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

The study is of very high quality. On the one hand, it involves a large collaborative effort, with five large clinical cohorts and one cohort with anatomopathological data (autopsy evidence of Alzheimer's disease), which is not easy. On the other hand, taking on the idea of autosomal semi-dominant inheritance, gathering a population of this size to demonstrate it (the percentage of e4 homozygotes in the general population is very low) and giving it the appropriate statistical approach (as if it were hereditary Alzheimer's disease) reflect an undeniable originality, tenacity, scientific quality and capacity for effort. 

The fact that e4 homozygotes have a very high probability of Alzheimer's is nothing new, we have known it for years and we see it in our practices. Until now, there were no data on large population sizes (as they have a low frequency, in the usual studies they are analysed jointly with heterozygotes, with the population analysed in this study this is exceeded) nor were the data analysed with the necessary approach to assess this aspect (this is the most original aspect of the study, how they approach the problem and carry out the analyses with the strategy of hereditary Alzheimer's cases). The study provides solid evidence to change the conceptual framework: we move from thinking of e4 homozygotes as a risk factor to considering it as a determinant of the disease.  

The implications are important. We are entering an era in which drugs with a potential disease-modifying effect on Alzheimer's disease are beginning to arrive, fundamentally on cerebral amyloid accumulation, which is universal in e4 subjects and an early phenomenon (as early as the 40s). Perhaps, in the near future, these subjects may be candidates for population screening to treat them from a very early age, avoid this accumulation of beta-amyloid and delay/prevent the disease. In addition, there is preliminary evidence of drugs that can block the effect of ApoE e4, making them an ideal population to test.  

The main limitation of the study is already mentioned by the authors in the article. It is a cross-sectional study, bringing together different cohorts, which gives heterogeneity. In addition, there is an overrepresentation of subjects of European-Caucasian origin, which limits the extension of these findings to other populations (it is known that the effect of ApoE is different between races or human populations). Longitudinal population-based studies are needed to confirm these findings.