November 28, 2020

I, Science

The science magazine of Imperial College

A vaccine could be designed to cause the body's own immune system to recognise and target the protein aggregates thought to underlie the symptoms of Alzheimer's. Such approaches have been developed but all failed in high profile clinical trials. Why have these promising approaches not yet been successful?

Since the introduction of vaccination programmes, vaccines have prevented millions of deaths from infectious diseases and have thereby earned their recognition as one of the greatest public health achievements. Research is now underway to test whether the principles and success of vaccines can be transferred to help tackle one of the greatest health challenges facing our society, Alzheimer’s disease.

Alzheimer’s disease is the leading cause of dementia and currently affects around 50 million people worldwide, the majority of whom are over the age of 65. As our aging population continues to grow, the number of cases of this devastating condition is expected to triple by 2050. Despite decades of research, no medication yet exists that is capable of slowing or reversing Alzheimer’s disease. Vaccination approaches have, however, shown promising results in mice and are now in the late stages of clinical testing in humans.

Vaccine trials and tribulations

The ability of the immune system to fight off infections relies on the generation of antibodies, which bind specifically to invading pathogens. Antibodies act as a flag to the immune system and help to wave down immune cells, which can destroy the pathogen before it causes disease. Vaccines work by training the immune system to recognise specific pathogens, such that a supply of antibodies is already on hand to fight off an infection, should the patient be exposed to it in the future. The hope is that the same principle can be applied to train the immune system to recognise the early signs of Alzheimer’s disease and stop it in its tracks.

In the brains of Alzheimer’s patients, widespread cell death and damage occurs, causing disruption of the communication between nerve cells. This leads to the behavioural and cognitive changes associated with the disease. The two prime suspects for causing this damage are the proteins amyloid beta and tau, which progressively accumulate in the brains of Alzheimer’s sufferers, where they are toxic to surrounding brain cells. It is thought that amyloid beta accumulation itself promotes the generation of toxic tau and, therefore, that vaccines targeting amyloid beta will also lower tau levels.

Development of the first Alzheimer’s vaccines began two decades ago and used a so-called ‘active immunisation’ approach. These vaccines included fragments of amyloid beta, which upon injection resulted in the generation of amyloid beta-specific antibodies. When tested in humans diagnosed with mild to moderate stage Alzheimer’s disease, amyloid beta levels were reduced, but this failed to benefit disease progression or mental function. Additionally, trials had to be stopped as autoimmune inflammation was induced in 6% of patients.

Due to the safety risks of ‘active immunisation’, researchers began developing ‘passive immunisation’ approaches, whereby amyloid beta-specific antibodies were produced in a lab and injected directly into patients. When tested in mice genetically engineered to exhibit the features of Alzheimer’s, cognitive impairments were rapidly reversed. Several ‘passive’ vaccines have now been tested in Alzheimer’s patients. Despite their effectiveness at reducing amyloid beta levels, none have had a beneficial effect on the mental function of patients.

Time for some troubleshooting

Scientists are now investigating why ‘passive immunisation’ has not been as effective as once hoped. One suggestion is that the vaccine doses tested so far are too low. Consequently, different dose ranges are now being tested in human trials. Another possibility is that a vaccine would need to simultaneously target both amyloid beta and tau proteins. Both ‘active’ and ‘passive’ anti-tau vaccines are currently in development.

It is also likely that in patients who have already been diagnosed with Alzheimer’s, a vaccine may be too little, too late, as it is suspected that unlike in mice, the damage caused by amyloid beta and tau in humans is irreversible. A challenge will, therefore, be to develop better diagnostic tests to detect Alzheimer’s-like changes before lasting damage has occurred. An approach which is currently being trailed is the preventative vaccination of healthy individuals carrying a genetic mutation which makes them more susceptible to developing Alzheimer’s.

A return to ‘active immunisation’

This week, a study was published which has reignited interest in ‘active immunisation’ against Alzheimer’s. Conducted at the University of Texas, the research involved the injection of DNA coding for amyloid beta into the skin of Alzheimer’s mice, rather than the protein itself. Following vaccination, amyloid beta levels were reduced by up to 40% and tau was reduced by 25-50%. Importantly, there were no signs of autoimmune inflammation. The authors are hopeful that their approach could soon be tested in humans.

Despite the current hurdles, the senior author of the study, Dr. Doris Lambracht-Washington emphasises the huge potential of vaccination for minimising the burden of Alzheimer’s disease. “If the onset of the disease could be delayed by even 5 years […] the number of dementia cases could drop by half.”


Harriet Hardy has just graduated from the University of Bath with a Masters in Medical Biosciences

Banner Image: Vaccine, Wikimedia