Fall 2020 > Research Excellence

Plugging into the Brain

We all have occasional lapses in memory. It can be as random as having a name on the tip of your tongue, but being unable to recall it, or as annoying as leaving the house without your cell phone! Many of us, particularly older adults, do not take occasional forgetfulness too seriously, as we often consider it a normal part of the aging process.

A report published in the journal Neuron by Prof. Paul FRANKLAND and Prof. Blake RICHARDS at the University of Toronto highlighted that forgetting things can actually make people smarter. They proposed that “only by combining persistence (remembering) and transience (forgetting) can individuals exhibit flexible behavior and generalize past events to new experiences.”1 In layman’s terms, it is similar to clearing the cache on a computer to enhance the system’s performance. However, if persistent memory loss hinders our ability to function normally in daily life, it can no longer be considered a virtue. In this case, the memory loss could be an early sign of Alzheimer’s disease, the most common form of dementia, which can steal more than just our memory from us.

Unraveling the Secret

The term “Alzheimer’s disease” (AD) was first coined in 1910 after a German psychiatrist and neurologist, Dr. Alois ALZHEIMER, who observed shrunken nerve cells in a postmortem examination of his female patient, Auguste DETER, who was in her early 50s and suffering from memory loss and other psychological problems. It was revealed that the cerebral cortex in Deter’s brain was thinner than normal, and contained amyloid plaques and neurofibrillary tangles, which are now considered hallmarks of this disease.2 This astonishing discovery by Alzheimer laid a solid foundation for future AD diagnostics and research.

Studies later confirmed that these amyloid plaques and neurofibrillary tangles are caused by a buildup of protein. Amyloid plaques are defined as “insoluble accumulations of beta amyloid proteins that clump together between the nerve cells (neurons),” while neurofibrillary tangles are “abnormal accumulations of a protein called tau that collect inside neurons, blocking the neuron’s transport system, which harms the synaptic communication between neurons.”3 Both amyloid plaques and neurofibrillary tangles spread and increase in abundance as AD develops.

Despite significant progress in AD research, neurological illnesses such as AD and dementia have a history shrouded in cultural and societal taboo, and in many countries this is still the case.

The “World Alzheimer Report 2019 ― Attitudes to dementia” released by Alzheimer’s Disease International indicated that “35% of caregivers across the world said that they have hidden the diagnosis of dementia of a family member.”4 It is reported that approximately 50 million people worldwide have the disease, and nearly 10 million new cases are diagnosed every year.5 Many patients, particularly the elderly, denied having the disease and perceived it as a disgrace. As a result of this entrenched stigma, they concealed their illness and failed to seek medical and professional assistance. Often, the debilitating impact of gradual memory loss and cognitive impairment significantly affects the patients’ relationships with their partners and family members. AD patients are rarely willing to participate in clinical trials, but Carol JENNINGS is an exception.

The Mind Thief

IAS Senior Visiting Fellow Prof. John HARDY, Chair of Molecular Biology of Neurological Disease at University College London (UCL), gave an IAS Distinguished Lecture on “Genomics in Neurodegenerative Disease ― What Are We Up To” during his last visit to the IAS. He shared a video depicting Jennings, whose father and several aunts and uncles had developed AD in their 50s.6 In 1986, Jennings was on a mission to find out the reason, and approached AD researchers to request to take part in their clinical research voluntarily. Hardy, then a doctor at St. Mary’s Hospital in London, received Jennings’s letter. At that time, neither Jennings nor Hardy knew that the courageous step Jennings took would become a pivotal moment in the history of AD research.

The critical breakthrough came in 1991. A rare form of AD, termed familial Alzheimer’s disease (familial AD), which had been affecting Jennings’s family for generations, was identified by Alison GOATE, formerly a junior researcher in Hardy’s team. In an interview, Hardy said, “when we found the mutations in amyloid in Carol’s family, we knew that is where the disease started.”6

Familial AD is caused by a faulty gene ― the “mind thief” affecting Jennings and her family members, which is inherited with a 50:50 chance of passing from generation to generation. It is also known as early-onset familial AD; in contrast to the more common late-onset AD, symptoms can appear in individuals in their mid-60s or even as early as their 30s or 40s. Caused by an inherited change in one of three genes, amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2), early-onset familial AD is rare and only accounts for 10% of AD cases.7

Sadly, Jennings also carries the APP gene mutation and is now suffering from moderately severe AD. She and her family have been advocates for those living with familial AD, promoting awareness of AD throughout the years. The contribution of Jennings’s steely commitment to the discovery of the genetic basis of AD is unquestionable and has transformed the research field.

