stages of deposition in normal aging. We also illustrate that resonance between high levels of Aβ and tau uptake is strongly associated with cortical thinning, emphasizing the effects of Aβ/tau synergy in AD pathogenesis.