This mode of pathogenicity may also explain the (familial) AD observed for the carriers of the p.R953H and the p.R953C ‘Seattle variant’ affecting YWTD-domain folding, for which functional studies have shown impaired trafficking [20], and the p.G511R variant, suggesting impaired binding of Amyloid-β to SORL1 [44, 54]. The gene discussed is SORL1; the disease is Alzheimer disease.