The pathogenicity ofPSEN2variants is tied to Aβ production and homology toPSEN1

ABSTRACT INTRODUCTION Though recognized as a potential cause of Autosomal Dominant Alzheimer’s Disease, the pathogenicity of many PSEN2 variants remains uncertain. We compared Aβ 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 homologous PSEN1 variants with the same amino acid substitution, in HEK293 cells lacking PSN1/2. Aβ production was compared to age at symptom onset (AAO) and between homologous PSEN1/2 variants. RESULTS Aβ42/40 and Aβ37/42 ratios were associated with AAO across PSEN2 variants, strongly driven by PSEN2 variants with PSEN1 homologs. PSEN2 AAO was 18.3 years later compared to PSEN1 homologs. Aβ ratios from PSEN1 / 2 homologs were highly correlated, suggesting a similar mechanism of γ-secretase dysfunction. DISCUSSION The existence of a PSEN1 homolog and patterns of Aβ production are important considerations in assessing the pathogenicity of previously-reported and new PSEN2 variants.