Battling Alzheimer's

31 July 2016

People are living longer, but not any healthier. As the world’s aging population grows and the birth rate declines, diseases like Alzheimer’s will have a much higher socio-economic burden than other terminal diseases like cancer.

This is precisely why Dr Dawn Hay Wun Lau decided to pursue the elusive treatment for Alzheimer’s, with a single-minded determination to understand the underlying mechanisms behind the disease, and to find a way to delay or treat it.

“Alzheimer’s disease is the most common form of dementia and if we don’t find a way to treat it now, many of us are at risk of getting it, because we’re living longer,” says Dr Lau.

“On the other hand, the population pyramid is skewing towards older groups but we don’t have enough young people to care for them in places like Hong Kong. The thought was scary, so I decided to contribute in a way I can.”

Dr Lau attended a class on neurodegenerative diseases during the final year of her undergraduate study on neuroscience, which discussed Huntington’s, Parkinson’s, and Alzheimer’s diseases. Her interest piqued after writing an essay on neurodegenerative illness. She worked on frontotemporal dementia for her master’s thesis and by the time she was in the PhD program she had decided to commit herself to work on Alzheimer’s.

Alzheimer’s disease

Much about the disease is still unknown and poorly understood at best, partly because of the multiple processes that cause Alzheimer’s.

There are several hypotheses surrounding this devastating disease. One of the more popular is the amyloid hypothesis, according to which amyloid beta (Aβ) proteins accumulate in the brain, starting off as a monomeric, soluble protein eventually binding together to form oligomers (multiple monomers stuck together), these oligomers then bind to one another in a large sticky mass known as a plaque.These plaques start collecting in the brain and trigger the process of Alzheimer’s.

Amyloid beta (brown) forming plaques in the cerebral cortex

This soluble form of amyloid beta either directly or indirectly interacts with Tau protein -- thought to be a stabilising protein for cells (though recent studies have found it at synapses), the loss of which is one of the key events in Alzheimer’s disease. It is known from previous studies that the Tau protein is a necessary element causing Alzheimer’s.

“It’s like Amyloid beta is the gun and Tau is the bullet, which actually causes the damage,” says Dr Lau. “But we don’t know how Amyloid beta interacts with Tau. Furthermore we aren’t clear on how Tau exerts its neurotoxicity.”

There is a hypothesis that Tau is secreted from brain cells to pass onto other brain cells, which in turn might propagate its neurotoxicity from one brain cell to another.

“But it’s still so unclear because none of us really know what exactly is happening,” says Dr Lau. “It’s such a heterogeneous disease, comprised of many different causes that there is no one way to pinpoint a definitive underlying mechanism.”

Alzheimer’s disease has two types: Familial and Sporadic, though familial Alzheimer’s accounts for less than 1 percent of all cases. It is caused by mutations on three genes, Amyloid Precursor Protein (APP), Presenilin-1, and Presenilin-2, which affect the production of Amyloid beta, increasing the amount of toxic protein.

Recent Genome-wide association studies (GWAS) have suggested other genetic risk factors factors playing a part in disease development. GWAS could be useful in figuring out other risk factors causing Alzheimer’s disease. Researchers also generally suggest that people keep their hearts healthy so as not to increase the risk of Alzheimer’s.

It is still unknown if sporadic Alzheimer has the same mechanism as familial, and hence more research in this process is necessary, says Dr Lau.

Studies on underlying mechanisms

During her PhD, Dr Lau studied Tau protein interaction, trying to find the missing link between Amyloid beta and Tau as it wasn’t clear was how these two proteins were interacting to cause Alzheimer’s.

Later, when the protein Fyn (the other protein present at synapses which can cause dysfunction of the synapses) was found to interact with Tau, Dr Lau investigated the interaction to see whether Fyn was involed in the spreading of Tau protein using organotypic brain slice culture. She also tried to find the precise binding site between Tau and Fyn proteins.

At the same time, Dr Lau’s team studied human brain tissue, comparing tissues from both patients with Alzheimer’s and without to see if there was any change in Tau and Fyn expression and if there was any correlation between the two.

Dr Lau is still working on Alzheimer’s in her post doc research, but is now investigating the interaction between two cellular organelles, the endoplasmic reticulum (ER) and mitochondria.

Micrograph of the ER and mitochondria (dark black circles) around the nucleus (lower right)

The ER and mitochondria, under normal conditions, interact with each other inside cells and form close contact with one another at specific points along their surface. Signalling that takes place at these points of contact is important for normal cell processes, as they generate energy for the cell, maintain balanced calcium levels within the cell, and help create lipids for the cell, among other things.

Dr Lau’s team found that in some disease conditions, like Amyotrophic Lateral Sclerosis (ALS), these contacts are broken; the endoplasmic reticulum and mitochondria are farther apart from each other than they are normally. As a result, mitochondria can’t produce enough energy for the cell, among other things. This could be one of the reasons why neurons die in ALS patients and the same could be happening with Alzheimer’s disease.

“I’m investigating whether the endoplasmic reticulum and mitochondria interactions are altered in Alzheimer’s disease as well and if they are, what’s causing the alteration,” says Dr Lau. “And once we figure that out, the next step would be to figure out a way to fix the altered interactions.”

