The pathogenicity ofPSEN2variants is tied to Aβ production and homology toPSEN1

Abstract

ABSTRACTINTRODUCTIONThough recognized as a potential cause of Autosomal Dominant Alzheimer’s Disease, the pathogenicity of manyPSEN2variants remains uncertain. We compared Aβ production across all missensePSEN2variants in the Alzforum database and, when possible, to correspondingPSEN1variants.METHODSWe expressed 74PSEN2variants, 21 of which had homologousPSEN1variants with the same amino acid substitution, in HEK293 cells lacking PSN1/2. Aβ production was compared to age at symptom onset (AAO) and between homologousPSEN1/2variants.RESULTSAβ42/40 and Aβ37/42 ratios were associated with AAO acrossPSEN2variants, strongly driven byPSEN2variants withPSEN1homologs.PSEN2AAO was 18.3 years later compared toPSEN1homologs. Aβ ratios fromPSEN1/2homologs were highly correlated, suggesting a similar mechanism of γ-secretase dysfunction.DISCUSSIONThe existence of aPSEN1homolog and patterns of Aβ production are important considerations in assessing the pathogenicity of previously-reported and newPSEN2variants.