From Dr Abu Bakar Abdul Majeed

In early June 2021, the United States’ Food and Drug Administration (FDA) approved a drug able to treat one of the most debilitating conditions known to mankind, Alzheimer’s disease. Alzheimer’s disease or AD, is a brain-related illness that hampers numerous human psychological and behavioural functions.

The most notable symptom of AD is memory loss, otherwise referred to as dementia. In the developed world AD is considered to be one of the major causes of death. In the developing world, the number of people living with AD (PLWD) is expected to rise significantly in the coming decades.

In fact, the number of PLWD is projected to increase exponentially as the worldwide population ages. Ten years ago, there were 35 million PLWD, rising to approximately 44 million recently. The total health cost to society and nations worldwide is estimated to be well over US$400 billion (RM1.7 trillion) a year.

Another 20 million patients are expected to join the ranks of PLWD in 2030, and by 2050 the number will almost double to more than 115 million. In Southeast Asia the estimated number of PLWD was 2.48 million in 2010. The number is projected to be around 5.3 million and 11.13 million in 2030 and 2050, respectively.

In Malaysia, a good number of PLWD are not diagnosed. This is of no surprise, as the world over, only around one in four people with the disease get diagnosed.

The estimated number of people with AD was 63,000 in 2006. The number of PLWD in the country is deemed to have doubled in 2020 and is projected to be half a million in 2050.

Symptoms of AD include difficulty in finding words when speaking, inability to recognise faces and the surroundings, and impaired reasoning and judgement. The mental degradation is irreversible and relentless.

AD progresses from mild, to moderate to severe. The condition is not only frustrating to the patient but also highly taxing on those caring for the patient.

However, it has to be emphasised that a certain form of memory or thinking problems may not be accompanied by personality, psychological and behavioural changes. This condition is known as mild cognitive impairment or MCI. People with MCI can lead an independent lifestyle as they can care for themselves. And unlike AD, MCI is reversible.

Signs of AD were first seen in a patient by Dr Alois Alzheimer in a hospital in Germany at the turn of 20th century. Since then, understanding the causes and developing treatments of AD has been the holy grail of brain diseases. Up to this point, three major instigators of AD have been suggested.

First, the accumulation of toxic clumps of a protein known as beta amyloid in the vicinity of brain neurons. Second, the formation of tangles, known as tau, within the brain cells. Both phenomena lead to the inability of the neurons to transmit information to and from the centre of information storage and processing in the brain, the hippocampus.

It’s like these cluttered, mangled proteins are obstructing the information superhighway, that is, the neuron. Hence, no new memory can be installed, while most, if not all stored memory becomes irretrievable.

Efforts to find a cure

The situation of AD and dementia is pretty dire all over the world. Efforts in finding a cure have been ongoing in hundreds, if not thousands of research laboratories for several decades now.

Among the early success were three or four drugs that were deemed able to slow down the progress of memory decline. They mostly act on two brain chemicals involved in the transmission of information from neuron to neuron. But their benefits are limited. They do not have any impact on dysfunctional proteins.

The approach of designing a drug that can mop off these detrimental proteins has thus far failed to bear fruit. This led to some scientists convinced that they were aiming at the wrong target.

Hence, a third cause of AD has been suggested, that is, inflammation.

It is thought that the main culprit that must be crushed are proteins that trigger the inflammation of the brain. Hence, another approach to reverse AD symptoms is by designing drugs that can suppress the function of the genes that produce these inflammation-promoting proteins. This was thought to be the magic bullet to stamp out the AD menace.

Sadly, despite enduring efforts to develop drugs to treat AD in the last 20 years, success has been elusive. Though a few candidate drugs made it to clinical trial, they all failed to clear the final hurdle to registration.

However, failure did not mean absolute wastage of the huge investment. Scientists noticed that by giving an engineered antibody, like the newly-registered AD drug aducanumab to patients, the mangled proteins might be cleared from the brain cells. The findings were initially presented at two scientific conferences in 2015.

Another important lesson of the failed clinical trials is that administration of the drug must be done early, preferably before the appearance of symptoms.

From research conducted in our laboratory at Universiti Teknologi Mara (UiTM) and elsewhere, patients could be identified early by determining the presence of predictive markers in their blood or brain fluid. Hence, prediction plus early treatment of AD may be the key to the long sought-after solution to the disease.

However, FDA’s action to allow the use of the first drug against beta amyloid to treat AD patients was met with disapproval by a certain section of the scientific community. This was due to the uncertainty of the ability of the drug to specifically remove bad proteins. But since the FDA-approved aducanumab under the accelerated pathway, the drug manufacturer will have to carry out a confirmatory clinical trial at a later date.

Despite this breakthrough in AD treatment, there are concerns about the access of the drug to patients, especially those in middle- and lower-income countries. The anticipation of significant revenue from the sale of the drug by the manufacturer Biogen Inc has pushed up the company’s share price by more than 50%.

If the drug is proven to be effective, it is only fitting that it is made accessible and affordable to all PLWD, perhaps through some form of patent waiver, much like the current initiative proposed for the Covid-19 vaccines.

Dr Abu Bakar Abdul Majeed is a professor with the Brain Research Laboratory at UiTM’s Faculty of Pharmacy.

The views expressed are those of the writer and do not necessarily reflect those of FMT.