For more than 100 years we have known that Alzheimer’s disease (AD) is associated with widespread deposits of amyloid-beta in the brain, also known as plaques. Even today, after decades of intense and fruitful research, brain amyloid remains an essential requirement for the diagnosis of AD. But the presence of something doesn’t necessarily imply causality, and the amyloid hypothesis, which predicts that brain amyloid directly causes AD remains controversial, with many pros and cons backed up by research and observational data.
So how could we prove that brain amyloid causes AD? Easy. If that is indeed the case, removing it should cure the disease, explaining the intense hunt over the past several decades for a drug that can do exactly that.
Fast forward to today, and we have six (!) drugs that, if given over a 12-18 month period, can completely remove brain amyloid plaque in a person with AD. This is a remarkable achievement, and an amazing opportunity to finally put the amyloid hypothesis to the test.
Several drugs that remove amyloid have been tested in clinical trials over past several years. Of these, a drug called aducanumab made headlines as it achieved almost complete removal of brain amyloid plaque in AD patients, although the impact on cognitive function, the holy grail of AD research, was very modest and controversial. In late 2022, analysis of a large Phase 3 clinical trial of the anti amyloid drug lecanemab was shown to substantially remove brain amyloid AND improve cognitive function in patients with mild AD, or Mild Cognitive Impairment (MCI). So far so good. If these terms are foreign to you, refer back to the following blog for a terminology refresher.
The lecanemab story (the short version)
If you were hoping for an easier drug name, sorry you are out of luck (again). Lecanemab was originally discovered by studying a very rare mutation causing AD in Iceland. It is an antibody that targets certain types of brain amyloid. You have probably heard of the term antibody before – it is the way our immune system protects us from pathogens such as bacteria and viruses. When the body detects foreign invader, such as a bacterium, it produces antibodies to specifically target the invading bacteria. The immune system has nearly unlimited capacity to make unique antibodies for unique invaders. This beautiful system can be harnessed to target other things too, such as brain amyloid in the case of lecanemab. In that case, antibodies are designed and manufactured in a lab, and made into a drug solution suitable for human consumption.
After many steps, lecanemab was assessed in a large clinical trial enrolling 1795 subjects with a diagnosis of either mild Alzheimer’s disease, or Mild Cognitive Impairment. Why so many subjects? If a drug works, could we not try a smaller sample, maybe 10? The answer to this important question depends on the outcome we are trying to change through drug treatment. In AD, one such outcome is always related to some composite measure of cognitive function. The duration of the lecanemab trial was 18 months. With “standard” treatment, outside of any research, some individuals with AD will hardly decline over 18 months, while others may decline a lot (we do not fully understand why this is the case). What if you chose 10 individuals for your trial, but simply by chance half the group were in the “no decline” group, and the other half in the “fast decline” group? If the drug you are testing was used in the slow decline group, you would pop the champagne and declare yourself a genius for having found a cure for AD. Except, sadly, the outcome had nothing to do with the drug, it was all due to random variability in the outcome you were testing. Many clinical trials have fallen for this unfortunate trap. Thus, and for many other good reasons, clinical trials that try to impact small changes over time that can vary substantially between individuals, are large, more than 1000 participants, such as the lecanemab trial.
OK, back to the trial. 898 participants received lecanemab, and 897 received placebo (non-active drug) through twice monthly intravenous infusions for 18 months. At the end of the trial, those receiving lecanemab had a substantial reduction in brain amyloid, as expected, to a level indistinguishable from a person without AD. Pretty amazing. But did this impact cognitive function or other measures such as the level of engagement in various activities of daily living?The short answer is yes. On a composite cognitive battery, known as the Clinical Dementia Rating – Sum of Boxes (CDR-SB), those receiving lecanemab declined 27% slower than those who received placebo. They also enjoyed and participated in more activities of daily living, such as household chores and hobbies. Overall, very positive news.
On the flipside, lecanemab did not stop progression of Alzheimer’s disease, rather it slowed it down a bit. Even after nearly complete removal of amyloid plaque, progression of symptoms continues. And it does not come without side-effects. More on this later.
There is more to the story, but where does this leave us? The best way to look at it is that over an 18-month period, a person with mild AD or MCI receiving lecanemab will decline as if it’s only been 12 months. This will not equate to dramatic changes for someone with AD in an 18-month period, but if this benefit could be extended further it could have a more significant impact. Let’s say someone was treated for 6 years with the same benefit. That person would
experience two more good years over that 6-year period. I am willing to bet most would view that as a small victory, akin to extending survival in cancer treatment. Several ongoing studies will address this important question, and I will fill in the gaps once we learn more. For now we only know that there is a modest effect if someone is treated for 18 months.
More on those side-effects
Removing amyloid comes with a price. It appears that areas of the brain with greatest amyloid removal may also experience swelling, known as edema. This problem related to amyloid removal is known as Amyloid Related Imaging Abnormalities, or ARIA for short, as it was originally seen on brain imaging without much clinical symptoms. Overall, 193 participants receiving lecanemab (21.5%) experienced ARIA, and in certain higher risk groups based on genetic profile, up to 39% experienced ARIA. Symptoms range from asymptomatic and seen on brain MRI only, to a range of neurological symptoms such as dizziness, headache, and lethargy. Most cases of ARIA resolve either while continuing the medication, and/or after stopping.
Some conclusions
Lecanemab was recently approved by the US FDA. It is currently under review by Health Canada, with a decision expected in March 2024. It is not known yet whether patients outside of the strict diagnostic in the study, mild AD and MCI, can benefit. The overall benefits after an 18-month treatment period are small. Ongoing studies will show us whether treating even earlier can give better long-term benefits, and whether the 27% slowing of decline extend beyond an 18-month treatment period. Both of these questions are critical, and once we know the answer I will let you know.
So was the amyloid hypothesis finally proven? My take is perhaps partially. But there are likely other mechanisms in addition to amyloid that lead to AD. Lots more to come in this area, we are just getting started!
Lecanemab is manufactured and marketed through a partnership between Eisai and Biogen. I have served, or currently serve as a paid advisor to both companies. I believe the above blog is free of bias.