The data from Leal et al. help to bring clarity to the relationships between Aβ accumulation and the AV-1451 tau signal. On a relatively small number of cognitively normal 75 years old subjects, followed over five years, those who were accumulating Aβ, even from sub threshold levels, could be seen to have developed an abnormal tau signal. These findings strongly support the current concept of AD pathogenesis in which Aβ drives cortical tau, and that cognitive impairment develops only when both Aβ and tau reach critical levels.
One issue that might need to be addressed when comparing markers of pathologic change is to account for the disparity in the concentration of Aβ and tau aggregates, given that tracer retention reflects the density of binding sites, and the concentration of tau aggregates in the brain is about one order of magnitude lower than Aβ. Other issues to be considered are tracer stoichiometry, binding affinity, and non-specific binding, which are unlikely to be the same for different tracers. Perhaps, we should qualify the statements about tau (and Aβ) by adding “detectable”, because there might be tau deposits in the brain that while present, are too low to be detected by PET.
We also noted that the analysis included both accumulators and non-accumulators. The advantage of having rates of Aβ accumulation is that they allow the separation of those subthreshold individuals who are on an AD trajectory from those who are not. It would have been preferable, in order to assess the true relationship between Aβ accumulation and tau burden, to examine Aβ accumulators and non-accumulators separately. That said, and as the authors acknowledge, even when non-accumulators were excluded from the analyses, it had little effect on the results. It would be extremely interesting to follow up these non- accumulators over time in terms of tau deposition, together with markers of neuronal injury as well as cognition.
Overall, coupling the longitudinal with cross-sectional data are most informative, and adds to the push to develop therapeutic strategies that, to be successful, will need to aim at those subjects who have yet to cross the threshold.
Evaluating the impact of various levels of amyloid or tau signal seen on PET imaging that may have some clinical associations is important for the field. The determination of cutpoints or thresholds that define characteristics of certain groups, such as people with AD dementia and normals, are also important. It is not that one approach is better than the other. Different approaches have different applications.
We can think of PET signal in terms of continuous change, to be most precise. At some point along the continuum, the level of protein may have an impact on a person. That level of “impact” could reasonably differ from one person to another. For example, amyloid and tau levels that cause symptomatic disease in one person may be distinct as compared to another person. These possibilities become complex and are important to consider as they may lessen our complete commitment to group level “cutoffs.” Having said that, cutoffs are what we live with in medicine, whether it is a blood pressure value or blood sugar measurement. There is a range and a cutoff that we all accept, while working within those guidelines to manage individuals who maybe don’t fit the mold perfectly.
In these recent papers, the investigators from the Jagust lab provide an intriguing look at modest elevations of the amyloid PET signal. It is very interesting and believable that cognition is affected at levels of amyloid that are “subthreshold”. We have to remember however that many of these “thresholds” were designed to characterize normal people vs. people with AD dementia. There isn’t really an applicable threshold in terms of detecting very subtle memory change in relatively cognitively unimpaired people and they therefore describe measuring subtle increases in amyloid. Using the term “threshold,” communicates the idea that the levels of amyloid being tested are lower than those typically used to distinguish AD dementia patients.
The researchers also demonstrate that subtle baseline elevation and increasing levels of amyloid are associated with tau signal at the end of the described amyloid imaging observation period. It is important to emphasize that this doesn’t demonstrate causation of tau accumulation but only association…or “prediction.” A very important distinction. We don’t know if these people had elevated tau when the first amyloid scans were performed. The tau scan was not done at that time. If tau was present first, maybe tau could have caused amyloid to increase. This can’t be determined with the data presented. Serial tau imaging in unison with serial amyloid imaging would be the best way to evaluate the interaction of amyloid and tau relative to causation. These answers await more data. To this paper’s point, the association of the two is an important finding and provides for hypotheses generation for future work.
These are fascinating studies. They remind us there is a lot we do not know about the biology of AD. They reinforce that we need to solve the mystery of how Aβ talks to tau. They also show that kinetics matter. There has been some literature (e.g. Wogulis et al, 2005) linking amyloid growth to toxicity in cultured neurons. Though I am not necessarily a fan of such artificial studies, it is worth considering that rate of accumulation might be more deterministic of toxicity than absolute amounts. This could further explain why overall amyloid levels in cross sectional studies tend to correlate poorly with symptoms. Perhaps if you are a slow accumulator you can reach high amyloid loads without symptoms whereas if you accumulate quickly, regardless of overall level, things are not so good. Enlisting these individuals for brain autopsy would be highly useful as that would provide even more information. Indeed, another possibility (speculative though it may be) is that the signal is low because there is efficient local clearance, which is actually causing bystander damage.
References:
Wogulis M, Wright S, Cunningham D, Chilcote T, Powell K, Rydel RE.
Nucleation-dependent polymerization is an essential component of amyloid-mediated neuronal cell death.
J Neurosci. 2005 Feb 2;25(5):1071-80.
PubMed.
