Lack of APOE Christchurch variant in five age of onset outliers with PSEN1, PSEN2 Alzheimer's disease and MAPT frontotemporal dementia

Abstract

Introduction: Age of onset modifiers are of considerable importance in Alzheimer's and related dementias. Arboleda-Valesquez et al., reporting on a single PSEN1 subject, suggested that homozygosity for the Christchurch variant of APOE could represent such a modifier.

Methods: We studied APOE Christchurch and Kloth-VS genotypes of five dementia age of onset outliers who carried their families' pathogenic variant, but were asymptomatic at ages beyond the families' average age of onset.

Results: Four age of onset outliers with PSEN1/2 and MAPT mutations did not carry the Christchurch variant and a fifth individual was also determined to not be homozygous for this variant. Among them, only one subject (APOE ε3/ε3) carries the Klotho-VS heterozygous genotype.

Discussion: From a small but informative sample of five age of onset outliers we show that neither the APOE Christchurch nor the Klotho-VS variant is a common age of onset modifier for three genetic forms of dementia. Larger studies of this association and further research is required to identify additional genetic modifiers.

Keywords: APOE; Alzheimer's disease; Christchurch mutation; Dementia; Modifiers.