‘These are exciting times for Alzheimer’s research; but do not lose focus on prevention’: MV Padma Srivastava
Photo from iStock for representation
An international team of researchers led by scientists at the Massachusetts General Hospital and MassEye and Ear, United States recently published a study in the journal Nature which was hailed as a milestone in the field of research on Alzheimer’s Disease, the commonest form of dementia.
They found a man from Colombia, who was genetically predisposed to losing his memory in his early 40s or 50s. But the man retained his memory until age 67.
He developed mild dementia at age 72 and died at 74, much later than he was expected to, based on his family history. The researchers found that a rare genetic mutation had protected the man and prevented him from developing dementia at an early age.
Down To Earth caught up with MV Padma Srivastava, Head of Department of Neurology and the Chief of Neurosciences Centre at the All India Institute of Medical Sciences, New Delhi and asked her about how the latest study will influence the field of Alzheimer’s research and the overall scenario regarding the neurodegenerative illness in India. Edited excerpts:
Rajat Ghai: Your initial comments on this latest study?
MV Padma Srivasatava: Alzheimer’s Disease is the commonest degenerative dementia in the world. It has special relevance for the developing world because we have a double whammy of an aging population and a lot of non-communicable diseases.
Also, we in India mostly have mixed dementia — Alzheimer’s Disease and vascular dementia (people who have heart and brain attacks or uncontrolled diabetes).
Research, as far as Alzheimer’s is concerned, has been on for decades on end without much of a breakthrough. Only a few drugs have been approved during all this time by the United States Food and Drug Administration (FDA) — for instance Donepezil, Rivastigmine, Memantine and Galantamine.
Alzheimer’s has genetic components. There have been definitive genes which have been identified that are known to increase a person’s propensity to develop Alzheimer’s. Today, even laypeople know about genes like APOE4.
Then, there are pre-senile dementias that are younger-onset which have a real genetic background as they are caused by genes like PS1 and PS2 (presenilin 1 and 2).
Research in the last few years about Alzhiemer’s pathology has found that it is caused by amyloid plaques and tauopathy, which centre around amyloid and tau proteins respectively.
Efforts till now have been focussed on cleaning amyloid plaques from the brain. Following the drug approvals, FDA also approved monoclonal antibodies.
The first monoclonal antibody that got FDA approval for cleaning amyloid plaques deposited in the brain was Aducanumab.
It got approval as it came closest to having a reasonable clinical impact. Subsequently, it was found that Aducanumab was not very effective. This led to the development of Lecanemab and now, Donanenab. These are supposed to clean the plaques more effectively and not cause side effects at the same time like swelling and bleeding in the brain.
This latest study is important since it does not target amyloid but rather goes after tau. Irrespective of how much amyloid there was in his brain, the person who was found to have the unique genetic mutation did not develop dementia compared to other patients.
The study is also important as it a focused follow-up of proven, familiar Alzheimer’s where it is known that the patient will develop the disease. The researchers discovered the individual in this family who was old and yet did not develop the disease.
They then looked into the reason and discovered a genetic mutation in the Reelin gene. They conducted an experiment on mice and found that they were protected from Alzheimer’s due to the presence of this genetic mutation.
They also found that this individual’s sister, who also had this mutation, had a slightly worse outcome since she had other problems like head injuries.
This drives home a couple of things. One, we may have different genes. But a gene’s power can be modified by other factors that modify the gene. These are called epigenetic factors and can be other genes or environmental factors.
For instance, let us assume that two individuals have this gene. One has uncontrolled diabetes and hypertension, drinks and smokes, has also had heart attacks and multiple strokes or had multiple head injuries.
This person will develop dementia much earlier and the disease will be much more severe as compared to the other person who has a predisposition to develop Alzheimer’s but his diabetes is very well under control and has other protective factors that he has taken care of.
The Lancet Commission Report which was published in 2017 had pointed that we should be optimistic, positive and aggressive about preventing dementia.
They found that at least 30-33 per cent of dementias can be prevented if one has a good cognitive reserve. If your cognition has good balance then even if there is attrition by any exigencies or factors that are adverse, you still have enough cognitive reserve to go by to carry out your daily activities.
There are ways to increase your cognitive reserve. For instance, when you are young, it is about your skills, knowledge and literacy power. More importantly, your propensity and aptitude to acquire new skills.
In middle age, be very careful about hearing, take care of your hypertension and blood pressure. Do not live in a virtual world. Have human contact. Do not be isolated. You should not be suffering from depression, especially if you are elderly.
These are proven things that can keep dementia at bay. One important finding is being physically active. If you are that then you also remain mentally active. And of course, nutrition has an incomparable influence. These factors are there to modify whatever genes you have.
What is important about this study is that they have identified a mutation in a definitive gene (Reelin) that is modifying another gene known to cause Alzheimer’s.
So now we know that there may be epigenetic factors in an individual which modify even if the person has an inherited, familial tendency to develop dementia.
Knowing these new genetic factors will pave pathways for pharmacological interventions. There is a foray into the pharmacological realm to discover agencies which will then help in gene interventions or gene therapy.
For instance, in this case, maybe doctors can start mutating this Reelin gene.
There is so much happening right now in gene therapy. You have drugs which have been developed for spinal muscular atrophy and genetically inherited bad muscle diseases. Now there are drugs that can stem the progress of such diseases in children. And all this is FDA-approved.
RG: These are exciting times for Alzheimer’s research, aren’t they?
MVPS: Yes, indeed, when compared to probably two decades ago. Many researchers had been studying the disease for a long time. But there was no breakthrough. Finally, we are looking at the light at the end of the tunnel.
RG: Is a cure for Alzheimer’s somewhere on the horizon in a few years?
MVPS: There seem to be cures for a lot of ailments on the horizon. But that should not shift our focus from the more practical and important aspects which are about prevention.
A lot lies in our hands to prevent Alzheimer’s from happening. Those preventive aspects may prevent us from developing dementia even if we have a genetic predisposition to it.
Beyond that, there are forays into genetic engineering, which is definitely an exciting aspect.
RG: What is the Alzheimer’s situation in India like?
MVPS: Researchers have been able to map which countries have more prevalence of people living with dementia. India features in the list of the so-called ‘Big Five’ countries with the most dementia burden.
There are reasons for this. We have a large number of patients with diabetes and other non-communicable diseases. India consequently has more mixed Alzheimer’s patients — Alzheimer’s Disease and Vascular Dementia.
This is not being helped by the fact that we are adding an aging population to one which is also young. We are younger than most of the world but also have a significant number of senior citizens since our total population is so large, compared to western countries.
This is why prevention is so important. Eat right, exercise, do not smoke or drink, have a good night’s sleep and keep your diabetes and hypertension under check. This much, at least, is in our hands.