Comments
Austin Hospital
University of Melbourne
The data from Leal et al. help to bring clarity to the relationships between Aβ accumulation and the AV-1451 tau signal. On a relatively small number of cognitively normal 75 years old subjects, followed over five years, those who were accumulating Aβ, even from sub threshold levels, could be seen to have developed an abnormal tau signal. These findings strongly support the current concept of AD pathogenesis in which Aβ drives cortical tau, and that cognitive impairment develops only when both Aβ and tau reach critical levels.
One issue that might need to be addressed when comparing markers of pathologic change is to account for the disparity in the concentration of Aβ and tau aggregates, given that tracer retention reflects the density of binding sites, and the concentration of tau aggregates in the brain is about one order of magnitude lower than Aβ. Other issues to be considered are tracer stoichiometry, binding affinity, and non-specific binding, which are unlikely to be the same for different tracers. Perhaps, we should qualify the statements about tau (and Aβ) by adding “detectable”, because there might be tau deposits in the brain that while present, are too low to be detected by PET.
We also noted that the analysis included both accumulators and non-accumulators. The advantage of having rates of Aβ accumulation is that they allow the separation of those subthreshold individuals who are on an AD trajectory from those who are not. It would have been preferable, in order to assess the true relationship between Aβ accumulation and tau burden, to examine Aβ accumulators and non-accumulators separately. That said, and as the authors acknowledge, even when non-accumulators were excluded from the analyses, it had little effect on the results. It would be extremely interesting to follow up these non- accumulators over time in terms of tau deposition, together with markers of neuronal injury as well as cognition.
Overall, coupling the longitudinal with cross-sectional data are most informative, and adds to the push to develop therapeutic strategies that, to be successful, will need to aim at those subjects who have yet to cross the threshold.
View all comments by Colin MastersMayo Clinic
Evaluating the impact of various levels of amyloid or tau signal seen on PET imaging that may have some clinical associations is important for the field. The determination of cutpoints or thresholds that define characteristics of certain groups, such as people with AD dementia and normals, are also important. It is not that one approach is better than the other. Different approaches have different applications.
We can think of PET signal in terms of continuous change, to be most precise. At some point along the continuum, the level of protein may have an impact on a person. That level of “impact” could reasonably differ from one person to another. For example, amyloid and tau levels that cause symptomatic disease in one person may be distinct as compared to another person. These possibilities become complex and are important to consider as they may lessen our complete commitment to group level “cutoffs.” Having said that, cutoffs are what we live with in medicine, whether it is a blood pressure value or blood sugar measurement. There is a range and a cutoff that we all accept, while working within those guidelines to manage individuals who maybe don’t fit the mold perfectly.
In these recent papers, the investigators from the Jagust lab provide an intriguing look at modest elevations of the amyloid PET signal. It is very interesting and believable that cognition is affected at levels of amyloid that are “subthreshold”. We have to remember however that many of these “thresholds” were designed to characterize normal people vs. people with AD dementia. There isn’t really an applicable threshold in terms of detecting very subtle memory change in relatively cognitively unimpaired people and they therefore describe measuring subtle increases in amyloid. Using the term “threshold,” communicates the idea that the levels of amyloid being tested are lower than those typically used to distinguish AD dementia patients.
The researchers also demonstrate that subtle baseline elevation and increasing levels of amyloid are associated with tau signal at the end of the described amyloid imaging observation period. It is important to emphasize that this doesn’t demonstrate causation of tau accumulation but only association…or “prediction.” A very important distinction. We don’t know if these people had elevated tau when the first amyloid scans were performed. The tau scan was not done at that time. If tau was present first, maybe tau could have caused amyloid to increase. This can’t be determined with the data presented. Serial tau imaging in unison with serial amyloid imaging would be the best way to evaluate the interaction of amyloid and tau relative to causation. These answers await more data. To this paper’s point, the association of the two is an important finding and provides for hypotheses generation for future work.
View all comments by Val LoweGoizueta Institute @ Emory Brain Health
These are fascinating studies. They remind us there is a lot we do not know about the biology of AD. They reinforce that we need to solve the mystery of how Aβ talks to tau. They also show that kinetics matter. There has been some literature (e.g. Wogulis et al, 2005) linking amyloid growth to toxicity in cultured neurons. Though I am not necessarily a fan of such artificial studies, it is worth considering that rate of accumulation might be more deterministic of toxicity than absolute amounts. This could further explain why overall amyloid levels in cross sectional studies tend to correlate poorly with symptoms. Perhaps if you are a slow accumulator you can reach high amyloid loads without symptoms whereas if you accumulate quickly, regardless of overall level, things are not so good. Enlisting these individuals for brain autopsy would be highly useful as that would provide even more information. Indeed, another possibility (speculative though it may be) is that the signal is low because there is efficient local clearance, which is actually causing bystander damage.
References:
Wogulis M, Wright S, Cunningham D, Chilcote T, Powell K, Rydel RE. Nucleation-dependent polymerization is an essential component of amyloid-mediated neuronal cell death. J Neurosci. 2005 Feb 2;25(5):1071-80. PubMed.
View all comments by Todd E. GoldeMake a Comment
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