In an earlier Blog about Aduhelm, the first FDA approved drug for Alzheimer’s disease, I argued that there was no real benefit for the drug because the cognitive measures showed no significant advantage for Aduhelm over the placebo condition. The FDA, in a controversial move, approved the drug because of its impact on secondary measures, such as amyloid burden in the brain.  Amyloid has been hypothesized to be the cause of Alzheimer’s disease, though another biomarker, tau, is becoming the current favored culprit.

In early January 2023, through the same mechanism of accelerated approval, the FDA authorized use of a new drug to treat early Alzheimer’s disease: Lecanemab (trade name is Leqembi).  The drug offered evidence of both cognitive efficacy and reduction of brain biomarkers for Alzheimer’s disease (e.g., amyloid burden).  So, do we now have a tool that can effectively reverse the effects of Alzheimer’s disease and related dementias?  The answer is no.  The drug does not improve cognition. Rather, it slows the rate of decline of cognition seen in this progressive disease.  This is still a breakthrough, though not the one most people would have hoped for, which would have been to have returned their loved one to a higher level of cognition, before the disease had started to take its toll.

So, we have both good news and bad news.

Amyloid levels in the brain were brought below the level seen as being a clinically significant burden for the Lecanemab group while it continued to rise a bit in the placebo group over the year and a half of monitoring.  So, why did a drug that reduced biomarkers strikingly not improve cognition instead of slowing the rate of decline? There are several potential explanations.  First, although I am oversimplifying here, once damaged, human brain tissue, particularly neurons critical for effective cognitive performance, does not appear to regenerate, unlike other damaged tissue systems such as your skin.  If you think of amyloid and tau, two substances linked to poor cognition in dementia as poisons, removing the poison does not permit new neuronal growth.  “What’s done cannot be undone,” was the lecture that Lady Macbeth gave her husband about the killing of the Scottish king in the Shakespeare tragedy.  Some tissues such as heart tissue and brain tissue typically do not repair themselves after being damaged (e.g., via stroke, heart attack).

In an ideal world, damaged neurons or heart cells would be replaced by new ones and return you to full functioning. The brain is still somewhat plastic after modest damage, much more so for younger than older brains.  The brain can rewire itself by changing connectivity patterns within intact neural networks, primarily through new dendritic growth. 

A second possibility for failure to halt cognitive decline is that amyloid and tau burden are not the primary causes of Alzheimer’s disease but a side effect of some other causal factor that is not sufficiently neutralized by the mono-clonal antibody Lecanemab. 

What that means is that we should not expect that class of intervention drugs (amyloid, tau removal) to improve cognition.  However, we might hope that if those biomarkers were the cause of cognitive decline, it might stabilize cognition.  Sadly, decline was evident in both the placebo and the Lecanemab conditions, but less decline was observed for Lecanemab.  How much less?  About 0.45 points by 18 months on a cognitive measure called the CDR-SB.  The overall decline for that time interval was about 1.2 points for the Lecanemab group and 1.7 points for the Placebo group.  Each group started the study by having a physician rate (using the CDR-SB measure) the patient’s level of cognition for domains such as memory, orientation, judgment, community affairs, home hobbies, and personal care.  That rating was at about 3.2 points when entering the study, a level consistent with the diagnosis of early dementia.  So, the rate of decline was significantly slowed in the Lecanemab group by about 25%.

Was the glass half empty (no stability of cognition) or half full (lower rate of decline)?  We’ll take slower decline and see the glass as half full.

One other concern raised by this clinical trial is that the Lecanemab group experienced a type of brain swelling (amyloid-related imaging abnormalities: ARIA) at about double the rate of the placebo group.

So, would I take Lecanemab if diagnosed with early dementia?  Probably not.  It appears that it might slow the rate of my decline (less than a half rating point over a year and a half) though it is quite uncertain whether that small change in the rate of decline is meaningful.  And the cost to take it is still quite high: an average of $28,000 per year, reduced from $56,000 initially.  We all continue to hope that scientists can do better with other intervention approaches.