A genome-wide investigation of clinicopathologic endophenotypes uncovers a new susceptibility locus for tau pathology at Neurotrimin (NTM).

We have identified two new ADRD susceptibility variants using an endophenotype approach. NTM is highly expressed in all astrocytic subtypes and OPCs based on single nucleus RNA sequencing; it has previously been implicated in neurite outgrowth. The UNC5C variant helps to orient this previously AD-associated locus (via a rare coding variant) towards CAA as a potential mechanism by which the locus affects syndromic manifestations of AD. It also illustrates the utility of the endophenotype approach to uncover allelic heterogeneity at known loci which extends our understanding of AD susceptibility. The gene is widely expressed but is enhanced in one subtype of glutamatergic and multiple subtypes of GABAergic neurons. These loci identify new targets that expand the range of potential therapeutic targets.