Asymptomatic carriers of presenilin-1 E318G variant show no cerebrospinal fluid biochemical signs suggestive of Alzheimer's disease in a family with late-onset dementia.

Background: Presenilin-1 (PSEN-1) is a component of the gamma-secretase complex involved in beta-amyloid Precursor Protein (A beta PP) processing. Usually, Alzheimer's disease (AD)-linked mutations in the PSEN-1 gene lead to the early onset and increase the production of the aggregation-prone peptide A beta 42. However, the PSEN-1 E318G variant has an unclear pathogenic role and is recently reported as a genetic risk factor for AD. In particular, E318G variant presence correlated with increased cerebrospinal fluid (CSF) levels of Total Tau (t-tau) and Phosphorylated Tau (p-tau). Objective: We describe a large Italian family, which we followed from January 2003 to January 2018, with the late-onset AD and the E318G variant, with the aim of assessing E318G-associated CSF or plasma biochemical changes in biomarkers of dementia. Method: CSF A beta 42, t-tau and p-tau, plasma A beta 42 and A beta 40 were assessed by ELISA tests, while CSF amyloid peptides profile was investigated by mass spectrometry. Results: We did not find any changes in CSF biochemical markers (A beta 42, t-tau, p-tau and amyloid peptides) of asymptomatic E318G carriers in 2010 and 2012, but plasma A beta 40 was increased at the same times. From 2003 to 2018, no asymptomatic E318G carrier developed AD. Conclusion: Our follow-up of this family may help elucidate E318G's role in AD and globally points to a null effect of this variant.