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

Abstract

Alzheimer's disease (AD) is defined by the presence of Amyloid-β (Aβ), tau, and neurodegeneration (ATN framework) in the human cerebral cortex. Prior studies have suggested that Aβ deposition can be associated with both cortical thinning and thickening. These contradictory results may be due 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 incompletely understood. We used 18F-MK6240 and 18F-Florbetaben/18F-Florbetapir positron emission tomography (PET) and magnetic resonance imaging (MRI) to quantify tau, Aβ, and cortical thickness in 529 participants ranging in age from 20 to 90. We applied a novel partial volume correction technique based on the absence of proteinopathy in young controls to optimize spatial resolution. Aβ/tau abnormality was defined at 95th percentile of the normal distribution of global Ab/tau observed in young participants. We performed multiple regression analyses to assess the distinct and joint effects of Aβ and tau on cortical thickness. Using 529 participants (83 young, 394 healthy older, 52 MCI) we showed that normal levels of Aβ deposition were significantly associated with increased cortical thickness regardless of the amount of tau (e.g., left entorhinal cortex with t>3.241). The relationship between tau deposition and neurodegeneration was more complex: abnormal levels of tau were associated with cortical thinning in several regions of the brain (e.g., left entorhinal with t<-2.80 and left insula with t<-3.202), as expected based on prior neuroimaging and neuropathological studies. Surprisingly, however, normal levels of tau were found to be associated with cortical thickening. Moreover, at abnormal levels of Aβ and tau, the resonance between them, defined as their correlation throughout the cortex, was associated strongly with cortical thinning when controlling for their additive 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 discuss potential pathophysiologic processes underlying this effect such as inflammation and hyperactivation (excitotoxicity). 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.

Seeing beyond the symptoms: biomarkers and brain regions linked to cognitive decline in Alzheimer’s disease

“…This ambiguity is reflected in conflicting reports regarding the relationship between the two best biomarkers in our study: Aβ and ATH. Some studies suggest that an increase in Aβ deposition is linked with neurodegeneration, such as cortical thinning and/or lower volume (Becker et al, 2009;Glodzik et al, 2012;Doré et al, 2013;Kaffashian et al, 2015;Llado-Saz et al, 2015;Susanto et al, 2015;Hedden et al, 2016;Sala-Llonch et al, 2017;Ten Kate et al, 2018), while others report the opposite, where higher Aβ deposition is associated with cortical thickening and/or increased volume (Whitwell et al, 2013;Rahayel et al, 2019;Batzu et al, 2020;Harrison et al, 2021;Hojjati et al, 2023). Fortea et al (2011) examined the association between Aβ values and cortical thickness 2013) investigated non-Aβ factors of neurodegeneration within AD regions in older HC adults and found that many had neurodegenerative biomarker abnormalities in AD-affected brain regions, despite having normal Aβ levels.…”