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Hanseeuw BJ, Betensky RA, Jacobs HI, Schultz AP, Sepulcre J, Becker JA, Cosio DM, Farrell M, Quiroz YT, Mormino EC, Buckley RF, Papp KV, Amariglio RA, Dewachter I, Ivanoiu A, Huijbers W, Hedden T, Marshall GA, Chhatwal JP, Rentz DM, Sperling RA, Johnson K. Association of Amyloid and Tau With Cognition in Preclinical Alzheimer Disease: A Longitudinal Study. JAMA Neurol. 2019 Jun 3; PubMed.
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Wake Forest School of Medicine
This JAMA Neurology paper by Hanseeuw et al. is a true tau-PET tour de force. With a sample of just 60 people who started with normal cognition and had seven years of follow-up data, the authors were able to provide some of the first in vivo longitudinal confirmation of the leading research hypotheses that we have in the field today about amyloid, tau, and cognitive function—“that Aβ precedes and accelerates neocortical tau pathology, which together precipitate cognitive decline.”
The results are a reaffirmation of recent research efforts, implying that the growing trends in AD studies—to focus earlier on preclinical disease, and to amplify use of imaging biomarkers—may prove critical to successfully measuring, predicting, and preventing cognitive decline in clinical trials of disease-modifying drugs.
While it is not exactly surprising, it is exciting to see it demonstrated that it is not just cross-sectional amyloid or tau levels that are most closely linked to cognitive function. Rather, as the mediation model shows, it is processes of amyloid and tau change that are most critical to final cognition seven years later.
This paper did a solid job of supporting the argument that serial tau-PET biomarkers will be critical to understanding whether neurodegenerative disease processes are truly being slowed by treatments, regardless of whether enough follow-up has occurred over the length of a standard clinical trial to see a slackening of cognitive decline. In other words, the take-home for clinical trialists is that these findings may bring us closer to using in vivo imaging biomarkers to measure the impacts of interventions in AD clinical trials, as neuroimaging may allow us to detect significant group differences over a shorter time and in an earlier disease state, even without observing differences in clinical and cognitive function.
View all comments by Samuel LockhartLund University
I think the paper is very well performed and the results indicate that tau pathology is more closely related to cognitive decline than Aβ pathology. More importantly, the study indicates that it is the rate in increase in tau pathology (as measured with change in FTP PET) that is strongly related to cognitive decline.
The results support investigating therapies aimed at halting spread of tau pathology. However, causal relationships cannot be proven until a therapy directed against an AD-relevant pathology has been shown to halt cognitive decline. Further, larger studies are needed evaluating this and other tau PET tracers before we can make more firm conclusions, because the study is quite limited in size and in the regions evaluated for tau pathology.
View all comments by Oskar HanssonThis paper provides a crucial window into the pathology of AD. The results appear to imply that tau is more directly related to cognitive decline than Aβ, and that developing therapeutics directed at abrogating tau might more likely to impede dementia than developing therapeutics directed at impeding Aβ. Perhaps this is so, but a crucial gap remains between Aβ, tau, and the onset of dementia symptomology, and this involves smaller, and potentially more toxic forms of Aβ that are difficult to measure using PiB. This means that missing from the cascade described by Hanseeuw et al. was the influence of smaller forms of Aβ on the symptomatology of AD.
As the authors of this paper highlight, PiB is not particularly sensitive to prefibrillar or low levels of fibrillar Aβ (also see Vlassenko et al., 2012), and an inverse correlation between the size of Aβ assemblies and the potency of toxicity has been implicated (Sengupta et al., 2016).
Thus, lacking data on this important subgroup of Aβ in the milieu of AD pathology and in the context of the sequential model by Hanseeuw et al. makes it more challenging to attempt to infer from these results that a therapeutic strategy directed at impeding tau will be more or less viable than a strategy directed at impeding Aβ.
References:
Vlassenko AG, Benzinger TL, Morris JC. PET amyloid-beta imaging in preclinical Alzheimer's disease. Biochim Biophys Acta. 2012 Mar;1822(3):370-9. PubMed.
Sengupta U, Nilson AN, Kayed R. The Role of Amyloid-β Oligomers in Toxicity, Propagation, and Immunotherapy. EBioMedicine. 2016 Apr;6:42-9. Epub 2016 Apr 5 PubMed.
View all comments by James WallaceMake a Comment
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