Alzheimer's disease - a paradigm for personalised prevention?

Corinna Alberg

28 July 2015

Alzheimer’s Disease (AD) is a very pressing health problem with a growing impact on society as the population ages. One person in three over the age of 85 will develop AD, creating far-reaching health and social care needs. The impact on carers, who are often elderly themselves, is enormous. The economic costs of providing medical care, social support and respite care are also considerable. 

At present, there is no cure or even effective treatment for AD. Current treatments help to mask symptoms, but do not treat the underlying disease or delay its progression. That is why the hope of a new drug – Eli Lilly’s Solanezumab - that can apparently slow the decline of the disease in those who are treated early in the course of the disease has caused so much excitement. 

The clinical trial

In two large clinical trials, Solanezumab was found to be no more effective than the placebo, but when the data was re-analysed looking at the results in a subset of the patients, those with mild AD, there was a modest but robust effect observed from the drug. One group of patients with mild AD received the drug 18 months earlier than another, and this group showed slower progression of the disease than the group who received a placebo for the first 18 months, before being switched to Solanezumab.  The differences in symptoms between the two groups were small but they suggest that treatment in the earlier stages of disease has the greatest effect.

The trial is still ongoing and will next report in early 2017, so the excitement of these preliminary results should be tempered until it is possible to make firmer conclusions on the true importance of this drug. 

Implications of the trial

There are a number of issues that this trial highlights.  Firstly, the desperate plight of patients and their families, illustrated by the fact that the possibility of even a relatively minor alleviation of disease progression can cause so much excitement, and even calls for the treatment to be made available immediately. Secondly, the trial seems to strengthen the amyloid cascade hypothesis of AD;  Solanezumab is an anti-amyloid monoclonal antibody that binds to the amyloid-beta peptide and is thought to increase clearance of soluble amyloid-beta. This may help focus further therapeutic discovery and development efforts.

Genomic testing for susceptibility to Alzheimer’s ?

Possibly of greatest interest for personalised medicine and personalised prevention is the contribution that genomic testing could potentially make in identifying those individuals most able to benefit from treatments (such as Solanezumab) effective in slowing the disease from early onset. This study underlines the importance of early intervention to make an impact on the progression of AD or ultimately stop or reverse the damage to the brain as seen in this study -  Solanezumab had no effect in those with moderately advanced disease.

 There are two main forms of AD – familial (inherited) disease, which accounts for around 5% of those diagnosed with AD. This occurs under the age of 65 and there are a number of genes that are highly predictive of developing this form of AD. Testing for familial AD is feasible and can predict those likely to develop the condition with a fairly high degree of accuracy. The vast majority of AD cases, in contrast, are late onset and seem to have multi-factorial causes with a variety of genetic, lifestyle and environmental factors underlying the development of the disease.  

Testing for late onset Alzheimer’s disease susceptibility genes

A number of genetic variants have been linked with increased risk of developing late onset AD, but the most predictive is the presence of the relatively common APOE4 variant. One APOE4 variant confers a three-fold  increased risk of developing AD, while two copies create  a twelve-fold increased risk. The presence of the APOE4 alleles also correlates with a typically earlier age of disease onset. 

Until now, there were overwhelming arguments against APOE4 genetic testing as a susceptibility test for AD , because of the lack of treatments available for pre-symptomatic or early-stage AD patients. Moreover, the presence of one or more APOE4 variants, whilst increasing risk, by no means guarantees that a person will actually go on to develop AD. However, if a treatment was to become available that was only effective if received  in the early stages of the disease - as this study suggests may well be the case for Solanezumab -  the potential benefits of knowing one’s risk for developing AD might then outweigh  the harms.  Those at greatest risk could be monitored more closely for preclinical signs of AD, where subtle cognitive alterations are detectable years prior to clinical symptoms becoming apparent. While this might cause anxiety, for many the potential ability to delay the clinical symptoms of AD would far outweigh the distress caused by pre-symptomatic testing and monitoring.  

The emergence of new treatments means that we may need to re-evaluate accepted positions on the utility of predictive genetic testing. This evolving situation for AD may also to hold for a wide range of other conditions as new or improved treatments, including drug and gene therapies, become available – thanks to our growing understanding of genomic and other molecular pathways.