A First True Win For Alzheimer’s Prevention, Or Another Bust?

Getting your Trinity Audio player ready...

A clinical trial appears to have shown that gantenerumab, a drug designed to remove amyloid plaque from the brain, might be quite effective for preventing familial Alzheimer’s disease. Unfortunately, there are a lot of caveats, but some reasons to remain optimistic. Let’s take a look in more detail.

The Amyloid Problem

A prominent feature of Alzheimer’s disease is the accumulation of amyloid beta plaque within the brain. This material, made from misfolded proteins layered on top of each other, was long believed to be a primary cause of Alzheimer’s disease. However, that has been called into question for several reasons. Some people seem to avoid Alzheimer’s disease and retain normal cognitive function despite having significant amyloid deposits. More importantly, drugs designed to remove amyloid beta from the brain have at best produced only modest benefits when it comes to slowing the progression of Alzheimer’s disease, and at worst have achieved nothing at all. This has led to speculation that the driving forces behind this disease are more fundamental, such as inflammation and the dysfunction of ‘housekeeping’ cells within the brain.

That said, we can and should be exploring every possible avenue to treat Alzheimer’s disease, and scientists have not given up on targeting amyloid plaque. Now it seems like that persistence has finally paid off… perhaps.

The Trial

The clinical trial in question was an investigation of the drug gantenerumab, an antibody that targets amyloid plaque. The participants were people with Dominantly Inherited Alzheimer’s Disease (DIAD), which means they all carried at least one of several gene variants making them almost certain to develop Alzheimer’s at some point, most commonly between the ages of 30 and 50. This form of Alzheimer’s is rare, representing fewer than 1% of cases, and is not the same as more common forms – a point we’ll return to later.

The trial originally lasted from 2012 to 2019 and was designed to investigate whether gantenerumab could prevent Alzheimer’s from occurring in people with DIAD and normal cognitive function to mild dementia. It was a failure, but researchers decided to have an open-label extension for three years. This is where participants, including those in the placebo group, are allowed to choose whether they want to take the drug for an extended period, sometimes at higher doses. 73 participants took up this offer, though fewer than half of them actually finished the trial for various reasons.

The Results

Since there was no placebo group in the open-label extension, the researchers had to use the placebo group from the original 2012-2019 study as the control group. What they found was that, among a subset of 22 participants, there was a large (around 50%) and statistically significant reduction in Alzheimer’s risk compared to members of the control with similar starting symptoms and similar forms of DIAD. What was special about these 22? They had the fewest symptoms of dementia at the beginning of the original study, and also took the drug for the longest period of time.

The Optimist’s Take

This study might be evidence that amyloid-targeting drugs can greatly reduce Alzheimer’s risk, they just have to be taken for long periods of time and targeted at people who have few to no symptoms (at the outset). Since changes in the brain appear to predate Alzheimer’s disease by many years, sometimes decades, there may be ways of identifying such individuals.

The Pessimist’s Take

Despite the large risk reduction, this study can’t be taken as proof of effectiveness due to the lack of a true control group. The people in the initial study were selected according to the researchers’ criteria, then randomized into either the gantenerumab group or the placebo group. By contrast, the people taking gantenerumab in the open-label extension were doing so by choice, which introduces all kinds of potential bias. For example, they may have felt that the drug was working for them, and were probably more optimistic or more motivated in general to try to fight off Alzheimer’s, and therefore more likely to be doing other things to delay the disease. Comparing these two groups is therefore not as valuable a comparison as a true randomized, placebo-controlled trial.

Even if these results are somewhat accurate, it is by no means certain that they would translate to the more common forms of Alzheimer’s disease that occur in old age. That’s because DIAD is caused by mutations in genes related to amyloid plaque formation, which means that amyloid accumulation is in most cases the only thing that is wrong with these patients. The same cannot be said of most Alzheimer’s disease patients, who are often elderly, frail, and have cardiovascular and metabolic conditions that predate their Alzheimer’s disease and probably contributed to it.

The Take Home Message

This study is great news for those with familial Alzheimer’s disease if it can be confirmed, but we shouldn’t get our hopes up about non-familial Alzheimer’s disease developed in old age, which represents the vast majority of cases. The best way to prevent this disease as well as other forms of dementia remains alterations to lifestyle, which is believed to determine nearly 50% of dementia risk.