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Explained: Another failure extends the elusive search for Alzheimer’s ‘silver bullet’

An experimental Alzheimer’s drug aimed at slowing or preventing cognitive decline in people at risk of developing the disease early has failed in clinical trials, landing a blow to efforts aimed at finding a trailblazing treatment to the neurodegenerative disease. What is Alzheimer’s disease, and why has finding a ‘silver bullet’ cure proved elusive?

What is Alzheimer’s disease?

Alzheimer’s is a degenerative brain disorder that slowly robs people of their memory and thinking abilities. Worldwide, it is the most common form of dementia or loss of cognitive functioning — thinking, remembering, and reasoning – contributing 60%-70% cases, according to the World Health Organisation (WHO).

Progressive and irreversible, it usually begins with mild memory loss, and as symptoms grow severe, patients lose the ability to perform even simple tasks.

“Pathology of the disease is deposition of an abnormal protein called beta-amyloid in the brain….The disease starts much before the symptoms show up. The symptoms may come at a certain age, but the pathology changes almost a decade earlier,” Dr Manjari Tripathi, professor of neurology at the All India Institute of Medical Sciences, New Delhi, said.

The disease was discovered after Dr Alios Alzheimer examined a memory-loss patient’s brain after her death in 1906 and found abnormal clumps (beta-amyloid plaque) and bundles of fibres (neurofibrillary tangles). The plaque and tangles, along with loss of connections between the neurons to transmit messages inside the brain, are key markers of the disease.

What was the latest trial that failed?

The decade-long effort used crenezumab, a drug designed to block beta-amyloid, and involved people with a specific genetic mutation which leads to the early onset of Alzheimer’s around the age of mid-40s. The trial was backed by drugmaker Roche, the United States National Institute on Aging and the Arizona-based nonprofit Banner Alzheimer’s Foundation. It targeted the less-prevalent autosomal-dominant Alzheimer’s disease (ADAD).

Earlier in 2019, Roche had stopped crenezumab phase 3 trials for sporadic Alzheimer’s, which accounts for over 90% cases, after results fell short of expectations.

Roche announced last week that the results for its latest trial too were disappointing and did not show “significant clinical benefits”. Both ADAD and sporadic AD, according to researchers, have similar neuropathological and clinical features.

Why is the failure seen as a major setback?

A drug to prevent and treat the memory-robbing disease has proved elusive for years. According to WHO, dementia is currently the seventh leading cause of death among all diseases and one of the major causes of disability and dependency among older people globally.

In 2020, there were 121 unique therapies being tested in 136 trials to find a cure for AD, according to research published in the journal of the Alzheimer’s Association (of the US). This drug development pipeline, scooped from a review of the US FDA’s clinical trials registry, sounds impressive — until juxtaposed with another statistic.

Prior to this, a similar review of the AD drugs pipeline by researchers had looked at 244 compounds in 413 clinical trials between 2002 and 2012, and found a staggering 99.6% failure rate — against 81% for cancer. By the time a drug pipeline review was published in 2020, no drug had made it past the finish line.

In 2021, however, the USFDA approved Biogen’s beta-amyloid targeting drug aduhelm, making it the first new Alzheimer’s drug to receive approval in the US in almost 20 years. But the fast-track approval was followed by a fierce debate among scientists over its trial data.

While that controversy continues to rage, crenezumab’s failure has called into question the very approach of relying too much on neutralising beta-amyloid to fight the disease, the strategy being tried in the majority of Alzheimer’s studies.

“You cannot say that just hitting beta-amyloid is going to take care of everything…You cannot hit such a complex disease with just one stone,” Dr Tripathi said.

The latest drug pipeline review published in May this year says that there were 143 agents in 172 clinical trials for AD as on January 25, 2022.

What else does the search for an Alzheimer’s cure involve?

Another approach involves the targeting, instead of the toxic beta-amyloid plaque, the tau protein that misfolds and deposits in brain cells in the form of twisted fibres called neurofibrillary tangles. But drugs targeting these proteins individually – the ‘one drug, one target’ model – have not achieved a breakthrough yet.

Some scientists are also turning their focus to a drug strategy that targets multiple enzymes and pathways that contribute to the progress of the disease. This involves multifunctional compounds or multi-target-directed ligands (MTDL) that attempt to engage or modulate multiple biochemical targets, and are seen as a potential master key that would open several locks.

Another approach is aimed at modifiable lifestyle factors to slow cognitive decline. This is the basis of the World-Wide FINGERS study, which expanded out of encouraging results of the two-year FINGERS (Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability) randomized clinical trial. The FINGERS study showed a 40% improvement in memory function, and 25% in overall cognition in the 1,260 participants aged 60-77 years.

Dr Tripathi said: “Genetics and aging are non-modifiable, irreversible factors in Alzheimer’s. Genetics is a loaded gun, the trigger for which are the modifiable factors. The strongest modifiable factors linked to the disease are hypertension, diabetes, smoking, alcohol consumption, and sedentary lifestyle.”

Also, she said, “something that has come up in the last 4-5 years is that the lack of a social network and isolation can also be triggers for the disease. Studies like FINGERS targeted such modifiable lifestyle factors, and they have found a reduction in the incidence of Alzheimer’s in the Western scenario”.

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What is the India scenario?

In India, only 1 in 10 people with dementia receive any diagnosis, treatment or care for the disease, according to the World Alzheimer’s Report, 2021. Lack of awareness is a major problem in battling the disease. “Most of our population accepts it as normal aging, which is incorrect. Only when it reaches an unmanageable stage – like when patients start wetting their clothes and are not aware of it, is when medical help is sought. Unfortunately, most patients come to us very late,” Dr Tripathi said.

An increasing prevalence of diabetes, hypertension, and obesity is expected to drive up the incidence of dementia in India in the coming decades. According to the Global Burden of Disease study published this year in The Lancet, India could see a 197% jump in dementia, including Alzheimer’s, from 3.84 million cases in 2019 to 11.44 million cases by 2050.

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