The elusive treatment

There is no drug treatment available targeting the cause of Alzheimer’s disease at the moment. At most, there are drugs available to temporarily treat symptoms, so the primary hope of researchers has been to find a disease-modifying treatment.

“We’ll save a lot of suffering and release a lot of socio-economic burden if we find a drug that is able to modify the course of the disease or delay the onset, even if only by few years,” says Dr Lau.

However, finding the drug that will delay the onset of the disease is quite a long way off at the moment. Given the heterogeneous nature of the disease, Alzheimer’s researchers are targeting several areas but figuring out the underlying mechanisms in order to design drugs remains the highest priority.

Clinical trials have been running for a long time and they usually target Amyloid beta and Tau to try and stop the accumulation of protein in the brain. Once the results are known, Dr Lau is confident that it could be key information that can be used in further research to try and find drugs for Alzheimer’s.

“I’d hesitate to say a cure might be found in the near future. But I’m optimistic that some sort of treatment will be found in the next 20-30 years, we’ll find something in my lifetime,” says Dr Lau with confidence.

But Alzheimer’s disease isn’t only about finding drugs. In many places including Hong Kong and China, the disease is often considered taboo and people refrain from reporting it. People with Alzheimer’s need support, care, and friendly treatment more than anything else. Dr Lau enjoys engaging with the public to increase awareness of Alzheimer’s disease and speaking to people with a connection to this disease.

Limitations and challenges

“The most challenging aspect is narrowing it down to researching one particular mechanism,” says Dr Lau. “And also finding new technologies to look at Alzheimer’s disease.”

Dr Lau explains that current diagnosis methods pose a major limitation for clinical trials because Alzheimer’s disease can’t be completely diagnosed without looking at brain tissue. In most cases this can’t be done before death, as it requires a brain autopsy.

Finding a better diagnosis method is of the highest priority at the moment.

Most trials rely on a cerebrospinal fluid test at the moment, which is a very invasive procedure and the results aren’t always accurate. There is concern that some of the patients enrolled in clinical trials and considered healthy were probably going to develop Alzheimer’s disease but the current method of diagnosis (usually a combination of cerebrospinal fluid tests and brain scans, along with memory testing) was unable to detect them.

“One of the primary reasons we think that the previous clinical trials haven’t been successful is that we haven’t been able to diagnosis Alzheimer’s patients successfully,” explains Dr Lau. “Another thing is we might be treating the patients too late.”

It’s not necessarily the big proteins that clump up the brain that are toxic species. Many researchers think intermediate, smaller species of proteins are more toxic, but as they are much harder to detect, they might have been running around in the brain for several years prior to the accumulation.

“Finding a better diagnosis method is of the highest priority at the moment,” Lau adds. “Researchers at my university are trying to see if a simple blood test could be more accurate. Another option is brain scan. Researchers are also looking at developing new tracers which can bind with more specificity to Tau and Aβ, which will allow doctors to see these proteins in brain scans with more accuracy.”

Researchers can screen people’s genomes for mutations but it is not necessarily ethical and not very cost effective. But most of all, only 1-5 per cent of Alzheimer’s cases are inherited. The rest of the cases need different methods of diagnosis.

Dr Lau is also worried the political changes in Europe will lower the funding in a field already suffering from limited resources. Alzheimer’s still doesn’t get as much funding as cancer research despite its possibly higher socio-economic burden on society.

“There are better treatments for different types of cancer today but there is absolutely no disease modifying-treatment for Alzheimer’s,” says Dr Lau. “The UK’s decision to leave the EU could mean funding is under threat of falling, when we actually need better resources and support from governments to battle the growing risk.”

As for Hong Kong, the limited number of Alzheimer’s researchers in the city might be indicative of the fact that there isn’t much funding, says Dr Lau. Additionally, the administrative burden and teaching requirements in Hong Kong severely cut into research time of scientists.

New developments

Lack of treatment and definitive understanding of the underlying mechanism behind the disease might present a bleak scenario for many, but continuous studies in the field are also resulting in findings that could be important pieces in solving the puzzle.

A new mutation was found recently in the Icelandic population, one that protects them from Alzheimer’s. The mutation reduces the production of the toxic form of Amyloid beta. Scientists are studying how and if this mutation can be used to develop treatment.

In another recent clinical trial, several members of a family in Colombia have been diagnosed with Alzheimer’s disease due to a mutation in their genes. The difference in this trial is that researches are testing new drugs on these patients who are yet to show any symptoms. Dr Lau suspects this might be a better time to start treatment.

Although possible treatments are limited to Alzheimer’s cases caused by mutations for now, results of these studies could be significant; the Colombia trial in particular could uncover insight into the mechanisms underlying both familial and sporadic forms of Alzheimer’s. But while new developments are taking place, one shouldn’t forget to keep a healthy lifestyle.

Dr Lau Hay Wun Dawn obtained both her Bachelor's and Master’s degrees in Neuroscience from University College London. She completed her PhD at King’s College London. She is currently a postdoctoral research associate at the Maurice Wohl Clinical Neuroscience Institute, King's College London. She was awarded a Croucher Scholarship in 2012 at King’s College London.

To view Dr Lau’s personal Croucher profile, please click here.