Genetic research has brought a “cure for Alzheimer’s a step closer”, according to The Times , which said scientists have found two genetic mutations that could be the cause of more than one-in-five cases of Alzheimer’s disease.
There is already a known association between the APOE gene and late-onset Alzheimer’s disease but the separate French and British studies have confirmed that a new genetic variant on chromosome 8, near the ‘CLU gene’ is associated with the risk of Alzheimer’s disease. This gene contains the code to produce an apolipoprotein, a molecule combining a protein and a fat. The studies also identified associations with two separate gene variants. Overall, these were robust, well-conducted studies.
Alzheimer’s disease is a complex disorder and the variations discovered by these studies are not responsible for all cases of the disease. Equally, having the variants does not mean that a person will get the disease, simply that their risk is increased. These discoveries may one day be applied to the screening and diagnosis of Alzheimer’s disease and may be early steps towards trials using general anti-inflammatory medication or treatments specifically targeting the disease.
Two separate studies published in the peer-reviewed medical journal Nature Genetics have assessed the association between gene variants and late-onset Alzheimer’s disease. The first was by French researchers Dr Jean-Charles Lambert and Philippe Amouyel and international colleagues affiliated to a number of academic and medical institutes across France. The study was supported by France’s National Foundation for Alzheimer’s Disease and Related Disorders, the Institut Pasteur de Lille and the Centre National de Génotypage.
The British research was conducted by Drs Denise Harold and Julie Williams and several colleagues from academic and medical institutions across the UK and Europe. The researchers were supported by a number of sources including The Wellcome Trust, the Medical Research Council and the Alzheimer’s Research Trust.
Scientists have previously found an association between a gene known as APOE - which is located on chromosome 19 - and late-onset Alzheimer’s disease. APOE is responsible for the production of an apolipoprotein, a type of protein that binds to fat. To date this is the only gene that has been linked to late-onset Alzheimer’s disease, although others have been linked to early-onset Alzheimer’s disease. Alzheimer’s is the most common form of dementia affecting around 5% of people aged 65 years or older.
To investigate the role that other genes might play in Alzheimer’s disease, French and British scientists carried out genome-wide association studies, comparing the genes of people with Alzheimer’s disease to those who do not have the illness. The British study included an initial sample of 11,789 people from across the world, 3,941 of whom had Alzheimer’s disease and 7,848 did not. The genetic sequences of all individuals were analysed in an attempt to identify variations that were more common in people with Alzheimer’s disease. The researchers analysed over 500,000 separate gene variants for their association with the disease.
In a second stage of their experiment, the researchers wanted to confirm any associations they had found by analysing the genetics of a separate international sample of 2,023 people with Alzheimer’s disease and 2,340 age-matched people who did not have disease.
The French study analysed the genetic sequences of 2,032 people with Alzheimer’s disease and compared them to those of 5,328 control subjects from France, as well samples from 3,978 Alzheimer’s patients and 3,297 control subjects from across Europe.
In addition to the known association with the APOE region on chromosome 19, the British study found two new variants that were much more common in people with late-onset Alzheimer’s disease. These variants were located near the CLU gene on chromosome 8 and near the PICALM gene on chromosome 11, and were called rs11136000 and rs3851179 respectively. These associations were confirmed in the second stage of their experiment and each of the variants was independently associated with disease.
The researchers go on to discuss the possible links that these variations have with functional genes. Like the APOE gene, one of the variants they found codes for is another major brain apolipoprotein, called clusterin. The others, the variant near the CR1 gene and that near the PICALM gene are involved in protein binding and the movement of proteins and fats in cells, respectively.
The French study had similar findings, identifying a strong association with gene variants within the APOE gene regions and also recognising two other regions that were significantly associated with Alzheimer’s, including one that was also identified in the British study. These gene variants included the CLU gene on chromosome 8 (including rs11136000) and variants in the CR1 region on chromosome 1.
The British researchers say there is compelling evidence of an association between the two gene variants they identified and Alzheimer’s disease.
The French researchers say that in addition to the previously known APOE region, they have identified two other regions at CR1 and CLU that are possibly associated with the risk of late-onset Alzheimer’s disease.
These two well-conducted genome-wide association studies have similar findings, both identifying a variant called rs11136000 on chromosome 8 near the CLU gene. Both studies estimated the population attributable risk fraction to be 8.9%, meaning if the risk factor (the variant) were removed from the population it would reduce incidence of the disease by about 9%.
The British study found other gene variants linked to Alzheimer’s: one near the PICALM gene on chromosome 11 and another near the CR1 gene on chromosome one. The French study confirmed the association with CR1.
Studies such as this are important and may contribute towards the development of screening tests for Alzheimer’s disease. Importantly though, having the variants does not guarantee disease, but only increases the risk of going on to develop the condition. Alzheimer’s disease is a complex illness that is likely to have many causes and the results from further genome-wide association studies may overturn other significant associations.
Both of the studies confirmed their findings in separate populations and the findings are reliable. How they will translate into diagnostic benefits remains to be seen, and any treatment benefits mentioned in newspaper reports and press releases will be several years away. The researchers say that larger, additional genome-wide association studies may be required to identify remaining susceptibility variants for Alzheimer’s disease.