Reacción a "Reactions: Spanish researchers propose new genetic form of Alzheimer's disease"

What do you think of the study?  

‘It is a solid study, the result of an exhaustive work carried out on a large number of patients for whom a very important and systematised amount of biochemical, genetic and clinical information was available. This makes the results of high interest per se, irrespective of their interpretation (which is also the case). One of the fundamental limitations in the study of even the most common diseases lies in the difficulty of having well-characterised patient cohorts of sufficient size for the findings to be statistically significant. The latter is very important; a finding can be anecdotal and the scientific method establishes a working methodology that serves to discriminate the anecdotal from the general and thus advance knowledge.  

How does it fit with the existing evidence and what is new about it?  

‘That the E4 allele is a factor related to Alzheimer's disease (AD) is not new in itself. We have known for more than 30 years that having one or two E4 alleles in our genome increases the risk of developing AD in later life. Furthermore, we knew that the number of copies of the E4 allele (1 or 2) was related to the age at which the disease appears, earlier with two copies than with one, and also to the number of characteristic AD lesions, the senile plaques. Individuals with two alleles had more of these lesions (called senile plaques). In other words, we knew that having two alleles was ‘bad’ from the point of view of AD development. But there were cases of individuals with two copies of the bad allele who did not develop AD despite living to very old ages, which seemed to support the idea that the E4 allele of APOE was a risk factor, i.e. a predisposing factor for the disease but not its cause. 

This work, through the analysis of a large number of patients, demonstrates that having two copies of the E4 allele can be considered a new genetic form of AD, adding to the already known forms caused by genetic variants. In other words, APP, PSEN1 and PSEN2 are added as genes responsible for familial forms of AD. In other words, it aims to change the existing paradigm in which having two copies of the E4 allele increased the probability of having AD to a new one in which having these two copies implies developing the disease with certainty. 

This should be taken with some caution as there are still a number of individuals who do not follow this direct relationship: individuals who have two copies of the E4 allele but who neither develop the disease nor show signs of developing it. In other words, the existence of individuals homozygous for the E4 allele without AD seems to run counter to the conclusion reached in the previous paragraph. However, contrary to the generally held perception, being a carrier of a genetic variant that causes a disease does not always mean that the disease will manifest itself. There are many genetic diseases in which certain carriers of the disease-causing variant escape the disease. This, known as reduced penetrance, cannot be ruled out in these cases.   

Are there any important limitations to consider?  

‘The article does not include the degree of familial aggregation that this phenotype may have, i.e. it does not answer the question to what extent this disease runs in families. The frequency with which the E4 allele appears in the population is sufficient for more individuals with the same disease to appear in several of the families to which the individuals studied by the authors and carriers of the E4 allele belong. On the other hand, there are families with late-onset AD in which certain affected individuals are homozygous for the E4 allele while others are heterozygous. In other words, the disease appears with a certain independence of phenotype. 

But what may be the main limitation of the study is that it establishes a causal relationship between being a carrier of two alleles of the APOE gene and the appearance of AD, but ignores the fact that a person's genome contains some 20,000 variants with respect to the reference genome and that, overall, there are some 3,000,000 positions in the genome (out of the 3,000 million bases contained in the human genome) where genetic variants may exist, some of which could contribute in part to the effect observed. This is not to deny what is a clear and indisputable result of the study, that having two copies of the E4 allele results in an earlier onset of AD and with biomarker levels also reaching abnormal levels earlier than those without any copies of this allele, and that this effect resembles that seen in familial forms, but I think it is unclear to what extent it can be considered a causal factor. Especially since there are other genetic variants in the region where APOE is located which also seem to influence the onset of the disease and which are often associated with the E4 allele.  

In conclusion, this work represents a clear advance in the study of the causes of AD as it puts the focus on a cause that, although it had not been ignored until now, had not received the attention that it was possibly necessary for the development of new therapies and also for the design of the therapeutic trials that could be carried out, given that what until now was considered as just another variable should be considered, in the light of these results, as a criterion for defining the groups and the strategies to be applied’.