Researchers say they have developed a promising nasal spray therapy that could potentially delay the progression of Alzheimer’s disease by more than a decade.

Early-stage Alzheimer’s animal models by Texas A&M university showed the treatment reduced inflammation and protein build-up in the brain.

Does this idea have a future? It’s worth exploring, especially given the slow and expensive process of developing wonder drugs – monoclonal antibodies– that haven’t proved as wonderful as initially hoped.

The past four years have been a roller coaster in the development of monoclonal antibodies as a treatment for Alzheimer’s.

Monoclonal antibodies work by clearing the brain of the amyloid-beta plaques that clog up the brain.

How well they work to slow cognitive decline, and how safe they are, have been matters of contention and controversy from the start.

A case in point

In November 2020, an FDA advisory panel of experts voted against the approval of a monoclonal antibody called aducanumab.

A major concern with aducanumab was the frequency of side-effects: oedema (fluid on the brain), headaches, micro-bleeds on the brain, and falls.  About a third of participants in trials suffered these.

In a stunning turn-around, in June 2021, the FDA ignored the advice of its experts and granted accelerated approval for aducanumab as “the first and only Alzheimer’s disease treatment to address a defining pathology of the disease by reducing amyloid beta plaques in the brain”.

As part of the accelerated approval, the drug maker Biogen would conduct a controlled trial to verify the clinical benefit of aducanumab.

It had been found to slow the decline in people with mild cognitive impairment. Anyone who could afford the drug – more than $1000 a week – could access it. But it never lived up to its much-hyped promise.

From superstar to dud

In February, the British Medical Journal reported the following:

“The US drug company Biogen is walking away from its Alzheimer’s drug aducanumab (Aduhelm).

“Aduhelm was once billed as history’s greatest blockbuster drug, but ended up generating almost no income after insurers refused coverage and clinicians chose not to prescribe it …

“Biogen will halt a post-market trial designed to show a clinical benefit that was not apparent in original trials.

“Aduhelm’s demise will be seen as a victory for advocates of strong drug regulation and a warning to drug manufacturers who rely on marketing to paper over gaps in their data.”

Improved models, sort of

Last month, The New York Times ran an investigative piece about two new and improved monoclonal antibodies – lecanemab (from the drug maker Eisai) and donanemab (from Eli Lilly).

NYT discovered that, in clinical trials, the drug companies chose not to tell volunteers that their genetic profiles – which made them high risk for Alzheimer’s and thus good value as test subjects – also made them vulnerable to brain injuries, including severe bleeding.

Experts accused the companies of under-cutting “the principle of informed consent”.

NYT stumbled on to this scandal by accident.

The intended subject of their investigation was how “long, maddening and vastly expensive” was the search for an effective Alzheimer’s treatment.

On the upside, lecanemab and donanemab do a great job at clearing the brain of amyloid plaques. NYT described this as “a remarkable scientific achievement”.

But, it said, the drugs do not halt cognitive decline or reverse brain damage.

Lecanemab (under the commercial name Leqembi) “slows the decline for roughly five months”.

Donanemab (marketed as Kisunla) “achieves a slightly longer delay”.

As NYT described it, a devastating truth was emerging:

“The evidence of their limited benefit has contributed to a growing realisation that the dominant theory of Alzheimer’s – that sticky bands of amyloid trigger a cascade of toxic events leading to the disease – is at best incomplete and perhaps simply wrong.”

Australia’s Therapeutic Goods Administration “decided not to register Leqembi on the basis that the demonstrated efficacy did not outweigh the safety risks associated with the use of this medicine”.

So where to next?

It’s likely that these big companies will continue to develop and improve their monoclonal antibody treatments. At least for a while. There are billions of dollars at stake.

Meanwhile, what is the best hope for these patients? The obvious answer is that researchers need to explore new options.

Researchers at Texas A&M University College of Medicine are doing just that.

They have a new therapy that “may delay Alzheimer’s disease progression by 15 years”.

That’s a big claim, and certainly a premature one. But other researchers agree they are on to something promising.

In an experiment with mice – genetically modified to develop Alzheimer’s disease – a nasal spray cooled inflammation of the brain and delayed the progression of Alzheimer’s disease.

The scientists targeted microglia, immune cells within the brain that cause neuro-inflammation.

According to a report from Medical News Today, microglia in healthy brains, “protect nerve cells and remove damaged nerve tissue”.

But in Alzheimer’s, “after initially clearing beta-amyloid plaques, they become overactive and destroy nerve cells”.

Professor Ashok K. Shetty is associate director at the Institute for Regenerative Medicine in the Department of Cell Biology and Genetics.

He said the idea to develop a nasal spray for Alzheimer’s arose from efforts over a number of years to find a non-invasive way to deliver medicines derived from stem cells to the entire brain.

What happened with the mice

The modified mice – known as transgenic mice– were three months old and in the early stages of Alzheimer’s disease. They were administered two doses of a nasal spray containing an anti-inflammatory treatment derived from stem cells.

The aim was to target these immune cells to decrease inflammation and reduce the build-up of harmful proteins in the brain.

In this mouse model, Medical News Today reported, “untreated transgenic mice usually show characteristic signs of Alzheimer’s such as beta-amyloid plaques, increased microglial activity, and inflammation by the age of 4.5 months”.

However, at 4.5 months old, the dosed-up transgenic mice “had reduced microglial clusters, as well as reduced activation of genes associated with neuro-inflammation”.

In addition, they had less beta-amyloid plaque than the untreated mice.

These reduced inflammatory effects “were most notable in the hippocampus – the area of the brain that plays a major role in learning and memory – which is severely affected by Alzheimer’s disease”.

In behavioural tests, both male and female treated mice showed better cognitive and mood function than the untreated mice.

Obviously, these are very early days, and human trials are sorely needed to confirm the mouse experiments. But a brand new idea for a potential treatment can only be welcomed.