Relationship between amyloid and tau levels and its impact on tau spreading

Abstract

Purpose Previous studies have shown that Aβ-amyloid (Aβ) likely promotes tau to spread beyond the medial temporal lobe. However, the Aβ levels necessary for tau to spread in the neocortex is still unclear. Methods Four hundred sixty-six participants underwent tau imaging with [18F]MK6420 and Aβ imaging with [18F]NAV4694. Aβ scans were quantified on the Centiloid (CL) scale with a cut-off of 25 CL for abnormal levels of Aβ (A+). Tau scans were quantified in three regions of interest (ROI) (mesial temporal (Me); temporoparietal neocortex (Te); and rest of neocortex (R)) and four mesial temporal region (entorhinal cortex, amygdala, hippocampus, and parahippocampus). Regional tau thresholds were established as the 95%ile of the cognitively unimpaired A- subjects. The prevalence of abnormal tau levels (T+) along the Centiloid continuum was determined. Results The plots of prevalence of T+ show earlier and greater increase along the Centiloid continuum in the medial temporal area compared to neocortex. Prevalence of T+ was low but associated with Aβ level between 10 and 40 CL reaching 23% in Me, 15% in Te, and 11% in R. Between 40 and 70 CL, the prevalence of T+ subjects per CL increased fourfold faster and at 70 CL was 64% in Me, 51% in Te, and 37% in R. In cognitively unimpaired, there were no T+ in R below 50 CL. The highest prevalence of T+ were found in the entorhinal cortex, reaching 40% at 40 CL and 80% at 60 CL. Conclusion Outside the entorhinal cortex, abnormal levels of cortical tau on PET are rarely found with Aβ below 40 CL. Above 40 CL prevalence of T+ accelerates in all areas. Moderate Aβ levels are required before abnormal neocortical tau becomes detectable.

Tau Imaging with 18F-MK6240 across the Alzheimer’s Disease spectrum

“…We found that a non-linear fit best explains the data, showing that a rise in detectable Aβ precedes a detectable increase in tau. We have previously shown that Aβ levels above ~50 CL are required to show significant cognitive and clinical change in cognitively normal older persons followed for 8 years (van der Kall, Truong et al 2020 point where a significant rise in the prevalence of T+ cases in CU as well as MCI and AD patients occurs (Dore, Krishnadas et al 2021).…”

Amyloid-associated increases in soluble tau is a key driver in accumulation of tau aggregates and cognitive decline in early Alzheimer

“…All image processing was done locally. Images were realigned, averaged, resliced to 1.5mm 3 , and smoothed to a resolution of 8mm 3 FWHM. Each PET image was registered to the closest structural T1-weighted MRI image.…”

“…Alzheimer’s disease (AD) is characterized by a cascade of molecular and neurodegenerative brain changes, in which Aβ plaques start to accumulate ∼20 years before symptom onset followed by the accumulation and spreading of neurofibrillary tau aggregates with ensuing neurodegeneration and AD dementia 1,2 . Multiple imaging studies of in vivo pathological processes with positron emission tomography (PET) in AD showed that cortical Aβ deposition precedes neocortical tau aggregation by several years 1,3 , and Aβ has been shown to amplify tau spreading in preclinical studies 4,5 . In contrast, age-related tau pathology typically occurring in the medial temporal lobe rarely spreads widely into the neocortex in the absence of cortical Aβ 6,7 , suggesting that the progression of tau aggregates is modified by Aβ 1,5 .…”

At a Glance: An Update on Neuroimaging and Retinal Imaging in Alzheimer’s Disease and Related Research

“…A recent study on the histopathological interactions between global amyloid and medial temporal neuroinflammation (48) reported that, in relation to tau spread, amyloid appeared to interact with transentorhinal neuroinflammation which, in turn, triggered the spread of tau across the neocortex (Braak stages II-III), followed by a subsequent spread of tau across Braak stages III-IV and the associated brain regions. A sentiment that was supported a year later, among a group of researchers who concluded that a "moderate" Aβ level is required for tau within the neocortex to be detectable, and that >40 centiloid of global Aβ burden is required to induce an accelerated spread of tau (49).…”