March 21, 2017

expert reaction to genetic markers for predicting risk of Alzheimer’s

Researchers publishing in PLOS Medicine have developed a polygenic hazard score (PHS) as a possible way of quantifying the likelihood of developing Alzheimer’s disease.

Dr Rosa Sancho, Head of Research at Alzheimer’s Research UK, said:

“With 1 million people estimated to develop dementia by 2025 and Alzheimer’s disease responsible for the majority of cases, a better understanding of who is most at risk is crucial for researchers looking for new ways to prevent the disease. We know that Alzheimer’s disease starts to take hold in the brain many years before people show symptoms, and current clinical trials have struggled to test potential new medicines in the early time window when they could be most effective. Being able to detect who is at an increased risk of developing Alzheimer’s could revolutionise the way we evaluate potential new drugs.

“This study is one of a number of initiatives combining different genetic factors to assess Alzheimer’s risk. While these genetic risk scores hold promise as valuable research tools, they will need to be thoroughly evaluated, tested and refined before they could ever be used to help doctors diagnose or treat the disease. This particular study focused on people of European descent and the risk score now needs to be applied in other populations, as we know that Alzheimer’s risk can vary between different ethnic groups.

“This study does not suggest that having a high polygenic hazard score means you will definitely develop Alzheimer’s, nor does a low score mean you are immune from the disease. Genetics is only part of the story and we know that lifestyle factors also influence our risk of developing Alzheimer’s. The best current evidence points to habits we can all adopt to help lower our risk and indicates that what’s good for your heart is also good for the brain. Eating a healthy balanced diet, keeping physically and mentally active, not smoking, drinking in moderation, keeping blood pressure and cholesterol in check and maintaining a healthy weight are all ways to support healthy brain ageing.”

Prof. Paul Morgan, Director of Systems Immunity Research Institute, Cardiff University, said:

“Understanding of the genetics underpinning Alzheimer’s disease (AD) has exploded over the last decade with a growing number of new risk genes emerging from genome-wide association studies (GWAS). Many more genes that fail to show significance in this very stringent approach have been associated through more targeted approaches often focussing on biologically circumscribed pathways. In this latter group, each of the many associated genes is relatively weakly associated in comparison to GWAS ‘hits’. The idea of combining all these different genetic factors into a single ‘AD risk score’ for an individual was sparked by successes of such approaches in other complex diseases. In a 2015 paper published in Brain, Escott-Price and co-workers demonstrated in large cohorts of AD patients and controls the predictive power of the polygenic score, an observation that has been replicated by several other groups.

“The paper by Desikan et al adds to the strong evidence that an approach that takes into account the polygenic nature of AD can be a useful way of aiding risk prediction. From an original set of 1854 moderately highly AD-associated genetic variants, they used stepwise regression to identify a set of 31 that was most informative and from these (with the ApoE status – Apolipoprotein E) generated a predictive score they termed the polygenic hazard score (PHS).  PHS was shown to predict the age-specific risk of developing AD for an individual; PHS also correlated with disease pathology measured by brain imaging or at autopsy in the populations studied.

“Taken together with previously published work on the polygenic architecture of the disease, this paper makes the case for a polygenic score approach to assessing risk of developing AD. The first applications are likely to be in stratification of at risk individuals for inclusion in clinical trials, but as effective therapies emerge, the approach might be used more widely to enable early intervention in those at highest risk.”

Dr James Pickett, Head of Research, Alzheimer’s Society, said:

“Preventing the development of dementia symptoms is the holy grail of Alzheimer’s research but to succeed we first need accurate methods to predict who is most likely to develop the condition. This study’s approach was fairly successful at predicting the likelihood of someone developing dementia over the coming year, but needs to be tested further in mixed, non US populations.

“This genetic risk score could help identify people to take part in research studies, but is not opening a door to genetic testing for dementia risk in the clinic. For anyone concerned about dementia the first step is to visit your GP. If you’re looking for ways to reduce your risk, remember what’s good for your heart is good for your head, and it may be possible to lower your risk by staying active, eating well, and learning new skills.”

* ‘Genetic assessment of age-associated Alzheimer disease risk: Development and validation of a polygenic hazard score’ by Desikan et al. will be published in PLOS Medicine on Tuesday 21st March.

Declared interests

Prof. Morgan: “None.”

Dr Pickett: “None received”