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 g-secretase complex involved in b-amyloid precursor protein (AbPP) processing. Usually Alzheimer's disease (AD)-linked mutations in the PSEN-1 gene lead to early onset and increase the production of the aggregation-prone peptide Ab42. However, the PSEN-1 E318G variant has an unclear pathogenic role, and was 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 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 Ab42, t-tau and p-tau, plasma Ab42 and Ab40 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 (Ab42, t-tau, p-tau and amyloid peptides) of asymptomatic E318G carriers in 2010 and 2012, but plasma Ab40 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.