The U.S. Food and Drug Administration has approved aducanumab to treat Alzheimer’s disease.

Like other similar drugs, it was designed to rid the brains of Alzheimer's patients of buildups of amyloid and, more importantly, slow the progression of the disease. After a decade of repeated failures of similar drugs, approval was welcome news for patients, their families and the Alzheimer’s association desperate for good news. Approval was also tacit vindication for the long-standing “amyloid hypothesis” as the primary cause of the disease.

That hypothesis is based on finding clumps of abnormal amyloid in the brains of patients with Alzheimer's. Not surprisingly, the earliest deposits are usually found in the parietal and medial temporal lobes – regions associated with memory, facial recognition and spatial orientation, whose functions are among the first to be disrupted in the disease.

Amyloid isn’t the only protein to accumulate in Alzheimer's – phosphorylated tangles of tau form inside nerve cells. So far, however, accumulations of amyloid have been the primary focus of research.

Amyloid accumulations can be detected using positron emission tomographic (PET) scans coupled with agents designed to latch onto and make visible, amyloid deposits in the scan.

PET studies reveal deposits of amyloid accumulating in the brain as early as one to three decades before patients and family members become aware of the disease, although closer scrutiny of the histories of patients often reveal early “soft” signs consistent with those early scan findings. These two observations, PET scans and the history of the earliest clinical symptoms, strongly suggest that if effective and most important, well-tolerated treatments were employed much earlier in the disease, those at high risk for Alzheimer's might not be fated to develop the cellular damage and losses and the associated cognitive and behavioural declines in later years.

As we’ve learned in this pandemic, approval of vaccines and, in this case, a new drug, face three hurdles, phase 1, 2 and 3 trials before approval. The first two are test safety and effectiveness in small numbers of patients while phase 3 trials involve much larger numbers of participants divided into two groups, those who receive the drug and the control arm of the study.

Clinical trials are highly complex affairs designed to test whether a given drug works. For aducanumab the most important questions centre on its effectiveness in clearing the brain of amyloid and slowing the cognitive and behavioural decline in patients, and whether any adverse side effects are manageable and not serious enough to fail the drug for clinical use.

Reviewing the phase 2 trial of aducanumab in 2018, I was impressed. The drug was clearly capable of reducing the amyloid load in the brain and of more importantly for me, the evidence suggested the rate with which cognition decline was slowed compared to controls. Enter the phase 3 trials.

There were two phase 3 trials: both showed that the drug reduced the amyloid load, as expected, but only one trial suggested a reduction in cognitive decline. The latter was a sticking point for the FDA’s own advisory panel and several outside advisers.

Despite those reservations, the FDA approved it. Most in the Alzheimer’s universe were delighted but some of the reviewers were concerned the evidence for a reduction in the rate of cognition decline was not convincing enough and perhaps might set too low a bar for future FDA approvals.

Clinical trials have become the gold standard by which drugs, vaccines and other treatments are assessed – and rightly so usually – but not always. Most clinical trials are double-blinded, that is the participants and assessors do not know who received the drug and who got the placebo.

That sounds fine but, in my experience, many drugs are associated with some effects that telegraph to the subject who received the drug. That was especially true in my days working in multiple sclerosis clinics where many of the drugs were associated with obvious symptoms and giveaways to who got what.

What do I think of the approval? My answer is a cautious yes – I can see why some experts disagreed. To all those who designed and participated in these studies, I tip my hat, but I wonder if it might be too late to treat symptomatic patients, if we are to see convincing effects on slowing or perhaps even reversing cognitive declines.

I think the future lies with treating all the neurodegenerative diseases as early as possible – well before any clinical symptoms such as those cases with an autosomal dominant disorder where possession of the mutant gene is virtually a guarantee of getting the disease. In those cases the fix will be with some form of gene editing. That would be true for Huntington’s disease and probably the autosomal dominant version of Alzheimer’s disease.

More about that at Infohealth in September.