Amyloid and tau imaging biomarkers explain cognitive decline from late middle-age

Abstract

This study investigated differences in retrospective cognitive trajectories between amyloid and tau PET biomarker stratified groups in initially cognitively unimpaired participants sampled from the Wisconsin Registry for Alzheimer’s Prevention. One hundred and sixty-seven initially unimpaired individuals (baseline age 59 ± 6 years; 115 females) were stratified by elevated amyloid-β and tau status based on 11C-Pittsburgh compound B (PiB) and 18F-MK-6240 PET imaging. Mixed effects models were used to determine if longitudinal cognitive trajectories based on a composite of cognitive tests including memory and executive function differed between biomarker groups. Secondary analyses investigated group differences for a variety of cross-sectional health and cognitive tests, and associations between 18F-MK-6240, 11C-PiB, and age. A significant group × age interaction was observed with post hoc comparisons indicating that the group with both elevated amyloid and tau pathophysiology were declining approximately three times faster in retrospective cognition compared to those with just one or no elevated biomarkers. This result was robust against various thresholds and medial temporal lobe regions defining elevated tau. Participants were relatively healthy and mostly did not differ between biomarker groups in health factors at the beginning or end of study, or most cognitive measures at study entry. Analyses investigating association between age, MK-6240 and PiB indicated weak associations between age and 18F-MK-6240 in tangle-associated regions, which were negligible after adjusting for 11C-PiB. Strong associations, particularly in entorhinal cortex, hippocampus and amygdala, were observed between 18F-MK-6240 and global 11C-PiB in regions associated with Braak neurofibrillary tangle stages I–VI. These results suggest that the combination of pathological amyloid and tau is detrimental to cognitive decline in preclinical Alzheimer’s disease during late middle-age. Within the Alzheimer’s disease continuum, middle-age health factors likely do not greatly influence preclinical cognitive decline. Future studies in a larger preclinical sample are needed to determine if and to what extent individual contributions of amyloid and tau affect cognitive decline. 18F-MK-6240 shows promise as a sensitive biomarker for detecting neurofibrillary tangles in preclinical Alzheimer’s disease.

Cohort study of electroencephalography markers of amyloid-tau-neurodegeneration pathology

“…Amyloid positive scans were defined qualitatively using established criteria ( Johnson et al , 2014 ). Tau PET imaging was conducted using [F-18]MK6240 from ∼70- to 110-min post-injection ( Betthauser et al , 2019 , 2020 ). Tau-positive PET scans were defined by setting the MK-6240 SUVR positivity threshold at 2 standard deviation above the mean of the PiB(−) group in the entorhinal cortex (entorhinal MK-6240 SUVR > 1.27) as in Betthauser et al (2020) .…”

“…The inconsistent findings across these studies, highlight the need for more EEG studies. Ideally, these studies should be extended to include markers of brain tau pathology, using tracers such as [18F]MK-6240 ( Betthauser et al , 2019 , 2020 ). We embarked on similar analyses in EEG in sensor space, avoiding the complexities of source reconstruction, to ascertain whether similar effects on alpha power would be observed in the EEG in our dataset.…”

Multiple markers contribute to risk of progression from normal to mild cognitive impairment

“…This evidence prompted the shift of clinical trials to the preclinical stage of AD, where individuals harbor elevated β-amyloid (Aβ) burden in the absence of significant cognitive deficits ( Sperling et al, 2014 ). Elevated Aβ burden alone, however, may not be sufficient to predict imminent clinical progression ( Belleville et al, 2017 , Berg, 1988 , Betthauser et al, 2020 ). Therefore, there is a need for additional markers to be used along with Aβ burden to identify individuals at high risk of clinical progression who would likely benefit most from treatment.…”

Sleep and Tau Pathology in Vietnam War Veterans with Preclinical and Prodromal Alzheimer’s Disease

“…In this clinic-pathological correlation paper, all samples who were elevated at stages I and II only did not have clinically de ned dementia, half of the 10 patients with each of stage III and IV tau had dementia, thus stages III and IV seem to represent a transitional zone between symptoms being evident or not. Tau PET signal related to age and not amyloid status has been reported, but the spatial patterns related to AD are seen much more commonly in Aβ + participants 29 . Thus, we would expect those in our Aβ + group with elevations in tau to decline, and we will analyze these longitudinal data once they become available.…”