Efforts to clear amyloid-β from the brains of Alzheimer's patients might have turned the corner these past few years, with immunotherapies beginning to show results that are something other than abject failure. The lengthy period of years in which trial after trial of potential anti-amyloid therapies failed inspired a great deal of theorizing on alternative models for Alzheimer's disease. I think it likely that the condition has several causes, each of which produces a sizable fraction of the overall symptoms. Combine that with the theories that suggest amyloid-β aggregation is an early mechanism that enables tau aggregration to do the real damage later on, and it looks plausible that clearing amyloid is both useful and necessary, but not enough on its own to reliably help patients.
This is why I favor development of the new and as yet unrealized approach of restoring drainage of cerebrospinal fluid, which holds the potential of reducing the buildup of all forms of molecular waste in the brain - amyloid-β, tau, α-synuclein, and so forth. Still, the signs of progress reported here join the 2016 aducanumab results and others as an indication that at some point immunotherapy to remove amyloid-β will become a solved problem, and that it appears possible to produce benefits for patients this way. We can hope that approaches that target more than one form of molecular waste, such as those based on restoring youthful levels of drainage of cerebrospinal fluid, will prove to be even more effective once piloted in humans.
The last full day of the Alzheimer's Association International Conference saw scientists pack a room the size of an aircraft hangar in anticipation of a late addition to the scientific program. They came to see the data behind a tantalizing press release issued earlier this month, which had claimed that BAN2401, the anti-Aβ protofibril immunotherapy, reduced amyloid in early Alzheimer's disease and also slowed cognitive decline. The upshot? According to the results presented, the antibody appears to have done what it was designed to do.
Over 18 months, fibrillar amyloid fell in all treatment groups compared with placebo; indeed, plaques melted by a whopping 93 percent in participants on the highest dose. This dose was reported to have reduced cognitive decline by 47 percent as measured by the ADAS-Cog, and by 30 percent on the ADCOMS, a new composite measure to detect early cognitive decline. At 856 participants with mild cognitive impairment due to AD or mild AD, this trial is the largest one yet to post both amyloid reduction and a downstream benefit on symptoms.
Statisticians and clinicians who gathered in the hallways after the presentation were cautiously upbeat. "Overall the results are positive and the amyloid effect is impressive. I believe this antibody works. In summary, there is dramatic amyloid lowering, with some apparent slowing in decline at the highest dose. The field is clearly moving forward with the ability of a fourth drug to remove amyloid to a normal level, as measured by PET. Now with aducanumab, gantenerumab, and n3pg, BAN2401 has demonstrated reversal of amyloid plaques to normal levels, representing a milestone in the history of Alzheimer's disease."