IAS Distinguished Lecture - Neurodegenerative Diseases: Anti-amyloid Therapies for Alzheimer’s Disease are the First Faltering Steps towards Mechanistic Therapy

Abstract

Aβ was isolated and sequenced from the amyloid angiopathy of Alzheimer’s disease in 1984 and from plaque cores in 1985. By oligonucleotide hybridization the APP gene was cloned and localized to chromosome 21 in 1987. After a false start, APP mutations were identified in Dutch amyloid angiopathy in 1990 and in a minority of early onset Alzheimer families in 1990. In other families with early onset Alzheimer’s disease, mutations were described in the presenilin genes in 1995 and the effects of both APP and presenilin mutations on APP processing was described in 1996. Mice with APP and mice with APP and presenilin mutations which deposited plaques but not tangles were made in 1994-1998. MAPT mutations were found in tangle only dementias in 1998 and these mutations allowed mice with tangles to be produced in 2000. Crossing these tangle mice with the plaque mice potentiated tangle formation but did not alter plaque production showing tangles and cell loss were downstream or amyloid in the pathogenic cascade. This sequence of findings largely made from the analysis of early onset mendelian disease is what has underpinned the amyloid hypothesis. More recently, genetic analysis of the much more prevalent late onset disease has identified many loci, most of which are involved in microglial Aβ clearance.

This background justified the three major therapeutic approaches to Alzheimer’s disease based on either reducing Aβ production or facilitating Aβ clearance.

Aβ is produced by the sequential cleavage of APP by β-secretase at the N terminal of Aβ and γ-secretase at the C terminal of Aβ. With this background, there have been three major therapeutic targets: β-secretase inhibition, γ-secretase inhibition/modulation and amyloid removal by antibody. Both  β- and  γ-secretase inhibition failed in clinical trials possibly because both enzymes have many other substrates besides APP or because the build up of C-terminal stubs of APP was neurotoxic. Attempts at γ-secretase modulation (altering the cleavage site of the enzyme) continue. The major developments have come from the use of antibodies to either prevent amyloid build up or to facilitate amyloid removal.

The first hint that antibodies to Aβ might be a useful therapeutic strategy came from the experimental treatment of transgenic mice in 1999. However, while this first antibody and some of the other early antibodies prevented amyloid build up, they did not cause amyloid removal except where there was blood brain barrier damage. These antibodies failed in clinical trials. After these failures and the failures of β- and  γ-secretase inhibitors there was concern and disagreement in the research community about whether amyloid therapies were worth further pursuing. However, more recently, antibodies which caused amyloid removal, aducanemab (controversially), lecanemab and dononamab have all caused amyloid removal, and have led to modest clinical benefit and have therefore received some regulatory approval. All though, cause blood vessel inflammation (ARIA) as the antibodies hit the amyloid angiopathy.

In this lecture, the speaker will review these issues and discuss the genetic and pharmacologic attempts to both improve anti-amyloid therapies and to decrease their side effects. He will discuss how biomarker analyses, particularly plasma pTau, allow the detection and monitoring of amyloid pathology and will conclude by arguing that we should consider switching to biomarker driven clinical trials, analogous to monitoring high cholesterol as a surrogate for heart disease and stroke. In this example, statins were approved by FDA as medications 7 years before they were shown to have disease modifying effects on heart disease.


About the Speaker

Sir John Hardy  received his BS in Biochemistry from the University of Leeds in 1976 and his PhD in Neurochemistry from the Imperial College London in 1981. He spent his early career at the University of Newcastle upon Tyne, the University of Umea and St Mary's Hospital (which later merged with Imperial College London). He moved to the US to take up the position of Eric Pfeiffer Endowed Chair in Alzheimer's Research at the University of South Florida. He then joined the Mayo Clinic Jacksonville in 1996 as a Consultant and Professor of Pharmacology and chaired the Department of Neuroscience during 1999-2001. In 2001, he moved to the National Institute on Aging of the US National Institutes of Health as the Chief of Laboratory of Neurogenetics. He returned to the UK in 2007 as a Professor of Neuroscience at the University College London (UCL). He is currently the Chair of Molecular Biology of Neurological Disease at the UCL Institute of Neurology. Additionally, he has collaborated closely with faculty at HKUST and serves as one of the Team Leaders at the Hong Kong Center for Neurodegenerative Diseases (HKCeND).

Sir John’s research interests are in the genetic analysis of neurodegenerative disease. He contributed to a critical breakthrough in understanding what goes wrong in the brains of people suffering from Alzheimer’s disease, the most common form of dementia. He has since led a broader effort to understand the genetic factors underlying several forms of degenerative brain disease, including Parkinson’s disease and motor neuron disease. He discovered that a mutation in the gene for amyloid precursor protein (APP) caused deposits of a substance called amyloid to form in brain tissue, associated with early-onset Alzheimer’s. Deposits of amyloid, which kills brain cells, later proved to be a primary cause of the disease.

Sir John 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 has received numerous 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 groundbreaking research in neurodegeneration, Sir John was awarded the prestigious Breakthrough Prize in Life Sciences in 2016 and the Brain Prize in 2018. In 2022, he received a Knighthood in the New Year’s Honours for his significant contributions to human health and dementia research. Additionally, he was conferred an Honorary Doctorate by HKUST in 2020 and an Honorary Doctorate by the University of Helsinki in 2022, both in acknowledgment of his exceptional research achievements.


Co-organizer

Hong Kong Center for Neurodegenerative Diseases (HKCeND)


For Attendees' Attention

Seating is on a first come, first served basis.