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

INTRODUCTIONThough recognized as a potential cause of Autosomal Dominant Alzheimers Disease, the pathogenicity of many PSEN2 variants remains uncertain. We compared A{beta} production across all missense PSEN2 variants in the Alzforum database and, when possible, to corresponding PSEN1 variants. METHODSWe expressed 74 PSEN2 variants, 21 of which had homologous PSEN1 variants with the same amino acid substitution, in HEK293 cells lacking PSN1/2. A{beta} production was compared to age at symptom onset (AAO) and between homologous PSEN1/2 variants. RESULTSA{beta}42/40 and A{beta}37/42 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. A{beta} ratios from PSEN1/2 homologs were highly correlated, suggesting a similar mechanism of {gamma}-secretase dysfunction. DISCUSSIONThe 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.