Therriault J, Pascoal TA, Lussier FZ, Tissot C, Chamoun M, Bezgin G, Servaes S, Benedet AL, Ashton NJ, Karikari TK, Lantero-Rodriguez J, Kunach P, Wang YT, Fernandez-Arias J, Massarweh G, Vitali P, Soucy JP, Saha-Chaudhuri P, Blennow K, Zetterberg H, Gauthier S, Rosa-Neto P. Biomarker modeling of Alzheimer's disease using PET-based Braak staging. Nat Aging. 2022 Jun;2(6):526-535. Epub 2022 Apr 25 PubMed. Nature Aging

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  1. Therriault and colleagues assessed biomarkers in 324 individuals who were cognitively normal or had mild cognitive impairment at baseline and longitudinally. They were assessed clinically, cognitively, and for several biomarkers including with amyloid imaging, tau imaging, CSF, and plasma. Using the tau imaging agent MK6240, which allows for high resolution, accurate imaging of tau fibril pathology, they classified individuals into different Braak stages (I-IV).

    Based on staging in this way, early Braak stages, e.g., stage 2, was associated with normal cognitive status or isolated memory impairment, usually CDR 0; stages III and IV with either normal cognition or mild cognitive impairment/very mild dementia (CDR 0.5); stages V and VI with very mild to higher degrees of dementia (CDR 0.5 to 2). 

    While amyloid deposition may or may not have been present in individuals up to stage III, it was always present in those with Braak stage IV or higher, emphasizing the idea that amyloid pathology drives progression of tau pathology. The authors concluded that PET-based Braak staging serves as a framework to model the natural history of AD and monitor AD severity in living humans. 

    I think this was a very well done study and agree with the authors’ major conclusion. Other studies have made similar observations but have not all done this with a tau imaging agent such as MK6240 that allows for very accurate determination of Braak staging. 

    The authors found a strong correlation with several CSF and plasma p-tau markers with Braak staging. However, they make the important point in the discussion that whether increases in soluble forms of p-tau are linked to the degree of amyloid deposition vs. the amount of tau pathology cannot be concluded from this study. For example, there are also strong correlations with the amount of amyloid deposition and CSF and plasma p-tau levels. 

    It seems likely from other data that soluble species of p-tau are mostly related to the amount of amyloid deposition and not the amount of tau tangles/insoluble tau. In that vein, it would have been interesting in this dataset to look at the relationship between a quantitative measure of MK6240 binding in individuals with Braak stages 0-III who were amyloid-positive or amyloid-negative. Then, in those who were amyloid-positive or amyloid-negative, is there is any relationship between the amount of p-tau species and MK6240 binding? If p-tau relates to the amount of tau pathology, one would expect the same correlation in both groups. If the correlation was much less in the amyloid-negative group, this would suggest that the relationship is driven by amyloid deposition and not tau pathology.  

    Overall, however, this is a very strong dataset and provides a nice framework to assess the overall progression of amyloid related changes, soluble tau changes, fibrillar tau changes and their relationships to clinical and cognitive status that should be useful in design of clinical trials, assessing treatments, and in relating previous pathological studies to the in vivo situation in living people.

    View all comments by David Holtzman

  2. This very nice study by Therriault and colleagues focuses on biomarker and cognitive changes associated with tau PET-defined Braak staging. Using a second-generation tau PET tracer with less off-target binding in choroid plexus, the authors show that increasing PET-based Braak staging is associated with increasing amyloid, increasing CSF and plasma p-tau, reductions in hippocampal volume, and cognitive decline, providing novel in vivo evidence of Braak staging with MK6240.

    While the present study highlights the potential for tau PET to be used in tracking AD progression as defined by staging procedures originating from postmortem work, tau PET also offers an excellent opportunity to provide insight into the spatial patterns of tau throughout the course of disease. Therriault and colleagues highlight the exciting potential to capture focal, early tau within the EC, which has also been demonstrated by Sanchez and colleagues using flortaucipir (Sanchez et al., 2021). 

    Expanding beyond the medial temporal lobe, the authors include 11 brain regions across frontal, temporal, parietal, and occipital lobes in their definition of Braak V and four brain regions (i.e., paracentral, postcentral, precentral, pericalcarine) in their definition of Braak VI. These definitions mirror postmortem assessments, which typically sample hippocampus, entorhinal cortex (EC), middle frontal gyrus, superior and middle temporal gyri, inferior parietal lobule, and occipital cortex (Hyman et al., 2012) to determine Braak V (defined as the presence of neurofibrillary tangles in high order association areas in frontal, parietal, occipital, and peristriate regions) and Braak VI (involvement of motor and sensory areas) staging (Braak and Braak, 1995). 

    The broad approach employed by Therriault and colleagues is also consistent with other recent tau PET work that has quantified tau PET SUVRs across a large cortical meta-region of interest, and with most qualitative reading scales that incorporate a cortical positive/negative dimension, with some additionally classifying the medial temporal lobe (MTL) as positive/negative (Koran et al., 2020; Sonni et al., 2020). Taken together, these studies highlight the ability to capture a progression that is consistent with Braak staging in vivo (focal EC tau, greater MTL tau, then eventually some cortical involvement), and confirm that progression along this staging framework is associated with worse clinical function.

    Although tau PET imaging is limited by poor resolution and specificity, a key advantage of PET over postmortem analysis is the ability to survey the entire brain. In postmortem examination only a small set of regions are sampled, and this sampling is oftentimes only in one hemisphere (Hyman et al., 2012). Given this key difference, it is interesting that many tau PET studies have elected to summarize their data according to sparse sampling protocols used by postmortem research. Although this approach has the advantage of being hypothesis-driven and is clearly useful in distilling the data into relatively few labels (such as MTL tau positive/negative and cortical tau positive/negative as done in qualitative reads of tau PET), we are potentially overlooking spatial information that may be clinically important and may inform disease mechanisms.

    Indeed, data-driven subtyping efforts have demonstrated heterogeneity in tau spatial patterns across the AD spectrum (Franzmeier et al., 2020; Vogel et al., 2021; Young et al., 2018; Young et al., 2022). Along these lines, Therriault and colleagues demonstrated that 7-11 percent of the atypical AD participants (behavioral/dysexecutive, logopenic PPA, PCA) included in their study were Braak-stage discordant, usually because there was cortical signal in the absence of elevated MTL signal. Additionally, the tau PET images of Braak-discordant cases shown in Extended Data Figure 2 demonstrate asymmetrical (in behavioral/dysexecutive AD and logopenic PPA) and precuneus-dominant (in PCA) tau patterns that are similar to the subtypes described by previous efforts (Vogel et al., 2021; Young et al., 2022). 

    Other work has suggested no difference in MTL uptake in atypical AD, though cortical patterns of tau elevations are clearly different in atypical presentations compared to typical AD (La Joie et al., 2021; Ossenkoppele et al., 2016; Petersen et al., 2019). These different trajectories (MTL-first pathways as well as variability in cortical patterns of spread both with and without MTL involvement) are intriguing and warrant further investigation regarding their time-course, underlying mechanisms, and clinical relevance. Overall, the full brain coverage provided by tau PET will allow us to go beyond Braak staging and characterize the different sources of tau heterogeneity.

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    View all comments by Elizabeth Mormino

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