On 2015 May 29, Karl Herrup commented:

Shakespeare makes several good points. The tandem article was meant from the beginning as a strong 'counterpoint' to my own article. I find that it is a scholarly and well written piece and I encourage people to read both (especially students).

As for setting the age of onset where sporadic and familial AD diverge, I would have two responses. The first is to thank Dr. Shakespeare for raising the very real point that there is no bright line that separates the two. It is only a question of odds: AD that starts before age 65 is most likely fAD; AD after age 65 is most likely sAD. But "likely" is different from "is". The second response is to confess that I smiled when I saw the comment about how this was an 'unattributed' remark. I too complain about authors who assert that "it is commonly known that...." even when there is little or no primary source offered to back up the point. I have to admit that I was hoisted on my own petard here. I have glanced at the cited reference and am pleased to incorporate its findings in future writings...and to choose my words a bit more precisely.

Concerning my contention that there can be Alzheimer's without plaques. Here Shakespeare actually makes the exact point I was trying to make and I wish I had been clearer. Plaques may well contribute to the disease process and then disappear, which I assert is the message from the vaccine trials. The result is that mechanistically the plaques could have started the disease but then vanish. But given our current approaches, I assert that this is a serious problem. If this individual were to die and his brain come to autopsy, a trained neuropathologist would assure us that the individual's dementia could not possibly have been Alzheimer's, even though it was. I was trying to argue that the implications of this is that we may well distort our findings if we require the presence of plaques to reach a diagnosis of AD. My suggestion is that we should relax our dependence on them, detected through PET scans or neuropathologically, in our diagnostic regimens.

On 2015 May 27, Timothy Shakespeare commented:

This is an interesting article that I'm sure will stimulate much discussion. Readers may wish to see an alternative perspective published in tandem here: http://www.nature.com/neuro/journal/v18/n6/full/nn.4018.html

Working in the area of sporadic Alzheimer's disease with age at onset <65, I would disagree with the sentence "Sporadic AD first appears clinically after the age of 65." This sentence is uncited and incorrect. There is occasionally confusion between early onset or young onset Alzheimer's disease, and Dominantly Inherited Alzheimer's Disease (also known as Autosomal Dominant Alzheimer's Disease, familial Alzheimer's disease). An onset before 65 (early or young onset) should not be confused with a dominantly inherited genetic form of Alzheimer's disease. In fact sporadic AD is more common that familial AD even in people with an onset <61 http://dx.doi.org/10.1086/302553.

I would also make a point regarding the interpretation of vaccine trials that have not had great success in providing cognitive benefits. In this paper the interpretation is that this shows you can have Alzheimer's disease without plaques "The implication is that just as there can be plaques without AD, there can also be AD without plaques." The alternative interpretation, that the amyloid is being removed too late and has already had its effect, should be given consideration. I.e. you need to have plaques at some point, but perhaps only earlier in the disease process. Perhaps this would fit into the idea of rejecting the simple linear pathway tracing disease progression from Aβ to AD.

On 2015 May 27, Timothy Shakespeare commented:

This is an interesting article that I'm sure will stimulate much discussion. Readers may wish to see an alternative perspective published in tandem here: http://www.nature.com/neuro/journal/v18/n6/full/nn.4018.html

Working in the area of sporadic Alzheimer's disease with age at onset <65, I would disagree with the sentence "Sporadic AD first appears clinically after the age of 65." This sentence is uncited and incorrect. There is occasionally confusion between early onset or young onset Alzheimer's disease, and Dominantly Inherited Alzheimer's Disease (also known as Autosomal Dominant Alzheimer's Disease, familial Alzheimer's disease). An onset before 65 (early or young onset) should not be confused with a dominantly inherited genetic form of Alzheimer's disease. In fact sporadic AD is more common that familial AD even in people with an onset <61 http://dx.doi.org/10.1086/302553.

I would also make a point regarding the interpretation of vaccine trials that have not had great success in providing cognitive benefits. In this paper the interpretation is that this shows you can have Alzheimer's disease without plaques "The implication is that just as there can be plaques without AD, there can also be AD without plaques." The alternative interpretation, that the amyloid is being removed too late and has already had its effect, should be given consideration. I.e. you need to have plaques at some point, but perhaps only earlier in the disease process. Perhaps this would fit into the idea of rejecting the simple linear pathway tracing disease progression from Aβ to AD.

On 2015 May 29, Karl Herrup commented:

Shakespeare makes several good points. The tandem article was meant from the beginning as a strong 'counterpoint' to my own article. I find that it is a scholarly and well written piece and I encourage people to read both (especially students).

As for setting the age of onset where sporadic and familial AD diverge, I would have two responses. The first is to thank Dr. Shakespeare for raising the very real point that there is no bright line that separates the two. It is only a question of odds: AD that starts before age 65 is most likely fAD; AD after age 65 is most likely sAD. But "likely" is different from "is". The second response is to confess that I smiled when I saw the comment about how this was an 'unattributed' remark. I too complain about authors who assert that "it is commonly known that...." even when there is little or no primary source offered to back up the point. I have to admit that I was hoisted on my own petard here. I have glanced at the cited reference and am pleased to incorporate its findings in future writings...and to choose my words a bit more precisely.

Concerning my contention that there can be Alzheimer's without plaques. Here Shakespeare actually makes the exact point I was trying to make and I wish I had been clearer. Plaques may well contribute to the disease process and then disappear, which I assert is the message from the vaccine trials. The result is that mechanistically the plaques could have started the disease but then vanish. But given our current approaches, I assert that this is a serious problem. If this individual were to die and his brain come to autopsy, a trained neuropathologist would assure us that the individual's dementia could not possibly have been Alzheimer's, even though it was. I was trying to argue that the implications of this is that we may well distort our findings if we require the presence of plaques to reach a diagnosis of AD. My suggestion is that we should relax our dependence on them, detected through PET scans or neuropathologically, in our diagnostic regimens.