In 2016, Hardy became the first ever UK scientist to receive the Breakthrough Prize in Life Sciences in recognition of his pioneering research in neurodegeneration and the discovery of the APP mutations that cause early-onset AD. Hardy acknowledged the families, including Jennings’s, who volunteered to take part in the research studies, “Special people who took us into their hearts and into their homes. I truly hope we can repay you by curing your diseases.”8

Two years later, Hardy together with other international scientists was awarded the Brain Prize by the Lundbeck Foundation in Denmark for “groundbreaking research on the genetic and molecular basis of AD.” However, there is still far more work to be done.

Finding the Brain Band-Aid

In recent years, researchers have gained a better understanding of neurodegenerative diseases like AD, Parkinson’s, and amyotrophic lateral sclerosis (ALS), and a variety of therapies have been developed that can alleviate symptoms. Nevertheless, such neurodegenerative diseases are incurable and irreversible. Hardy and his team have been working on Parkinson’s disease and motor neuron disease with an increasing focus on the genetic analysis of complex traits related to these diseases. His research team is also interested in population genetics, studying how the risk variants for human traits differ in different racial groups. Hardy has been collaborating with the faculty at HKUST to identify and characterize the genetic risk factors for AD and Parkinson’s in the Chinese population and East Asians, respectively.

In 2019, thanks to the assistance of Hardy, a Memorandum of Understanding was signed to establish the Center for Neurodegenerative Diseases at the Hong Kong Science Park. With funding support from Health@InnoHK, one of the research cluster programs focusing on health-related technologies under the government’s Innovation and Technology Commission, the Center is led by Prof. Nancy IP, Vice-President for Research and Development at HKUST, The Morningside Professor of Life Science, and the Director of the State Key Laboratory of Molecular Neuroscience. The Center will engage in advanced translational neuroscience research, aiming to gain new insights into disease pathways and drive translational research efforts to develop improved treatments and tools for early diagnosis.

As the population in many parts of the world ages, we are facing new challenges in tackling the increasing numbers of people with neurodegenerative diseases. It is a race against time for researchers. Combined with technological advancements in clinical trials and scientific research, there is a new sense of hope that in the not-too-distant future improved therapeutics will become available. Until then, adopting an active lifestyle and healthy diet may help to reduce the risk of neurodegenerative diseases.

Prof. John HARDY

Prof. Hardy is a world-renowned neuroscientist who is the most-cited AD researcher in the UK. He received his BSc in Biochemistry from the University of Leeds in 1976 and his PhD in Neurochemistry from Imperial College London in 1981. He spent his early career at the University of Newcastle upon Tyne, Umeå University, and St Mary’s Hospital (which later merged with Imperial College London). Between 1989 and 2007, he worked in the US, taking up several senior positions at the University of South Florida, the Mayo Clinic in Florida, and the National Institute on Aging at the National Institutes of Health. Since 2007, he has been Professor of Neuroscience at UCL and is currently the Head of the Department of Molecular Neuroscience and the Chair of Molecular Biology of Neurological Disease at the UCL Queen Square Institute of Neurology.

Prof. Hardy was elected a Member of the UK Academy of Medical Sciences in 2008, a Fellow of the UK Royal Society in 2009, of the Institute of Biology (now known as the UK Royal Society of Biology) in 2011, and of the European Molecular Biology Organization in 2015. He was awarded a Doctor of Science honoris causa by HKUST in 2020.

He has received numerous international awards including the Dan David Prize (2014), the Thudichum Medal (2015), the Hartwig Piepenbrock-DZNE Prize (2015), and the Helis Prize (2016). In recognition of his pioneering research in neurodegeneration, he was awarded the prestigious Breakthrough Prize in Life Sciences in 2016 and the Brain Prize in 2018.