van der Flier WM, Pijnenburg YA, Fox NC, Scheltens P.
Early-onset versus late-onset Alzheimer's disease: the case of the missing APOE ɛ4 allele.
Lancet Neurol. 2011 Mar;10(3):280-8.
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It was with great interest that I read the recent van der Flier paper from the groups of Philip Scheltens and Nick Fox, and I would like to congratulate the authors for advancing this important discussion. The conceptual change in the field of AD that this paper suggests is urgently needed.
Having followed the multiple failures in AD drug development during the last decade (mainly from an industry perspective), I find it difficult to understand that most companies still hope to target the entire AD spectrum with one single mode of action. It should be clear by now that we should stop considering AD as a single, uniform disease. Interestingly, the only approach that may work across the various dementia forms is the symptomatic one (i.e., "cognition enhancers," based on interactions with downstream neurotransmitter systems).
When "disease modification" is the goal, the situation appears to be quite different. Here, in addition to the factors of age at onset and ApoE status, which are the focus of this paper, numerous other aspects contribute to the clinical phenotype and should also be taken into account. Cerebrovascular status and its consequences, as well as metabolic aspects (such as glucose and insulin signaling), probably are among the obvious candidates, but there are certainly many other important factors to be looked at. Our understanding of the genetic basis for this complex interaction is only at the beginning.
The problem may be that both industry and academia will need to give up the promise of finding a "cure for AD" (there will be no single cure when there is no single disease). This may be painful in a situation when for more than a decade, very high hopes had been raised—but making promises that we will not be able to keep will not help in the long run.
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