Perry DC, Lehmann M, Yokoyama JS, Karydas A, Lee JJ, Coppola G, Grinberg LT, Geschwind D, Seeley WW, Miller BL, Rosen H, Rabinovici G.
Progranulin mutations as risk factors for Alzheimer disease.
JAMA Neurol. 2013 Jun 1;70(6):774-8.
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These are very interesting data, adding to the many cases of potential pleiotropy that we are starting to see more often by applying next-generation sequencing to the study of neurodegenerative diseases.
Before the availability of these technologies, sequencing would be performed only in the genes known to be associated with a specific clinical picture. Now what we are seeing is that some of these cases have mutations in genes that haven't been directly associated with that specific clinical entity, but rather with a similar disease, in this case, another form of dementia.
The early age at onset for these cases (especially case 2) makes it less probable that AD is co-occurring with FTD just by chance, and suggests the existence of common molecular pathways between FTD and AD. We can easily establish a parallel with TREM2 or C9ORF72. In the TREM2 gene, homozygous mutations were initially identified to cause Nasu-Hakola disease; later, the same types of mutations were found to cause FTD without any bone symptoms and, more recently, heterozygous variants were shown to increase the risk for AD. Similarly the expansion on C9ORF72 was initially found in cases diagnosed with ALS, FTD, or ALS/FTD, providing genetic evidence that these diseases are most likely part of a pathological spectrum.
Interestingly, TREM2 is also involved in inflammatory processes, and the roles of microglia and inflammatory cellular status are becoming more central as molecular pathological pathways for different dementias.
These results clearly stress the importance of taking a non-restrictive approach to the screening of genetic variants, which can now be achieved by using targeted sequencing panels or exome/genome sequencing. The identification of more cases like these will allow the study of previously unrecognized associations between genetic variability in the different genes involved in these disorders.
Perry et al. have identified two patients with Alzheimer’s disease (AD) pathology who also have a mutation in the progranulin (GRN) gene. This is an extremely important finding, considering that the GRN mutations are known to cause the autosomal-dominant form of frontotemporal dementia (FTD) through the haploinsufficiency of functional progranulin. This observation is consistent with previous work, which has suggested that certain variants of GRN, such as SNP rs5848, increase the risk of AD in different AD cohorts. Thus, it is possible that the mutations/variants in GRN may also play a role as risk factors in AD. However, that both patients also harbored the ApoE4 allele, which is the most prominent genetic risk factor for AD, emphasizes the importance of conducting further studies before making firm conclusions about GRN in AD.