Blog – Genetically determined Alzheimer’s: ADAD-DSAD Recap
Although genetically determined forms of Alzheimer’s disease are rare, they have been, and still are, crucial in research to understand Alzheimer’s disease mechanisms, pathogenesis and aetiology. Including both familial types of Alzheimer’s disease (autosomal dominant), and Down syndrome-Alzheimer’s disease, a newly established conference, termed ADAD-DSAD, explores the commonalities between these two groups. In this blog, I will discuss the outcomes from this meeting, and the important discussions it hosted.
Autosomal dominant Alzheimer’s disease (ADAD) is caused by a dominantly inherited mutation in the amyloid precursor protein (APP), Presinilin-1 (PSEN1) or Presinilin-2 (PSEN2) genes. APP is the protein which is cleaved to form the amyloid-beta peptide, which aggregates to form the hallmark amyloid-beta plaques in Alzheimer’s disease. The cleavage of APP is carried out by secretase enzymes, including gamma-secretase. The Presinilins are subunits of the gamma-secretase complex. Therefore, mutations in APP, PSEN1 or PSEN2 lead the production of longer, more aggregation prone amyloid-beta peptides, resulting in Alzheimer’s disease. These mutations are hereditary, running in families, and make up approximately one percent of all Alzheimer’s cases. Age at onset of dementia symptoms is much younger than in the general population, with disease diagnosis occurring in middle life.
Down syndrome is a second type of genetically determined Alzheimer’s disease. Resulting from trisomy of chromosome 21, on which the APP gene is encoded. People with Down syndrome have a third copy of APP, resulting in increased amyloid-beta production and deposition. The age of disease onset in Down syndrome is also significantly younger than the general population, with the average age of dementia diagnosis being 55 years in the United Kingdom.
Drawing on their similarities and opportunities to learn from the commonalities between these two types of genetically determined AD, the ADAD-DSAD conference was established in 2024, dedicated to sharing research on these two fields. I recently attended the second instalment of this conference in the beautiful setting of Hospital Moderne Sant Pau, Barcelona.
The conference largely had a human data focus, with sessions ranging from human neuropathology, to neuroimaging biomarkers, to AD clinical trials. A strong theme across many talks at the meeting focussed on understanding how the APOE genotype of an individual can influence the age at disease onset in genetically determined Alzheimer’s disease. In sporadic Alzheimer’s disease in the general population, being an APOE epsilon 4 allele carrier is associated with increased risk for developing AD, with homozygosity for APOE4 having an 11-fold increase in lifetime risk. But in individuals predetermined to get Alzheimer’s disease, does this risk allele have an effect?
The consensus across multiple talks was that it has a moderate effect at causing an earlier age at symptom onset.
This discussion was furthered by a focussed session led by Prof John Hardy and Dr Juan Fortea on how can we actually classify genetically determined Alzheimer’s disease. Research led by Dr Forteas group, published in 2024, showed that individuals homozygous for APOE4 were almost guaranteed to develop AD if they lived long enough. Dr Fortea argued that in the case of cancer, such as the BRCA gene mutations which cause breast cancer, and have a 50+% chance of disease, no one would argue that it is not genetically determined. Other audience members suggested that without any real treatments, considering APOE4 homozygosity a genetic form of AD is risky for patients and clinicians. This was a fascinating and thought-provoking discussion, and a debate which I’m sure will continue to be had in the coming years.
Another highlight of this meeting was the dedicated session on clinical trials for Alzheimer’s disease modifying therapies, specifically for these populations. The current usage guidelines for approved anti-amyloid-beta immunotherapies, Lecanemab and Donanemab, exclude individuals with Down syndrome over concerns of the side effect of amyloid related imaging abnormalities. This side effect, termed ARIA, is associated with brain bleeds or swelling, and symptomatically, can be seen as headache, confusion, but in severe cases, death.
Until now, no clinical trials for these therapies included people with DS. At the conference, Prof Michael Raffi gave an update on three clinical trials specific for people with Down syndrome, which will have all commenced by the end of 2025. These include the HERO study, which will test the safety of a genetic therapy, and the ALADDIN study, which will treat people with Down syndrome with the existing drug, Donanemab. Others at the meeting, including Prof John Hardy, stressed how unfair it is that people with Down syndrome have been excluded up to this point, despite the foundation of the amyloid hypothesis, on which these therapies are based, coming from data from people with Down syndrome. Therefore, this marks a positive step forward for the Down syndrome community.
The final stand out session for me, was a science and society session that included two people with Down syndrome, Laia and Greta, along with each of their mothers, and other panel members who have lived experience of Down syndrome or are working with people with Down syndrome. Laia and Greta themselves touched on how they have participated in various research studies, but also giving feedback to the community on what could improve their experience. They touched on having negative experiences with certain staff when having procedures such as MRI scans, having to attend clinics for lengthy periods, and having no contact from researchers on the outcome of studies in which they partook. These actionable points can hopefully be considered in future research study design and highlights the importance of PPIE in research.
Overall, this conference excelled at tackling the niche of genetically determined AD and applying findings back to the general population too. The full conference recording is available on YouTube and I would highly recommend for anyone in the Alzheimer’s field to browse the relevant sections.
Dr Clíona Farrell
Author
Dr Clíona Farrell is a Postdoctoral Researcher in the UK Dementia Research Institute at University College London. Her work focuses on understanding neuroinflammation in Down syndrome, both prior to, and in response to, Alzheimer’s disease pathology. Originally from Dublin, Ireland, Clíona completed her undergraduate degree in Neuroscience in Trinity College, and then worked as a research assistant in the Royal College of Surgeons studying ALS and Parkinson’s disease. She also knows the secret behind scopping the perfect 99 ice-cream cone.