Kovacs et al. report that autopsy-confirmed cases of amyloid-β predominant Alzheimer’s disease neuropathologic change (AP-ADNC)—marked by severe/widespread amyloid-β plaques but no/mild tau tangles—differ in clinical and genetic features from classical ADNC (amyloid-β and tau), with implications for in vivo studies. Here, MAPT is linked to early-onset autosomal dominant Alzheimer disease.