Mutational Landscape of Alzheimer's Disease and Frontotemporal Dementia: Regional Variances in Northern, Central, and Southern Italy

Abstract

Alzheimer's Disease (AD) and Frontotemporal Dementia (FTD) are the two major neurodegenerative diseases with distinct clinical and neuropathological profiles. The aim of this report is to conduct a population-based investigation in well-characterized APP, PSEN1, PSEN2, MAPT, GRN, and C9orf72 mutation carriers/pedigrees from the north, the center, and the south of Italy. We retrospectively analyzed the data of 467 Italian individuals. We identified 21 different GRN mutations, 20 PSEN1, 11 MAPT, 9 PSEN2, and 4 APP. Moreover, we observed geographical variability in mutation frequencies by looking at each cohort of participants, and we observed a significant difference in age at onset among the genetic groups. Our study provides evidence that age at onset is influenced by the genetic group. Further work in identifying both genetic and environmental factors that modify the phenotypes in all groups is needed. Our study reveals Italian regional differences among the most relevant AD/FTD causative genes and emphasizes how the collaborative studies in rare diseases can provide new insights to expand knowledge on genetic/epigenetic modulators of age at onset.

Keywords: APP; Alzheimer’s Disease; C9orf72; Frontotemporal Dementia; GRN; MAPT; PSEN1; PSEN2; gene; mutation.

Figure 1

Frequency of each of the six genetic groups APP, PSEN1, PSEN2, MAPT, GRN, and C9orf72 in the combined dataset of this study (a), in the Northern (b), in the Central (c), and in the Southern cohort (d) (p < 0.0001, Chi-square test).

Figure 2

Violin plots of age at onset for the six genetic groups APP, PSEN1, PSEN2, MAPT, GRN, and C9orf72 (p < 0.0001, Linear Mixed Model).