The level of amyloid (white shades in area encircled by green dotted lines) - the protein thought to drive neurodegeneration in Alzheimer’s disease, is high in the brain of Alzheimer’s disease transgenic mouse expressing familial mutation (left) and reduces after administration of the genome editing of the familial mutation throughout the brain (right). Source: HKUST

Finding new paths to early detection and treatment of Alzheimer’s disease

17 December 2022

At the Hong Kong Center for Neurodegenerative Diseases, a research team of more than 50 scientists led by Professor Nancy Ip, president of the Hong Kong University of Science and Technology, has made significant advances in the field of Alzheimer’s disease, undertaking an innovative dual approach in its treatment.

To find a cure for Alzheimer’s disease is a complex process, as it is difficult to synthesise a traditional pharmaceutical drug to cross the blood-brain barrier that would be both effective and safe. Most drugs fail in clinical trials as the patients tend to be advanced in the pathology of the disease process, and therapy may be too late. Ip’s research team is undertaking a dual approach: early diagnosis and the use of a gene therapy strategy.

Professor Nancy Ip (centre) with some members of her research (from left to right):  Dr Jason Jiang, Professor Fred Zhou, Dr. Fanny Ip, and Professor Amy Fu. Source: Hong Kong University of Science and Technology.

Since its founding in 2020, the research centre has worked assiduously to develop novel biomarkers and identify therapeutic targets including systemic factors to treat neurodegenerative diseases. Alzheimer’s disease affects more than 50 million people worldwide and this number will continue to grow with an ageing population as well as advances in treating other life-threatening diseases along the way. Alzheimer’s disease results from the abnormal build-up of proteins in and around brain cells. One such protein is beta-amyloid that accumulates into plaque, that may contribute to memory loss and altered thinking and learning behaviours. The early detection of biomarkers can provide patients more time to prepare for the onset of symptoms and management of the disease. For those currently suffering from Alzheimer’s disease, a safe and effective treatment would be a milestone scientific achievement for this debilitating disease.

To develop a novel Alzheimer’s disease diagnostic screening on a single drop of blood, Ip’s team collaborated with hospitals in Hong Kong. The initial clinical study for patients of Asian descent included 200 participants, which classified into two groups: an Alzheimer’s disease clinically diagnosed group and a healthy age-matched control group.

“More than 1100 proteins were examined of which 429 proteins have altered levels in Alzheimer’s disease patients, some are higher, some are lower when compared to the levels in healthy controls,” Ip said.

Researchers grouped the 429 proteins identified into 19 protein clusters based on co-expression analysis, and each with an identified ‘hub’ protein. These proteins represent the changes in the blood proteome that led to the identification of a biomarker panel used to diagnose and stage the disease. In the future, one drop of blood would be enough for this blood diagnostic test. Subsequent clinical studies at Hong Kong and overseas hospitals after the development of the biomarker panel have included more than 1500 patients to validate and optimise their blood tests.

The Hong Kong Center for Neurodegenerative Diseases research team has developed a simple and reliable blood test for Alzheimer’s disease, in which each blood sample is tested for the disease-specific biomarkers using an ultrasensitive protein detection and measurement technology. Source: Hong Kong University of Science and Technology.

The team developed a scoring system that distinguishes patients with Alzheimer’s disease from healthy controls with greater than 96% accuracy. This scoring system also assesses the stage of the disease: early, middle, or late. The turn-around time for the analysis can be done in as little as two days for the high-performance, blood-based test. These research findings provide a diagnostic pathway to identify the disease through a simple blood-based test and opens the way to novel therapeutic treatments.

In the area of genetic biomarker research, centre’s researchers have previously conducted whole genome sequencing analysis of patients with Alzheimer’s disease in the Chinese population and established the first comprehensive database of its kind, resulting in the identification of some novel Alzheimer’s disease genetic risk factors.

“Genetic information is intrinsic, persisting after birth. By establishing the Chinese genome database, we will be able to identify variants that associate with AD risk and develop genetic-based assays for early risk assessment of AD. Therefore, analysis of individual genomes may reveal disease pathogenic causes, as well as provide aid in clinical diagnosis and early intervention,” according to Professor Fred Zhou, a core member of Ip’s research team. 

In collaboration with the Department of Computer Science and Engineering at Hong Kong University of Science and Technology, the team developed the first scoring system of polygenic risk based on deep learning. The developed artificial intelligence algorithms can classify patients based on disease causes, determined by polygenic risk. This will facilitate tailored disease intervention strategies. The group expects to report soon on their findings. With advancements in AI and expansion of the genomic databases, polygenic risk-scoring is expected to become more accurate for prediction.

The centre has also developed a first in-class therapeutic approach using gene therapy. In a preclinical animal model study, the team delivered a genome editing tool that can cross the blood-brain barrier to the entire brain through a single non-invasive intravenous administration. For the experiments the team used genetically modified mice that express the human APP gene and PSEN1 gene. Both genes are associated with early-onset familial Alzheimer’s disease, and these transgenic mice show progressive phenotypes.

The level of amyloid (white shades in area encircled by green dotted lines), the protein thought to drive neurodegeneration in Alzheimer’s disease, is high in the brain of Alzheimer’s disease transgenic mouse expressing familial mutation (left) and reduces after administration of the genome editing of the familial mutation throughout the brain (right). Source: Hong Kong University of Science and Technology.

The research team treated the transgenic mice at the age of three months-old with the genome editing tool that target APP gene and examine the consequences of the genome editing up to and beyond nine months, at which the mice exhibit severe brain pathology. The genome editing tool was safe and effective to disrupt the disease-causing genes. There was an improvement in the pathology throughout the brain for the transgenic mice after treatment with the genomic editing tool. Also, there were apparently no obvious off-target effects observed after the treatment.

Genome editing of the familial mutation in Alzheimer’s disease transgenic mice improves their memory performance. Source: Hong Kong University of Science and Technology

Next, the researchers expanded this genome editing approach in non-human primates with the ultimate goal of testing in humans one day. This research is important for developing treatment for familial diseases directly and not just the symptoms, and this novel approach circumvents the difficulty of producing a synthetic drug to cross the blood-brain barrier.

The diagnostic test, polygenic risk scoring system, and genome editing tool developed by the centre can be translated and potentially commercialised, according to Ip.

“The diagnostic tool we developed can potentially be incorporated into a routine medical checkup,” she said. “If we want to do a large-scale screening of the population to identify those at risk, I think we have the tools to do that, both the genetic tools and the blood test to look at the protein levels…. We have also identified potential biological pathways that should be examined in further detail to develop drug screening and hopefully one day we will be able to develop innovative drugs to treat the disease.”