October 7, 2021

expert reaction to study looking at the genetic risk for Alzheimer’s disease, brain structure and cognitive function

A study published in Neuropsychopharmacology uses UK Biobank data to look at association between polygenic risk for Alzheimer’s disease, brain structure and cognitive abilities.

Dr Byron Creese, Senior Lecturer in Neuroscience at the University of Exeter, said:

“This study identifies a link between genetic risk for Alzheimer’s disease and brain structure as well as performance on measures of attention and reasoning. Its key strength is its size – with more than 30,000 people, the authors were able to perform a careful analysis which means we can have greater certainty that the finding is not due to the influence of other factors.   

“However, it is notable that only attention and reasoning were assessed.  Memory is a key cognitive domain affected in Alzheimer’s disease so it would be interesting to examine these relationships in a broader range of computerised tests. 

“This study is cross-sectional – people were not followed up over time – so we don’t know anything about whether the people analysed went on to develop Alzheimer’s disease.  This is an important limitation; we don’t know if these brain changes and test performance are early signs of Alzheimer’s.  It could be that, in some people, genetic risk for Alzheimer’s disease affects brain structure and performance on computerised tests, but it does not meaningfully influence the person’s risk of developing the disease in future.”

Fiona Carragher, Director of Research and Influencing at Alzheimer’s Society said:

“If we can accurately identify people at risk of developing Alzheimer’s disease later in life, it could be a real gamechanger. Early detection of those at a higher risk has the potential to pave the way for new treatments in the future and help researchers understand what causes diseases like Alzheimer’s to develop.

“The scale of this study is significant. It adds further evidence to the theory that some brain changes associated with Alzheimer’s disease can start many years before symptoms such as memory loss. However, it only looked at people from a white European background – we need to better understand whether there are associations between different genetic risk factors and changes in the brain in people from other ethnic communities.

“Research will beat dementia, but we need more funding. The Government must honour their commitment to double dementia research funding to provide hope for future generations. We owe to the 850,000 people in the UK currently living with dementia.”

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

“The overall genetic risk of developing late onset Alzheimer’s disease (LOAD), as reflected in the polygenic risk score (PRS), has the potential to identify individuals at high risk of developing LOAD long before clinical symptoms emerge. This early identification of risk could markedly change management, enabling interventions that prevent or delay disease onset. Correlation with biomarkers of disease would provide a validation of PRS in assessing risk in asymptomatic individuals; disease biomarkers may include measures of substances in blood or cerebrospinal fluid, brain imaging parameters, and measures of cognition.

“Tank et al. calculated PRS for LOAD in 32,790 healthy UK Biobank participants for whom brain imaging and cognitive assessment data were available. They found that higher PRS, predicting increased risk of developing LOAD, associated with a smaller hippocampal volume and lower cognition scores, both known markers of LOAD risk. The findings demonstrate that higher LOAD PRS correlate with imaging and cognition biomarkers in healthy individuals, bolstering the case for using PRS to identify those most at risk of LOAD.

“While brain imaging is costly and interventional, and cognition testing laborious, measuring PRS is relatively simple and inexpensive. Measurement of LOAD PRS, either alone or in combination with blood markers, is thus well-suited to population screening and stratification for LOAD risk. Although therapeutic options for LOAD remain limited, early risk prediction might encourage individuals to adopt lifestyle changes reported to delay disease progression.” 

Dr Susan Kohlhaas, Director of Research from Alzheimer’s Research UK, said:

“We’re at a tipping point for dementia research and global advances improving the detection of early brain changes could help identify those who develop diseases earlier and enable doctors to deliver existing drugs to people at a time when they have most benefit.

“In this large study, scientists used a scoring system to estimate a person’s genetic risk of developing Alzheimer’s disease and linked it to markers of brain health in a group of healthy volunteers. These results raise the prospect of a genetic risk score that may be able to indicate early Alzheimer’s related brain changes before memory and thinking problems set in.

“While large studies like the UK Biobank are powerful tools for identifying factors like genes linked to markers of poorer brain health, this research was not able to tell if these brain changes underly the development of dementia.

“We hope that in future, research will help open the door to revolutionary new approaches to detect the diseases that cause dementia much earlier. This would have a huge impact on people with dementia and their families.”

Prof Derek Hill, Professor of Medical Imaging Science, UCL, said:

“It has been known for years that one single gene called APOE-e4 is a major risk factor for Alzheimer’s disease (AD).

“These researchers are using more than 32000 individuals from the UK Biobank volunteers to see whether an algorthmic combination of genes – so called polygenic risk score – can provide an even better predictor of who will get AD.

“The researchers looked at how well the polygenic risk score could predict brain structure and cognitive test results associated with AD – and they do find some predictive ability, but it isn’t clear how useful that would be in practice.

“The scale of the study is impressive. But the results do not demonstrate that the polygenic risk score could be used reliably to detect and – when suitable treatments are available – treat people at risk of AD. For that a very different study would be needed – it would be necessary to study people over time and see how well the risk score can predict people who actually develop and rapidly decline due to AD. And it would be necessary to show that the polygenic risk score works better than other tests like blood tests and brain imaging which are also promising approaches.”

Dr George Stothart, Lecturer, Department of Psychology, University of Bath, said:

“This work has significantly scaled up the sample sizes of previous studies examining the links between genetic risk scores and brain structure and function. It is a really concise and easy to follow piece of work that helps reinforce the idea that genes play a meaningful role in increasing our risk of developing dementia. In the future we may be able to use this information to make decisions about lifestyle modifications as we age, to help mitigate any increased genetic risk we may have.

“Showing that hippocampal atrophy is linked with genetic risk is an important link, the crucial next step is understanding how this affects brain function. Related to this point I was surprised to see that given the hippocampal link that memory performance did not also emerge as linked with genetic risk. It may be that in these healthy older adults memory performance has not yet begun to emerge behaviourally, but that would beg the question as to why deficits have emerged in other cognitive domains. It would be very interesting in future studies to focus on those cognitive functions dependent on healthy hippocampal function.”

Prof David Curtis, Honorary Professor, UCL Genetics Institute, said:

“This study reports a weak association between a genetic risk score for Alzheimer’s disease and some aspects of brain anatomy and function. This may reflect the possibility that some of the research subjects, who had an average age of 64, had some degree of dementia since no rigorous measures were taken to exclude subjects with dementia. The study does not demonstrate that these brain abnormalities exist in people who will go on to develop Alzheimer’s disease in the future. Nor does it show that the genetic risk score has any clinical utility in predicting who will develop Alzheimer’s disease because the association is simply too weak to be helpful. APOE genotype is a much better predictor of who will get Alzheimer’s disease than the genetic risk score. We have known about APOE for years but it does not have any practical applications at present. If effective drugs can be developed to prevent Alzheimer’s disease then in future it will be helpful to identify high risk individuals so that they can be treated. APOE may well be helpful for this, as will be the measurement of blood markers for preclinical disease, but the potential value of genetic risk scores is less clear.”

‘Association between polygenic risk for Alzheimer’s disease, brain structure and cognitive abilities in UK Biobank’ by Rachana Tank et al. was published in Neuropsychopharmacology at 00:01 UK time on Thursday 7 October.

DOI: https://doi.org/10.1038/s41386-021-01190-4

Declared interests

Dr Susan Kohlhaas: “No conflicts.”

Prof Derek Hill: “No conflicts of interest.”

Dr George Stothart: “No competing interests or declarations.”

Prof David Curtis: “I declare no conflict of interest.”

None others received.