A recent study51 to assess the function of SMPD3 in AD-related pathology, using a 5xfad;fro-/- double mutant mouse52, is incompatible with the study reported here, using the unbiased smpd3-/- mutant, as substantiated by the high postnatal lethality of the fro-/- mutant compared with the extended lifespan (>20%) of the smpd3-/- mouse mutant and by the contrasting skeletal phenotypes of the fro-/- and smpd3-/- mutants19. The gene discussed is SMPD3; the disease is Alzheimer disease.