The pathogenicity of <i>PSEN2</i> variants is tied to Aβ production and homology to <i>PSEN1</i>

There were associations between the patterns of amyloid beta (Aβ) production across presenilin 2 (PSEN2) variants and age at symptom onset (AAO). PSEN2 variants for which there is a known, corresponding variant in presenilin 1 (PSEN1) are more likely to have abnormal Aβ production patterns that strongly correlate with AAO, compared to those that lack a known PSEN1 counterpart ("non-homologous PSEN2 variants"). Most PSEN2 variants lacking PSEN1 counterparts had Aβ42/40 ratios close to those of wild-type PSN2, arguing against their pathogenicity. Homologous PSEN1 and PSEN2 variants had correlated Aβ42/40 and Aβ37/42 ratios, indicating that the corresponding amino acid substitution in each presenilin may have largely similar biochemical effects on γ-secretase processivity.