Alzheimer’s, amyloid, and answers in genetics

Founder of the International Parkinson’s Disease Collaborative Network and molecular geneticist Sir Prof John Hardy, who was awarded multiple honours and a knighthood for his work in neurology, opened the first plenary session of the Irish Neurological Association and the Association of British Neurologists Joint Annual Scientific Meeting 2023.

In his presentation, ‘The genetics of neurodegenerative diseases’, he began with an overview of the pathologies of what he termed the “deposition disorders” – Alzheimer’s, Parkinson’s, and tangle diseases – and described how the latest discoveries in genetic research are bridging knowledge gaps in the current understanding of disease processes and treatment modalities. 

Prof Hardy described to attendees how these disorders can all be caused by gene duplications of the cognate gene, calling this “a very simple finding, but greatly significant”, before explaining how the proteins involved in these disorders are close to their deposition threshold, and that a marginal increase in expression will lead to deposition. 

With a primary focus on Alzheimer’s disease, Prof Hardy delivered an in-depth synopsis of amyloid theory, including an exploration of the microglial clearance mechanisms that occur in response to amyloid build-up. He then gave his overall interpretation of the data, breaking up the disease process into two segments – amyloid deposition, and microglial response to the deposition – describing how genetic variability in this ‘clean-up’ response to amyloid deposition appears to be a key component of Alzheimer’s risk. “Amyloid deposition is genetic, is driven almost entirely by [the] APOE [gene], but whether you get dementia in the context of that deposition depends on your microglial response,” he told his colleagues, before describing the microglial response as one that “takes time and is going on in that period when you are amyloid positive, but not demented”.

Looking briefly at the deposition and clearance mechanisms in Parkinson’s and tangle diseases, Prof Hardy described what he called “the same processes”, saying “it fits rather similarly into the story I’ve been telling you about amyloid and microglia…. Perhaps there is nothing intrinsically distinctive about the proteins, they are just proteins close to their deposition threshold. So, maybe the most important factor is the failure of the clearance pathways.” Addressing the issue of co-morbidities, he theorised that these overloaded clearance systems lead to a spill-over and overloading of other clearance systems, resulting in co-morbidities.

Concluding with what Prof Hardy termed “the good news”, he talked about the ongoing advances in treatment pathways and described why therapies to date have failed or taken so long. “They weren’t [amyloid] removal drugs, they were drugs that prevented further deposition and they were tested in humans at which the deposition was already high… analogous to giving a statin to somebody in the middle of a stroke or heart attack.” Describing renewed understanding of disease processes, future therapies, and emerging data from recent and ongoing trials, such as the donanemab phase two trial, he said “things are moving”.

“I think we’re on the road finally. It’s taken 30 years. I think we can see that amyloid removal does work; the amyloid hypothesis has at least enough validity to lead to clinical benefit…. We can see that perhaps anti-tau therapies are on the way and we need to be thinking of ways to modulate the microglial response, but we’re on the way.”