In this study the diagnosis of AD and PD was based on clinical evaluations, without histopathological confirmation. Post-mortem evidence indicates the co-occurrence of α-synuclein, tangle and amyloid pathology. 44 Therefore, one concern is that concomitant Parkinson’s pathology may have contributed to our MAPT associated effect in AD. In a small cohort of autopsy confirmed AD cases and controls, we replicated the directionality and magnitude of the A allele of rs393152 (Supplemental Figure 5) indicating that our AD-associated findings are not due to concomitant PD pathology. Furthermore, building on prior genetic work 45, among APOE ε4 non-carriers, we found a stronger relationship between rs393152 and both gene expression levels and medial temporal lobe atrophy (Figure 5) suggesting that MAPT may predominantly influence Alzheimer’s neurodegeneration in a smaller subset of individuals who do not possess APOE ε4 alleles. As a caveat, we note that since we primarily evaluated summary statistics from the discovery and replication cohorts, additional work with raw genotype data is needed to determine whether the AD-associated MAPT effect varies based on APOE ε4 carrier status. Another concern is the
