The pathogenicity of PSEN2 variants is tied to Aβ production and homology to PSEN1

INTRODUCTION: Though recognized as a potential cause of autosomal dominant Alzheimer's disease, the pathogenicity of many PSEN2 variants remains uncertain. We compared amyloid beta (A beta) production across all missense PSEN2 variants in the AlzForum database and, when possible, to corresponding PSEN1 variants. METHODS: We expressed 74 PSEN2 variants, 21 of which had known, homologous PSEN1 pathogenic variants with the same amino acid substitution, in HEK293 cells lacking presenilin 1/2. A beta production was compared to age at symptom onset (AAO) and between PSEN1/2 homologs. RESULTS: A beta 42/40 and A beta 37/42 ratios correlated with AAO across all PSEN2 variants, strongly driven by the subset of PSEN2 variants with PSEN1 homologs. A beta production across PSEN1/2 homologs was highly correlated. PSEN2 AAO correlated with AAO in PSEN1 homologs but was an average of 18.3 years later. DISCUSSION: The existence of a PSEN1 homolog and patterns of A beta production are important considerations in assessing the pathogenicity of previously reported and new PSEN2 variants.