“By the time you have Alzheimer’s symptoms, you already have a critical mass of amyloid plaque, and this stays relatively constant as you progress through the disease,” he said. “The question is, will any antiamyloid drug have a meaningful effect if it’s given after the plaques have already developed?”
It may be time, he said, to think of Alzheimer’s as a biphasic disorder, with different drugs for each phase. Initially, amyloid plaques appear in the disease, followed by tau neurofibrillatory tangling and its associated neurotoxicity. “Maybe our amyloid-based therapies should be used in the presymptomatic phase, before the plaques build to that critical level. Other drugs might be more useful in the symptomatic stage.”
Dr. Sabbagh said he wondered if some of the Alzheimer’s drugs that have been abandoned after failing their phase III studies might be more successful if used earlier in the disease course. “My fear is that a drug will be shelved when in fact it might be a good choice in a presymptomatic scenario, when amyloid plaques are just beginning to develop.”
With the enormous leaps now being made in amyloid imaging, researchers are pushing back the diagnostic timeline, identifying patients at the very onset of mild cognitive impairment – and perhaps even before any memory complaints appear. “A drug like semagacestat would be interesting to study in patients at that stage. Don’t chuck the product altogether; back it up into an earlier phase and see if the results are any different.”
Lilly sponsored the studies. Dr. Sabbagh reported no financial ties with the company.