Blog – Alzheimer’s Disease Takes a Lifetime
We all know that Alzheimer’s disease is complex. Despite being described over 120 years ago, the cause of Alzheimer’s disease remains unclear and often courts controversy. The amyloid cascade hypothesis arose from the observation that Alzheimer’s cases, whether obviously inherited or sporadic, universally showed amyloid-beta deposition in plaques. Genome-wide association studies showed us that the autosomal dominant genes were Amyloid Precursor Protein (APP) and the presenilins, which were then shown to be involved in APP processing — producing amyloid-beta, more so in its aggregation-prone form (Aβ42). Tau deposition intracellularly adds to the complexity, being also associated in tauopathies in the absence of amyloid-beta— and so the controversy was fuelled.
Studies that revealed amyloid-beta deposits did not correlate well with disease severity highlighted a significant role for tau. Updates to the amyloid cascade hypothesis pointed to oligomeric species of amyloid-beta, providing some explanation for the lack of amyloid plaque correlation and the poor efficacy of trials of amyloid-beta-removing drugs. More recently, neuroinflammation, synaptic loss, lysosomal impairment, oxidative stress, blood-brain barrier leakiness, herpes virus, and the gut-brain axis are among the ideas put forward to explain disease initiation and progression, and to provide new targets for therapy.
Why has this disease proven so difficult to understand, with each group of scientists focusing on different avenues of research?
I suggest that we are hampered by our strategic directions, with our preferred methodologies, and disease models. As a structural and cell biologist focusing on the roles of protein misfolding in disease, our models were necessarily reductionist. To gain insights into amyloid structures, we focussed on in vitro proteins, sometimes comparing findings to post-mortem brain imaging at the electron microscopy level. Cellular assays require higher concentrations for observations within suitably short timeframes, whether in immortalised cell cultures, animal model neurons, or differentiated human induced pluripotent stem cells. Organoids, tissue slices, and post-mortem tissue may provide more physiological relevance, but remain fundamentally model systems. Animal models offer living systems yet miss the human aspect, while intervention in living humans is clearly limited by ethics and practical considerations.
The uniqueness of a person cannot be captured by these models — their diverse genetics and epigenetics; the unique experiences accumulated over a lifetime as they age, within changing environments, with differing nutrition, hormonal changes, comorbidities, life experiences, learning, and exposure to toxins, pollutants, and infections. Within each individual, the vulnerability of the brain is shaped by the individuals genetics, thus influencing chaperone system, the immune response, and the diversity of brain cells, from neuronal types to glia. On top of this, we now know we must consider the microbiome, and probably many other factors not covered here. So, I suppose this explains why it is so difficult to solve the puzzle that is Alzheimer’s — but what can we do, and why does it really matter?
A Critical Moment in Research
In order to address the complexity of the human brain, we are increasingly expanding the complexity of our model systems — from dissociated cells to mixed models and mini-brains. We now know that there is heterogeneity in protein pathology in neurodegenerative diseases. Only recently have efforts stepped up to consider the contributions of hormonal changes. Ageing must also be considered, since we know this is a very slowly progressing disease. The likelihood is that the cascade begins long before symptoms appear, and before MRIs or PET scans can detect the diagnostic changes.
Biomarkers are being discovered that point to earlier diagnostic timepoints, while personalised medicine is being pioneered to account for a person’s genetics and proteome. Studies are broadening to expand beyond traditionally studied Western populations into Africa and Asia, promising a far clearer picture of the diversity of human genetics and environments.
We are truly at a critical point in research, with real advances in therapy and diagnosis. The collaboration of researchers with diverse areas of focus and expertise will be key to understanding Alzheimer’s disease. Understanding this extended timeline — and the factors that shape it — is essential to any meaningful advance in prevention and treatment.
Professor Louise Serpell
Author
Professor Louise Serpell is an Emerita Professor of Biochemistry at the University of Sussex. Her research focuses on how proteins misfold and form amyloid structures linked to Alzheimer’s disease and other neurodegenerative conditions, using approaches from structural biology and molecular biophysics. Louise completed her DPhil at the University of Oxford and later established her own research group in the UK. Alongside her research career, she has been active in mentoring, public engagement, and supporting early career researchers.