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Desikan RS, Schork AJ, Wang Y, Witoelar A, Sharma M, McEvoy LK, Holland D, Brewer JB, Chen CH, Thompson WK, Harold D, Williams J, Owen MJ, O'Donovan MC, Pericak-Vance MA, Mayeux R, Haines JL, Farrer LA, Schellenberg GD, Heutink P, Singleton AB, Brice A, Wood NW, Hardy J, Martinez M, Choi SH, DeStefano A, Ikram MA, Bis JC, Smith A, Fitzpatrick AL, Launer L, van Duijn C, Seshadri S, Ulstein ID, Aarsland D, Fladby T, Djurovic S, Hyman BT, Snaedal J, Stefansson H, Stefansson K, Gasser T, Andreassen OA, Dale AM. Genetic overlap between Alzheimer's disease and Parkinson's disease at the MAPT locus. Mol Psychiatry. 2015 Feb 17; PubMed.
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University of Eastern Finland
Based on the stepwise pleiotropic approach, Desikan et al. identified an SNP (rs393152) in the MAPT gene region that affected the risk of both PD and AD. Further investigations revealed that the observed pleiotropy between AD and PD was non-polygenic and most likely linked to the MAPT locus. Importantly, this pleiotropic locus associated with increased MAPT transcript expression levels and augmented brain atrophy at the hippocampus and entorhinal cortex, particularly among the ApoE epsilon 4 non-carriers. This is a very important study, which emphasizes the potential genetic overlap between AD and PD at the MAPT locus via altered expression of tau.
Although this study suggests shared pathology between AD and PD at the MAPT locus, it still possible that some other gene at the chromosome 17 locus could be responsible for the observed genetic association with AD. However, given the well-established role of tau in neurodegenerative disease, it is plausible that the observed results are actually mediated through MAPT-related mechanisms. As further support for this, the pleiotropic variant in MAPT tags the H1 haplotype, which has been previously associated with several tauopathies, such as corticobasal degeneration or progressive supranuclear palsy. It is also important to note that the present study successfully applied the use of hippocampal and entorhinal cortex atrophy rates as endophenotypes in the identification of AD-associated risk variant. Finally, this study sets the basis for future studies in which large GWAS data and a pleiotropic framework can be applied to the identification of novel AD-associated risk variants and their relationships between various neurodegenerative diseases.
Mayo Clinic, Jacksonville
The stepwise gatekeeper approach to uncover genetic overlap (pleiotropy) between AD and PD implemented in this study by Desikan et al. detected a single, study-wide, statistically significant association at the MAPT locus. Meta-analysis of five independent AD case-control cohorts achieved highly significant association, providing convincing evidence that genetic variation in MAPT plays a role in risk not only for PD, but also for AD. In this article, the authors also demonstrate that a MAPT variant in tight linkage disequilibrium with the top PD GWAS hit associates with increased risk of AD, increased levels of MAPT expression in brain, and increased atrophy in two medial temporal lobe regions that are selectively affected by neurofibrillary tangle pathology in the earliest stages of AD. Although these results are not entirely surprising given previous reports that show association of MAPT variants with AD risk and with MAPT gene expression (Allen et al., 2014), the study by Desikan et al. provides validation of the latter findings and implicates these associations in AD neurodegeneration.
References:
Allen M, Kachadoorian M, Quicksall Z, Zou F, Chai HS, Younkin C, Crook JE, Pankratz VS, Carrasquillo MM, Krishnan S, Nguyen T, Ma L, Malphrus K, Lincoln S, Bisceglio G, Kolbert CP, Jen J, Mukherjee S, Kauwe JK, Crane PK, Haines JL, Mayeux R, Pericak-Vance MA, Farrer LA, Schellenberg GD, Parisi JE, Petersen RC, Graff-Radford NR, Dickson DW, Younkin SG, Ertekin-Taner N. Association of MAPT haplotypes with Alzheimer's disease risk and MAPT brain gene expression levels. Alzheimers Res Ther. 2014;6(4):39. Epub 2014 Jul 1 PubMed.
Icahn School of Medicine at Mount Sinai
The major caveat of this paper is that the AD cases in all of the datasets used are not pathologically confirmed (i.e., the AD case status is assigned based solely on clinical diagnosis). This, combined with the fact that the association of the “Tau” SNP was dependent on the absence of the APOE4 allele, makes me wonder whether the “Tau” SNP association could be driven by misdiagnosis of other dementias. Indeed, the vast majority of APOE4 carriers with clinical diagnosis of AD dementia also have demonstrable Aβ deposition by PiB or autopsy. On the other hand, a sizable fraction of APOE non-carriers with clinical diagnosis of AD dementia are misdiagnosed, since they don’t show beta amyloidosis by PiB or autopsy. Therefore, validation of this finding with an independent PiB or autopsy-confirmed AD cohort is warranted.
View all comments by Edoardo MarcoraThis is a helpful comment. We did actually use a small cohort of autopsy-confirmed AD cases/controls to confirm our findings (see Discussion and Supplemental information from our paper). In this small cohort of autopsy-confirmed AD cases and controls, we replicated the directionality and magnitude of the A allele of rs393152 (Supplementary Figure 5) indicating that our AD-associated findings are not due to misdiagnosis from other dementias.
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