Early-onset Alzheimer's disease (EOAD) accounts for 1%-2% of all Alzheimer's 
disease (AD) subjects, with large variation in the reported genetic contribution 
of known dementia genes. In this pilot study, we genetically characterized a 
German EOAD cohort (23 subjects) by whole-exome sequencing, capturing variants 
in all recognized AD and frontotemporal dementia genes. After variant filtering, 
we identified 7 events of altogether 6 different rare variants in 6 subjects, 
including 4 novel variants. Four of the 6 variants, observed in 5 different 
index subjects (5/23 = 22%), were considered to be possibly pathogenic. These 
included 2 presenilin 2 (PSEN2) variants (p.N141I-previously denoted as a Volga 
German variant, observed in 2 index subjects; and p.L238P), 1 amyloid precursor 
protein (p.I716M), and 1 presenilin 1 (ΔE9). Using a control exome data set of 
96 ethnically matched neurodegenerative disease controls (Parkinson's disease), 
we identified only 1 variant (PSEN2 p.T18M) (1%), demonstrating a significantly 
higher mutational burden in the EOAD group (p > 0.0001). Our findings 
demonstrate a substantial frequency of variants in dementia genes in EOAD, 
including several seemingly "sporadic" subjects. This indicates that 
heritability in EOAD might be higher than assumed. The finding of 3 subjects 
carrying potential pathogenic PSEN2 variants suggests that, in specific 
populations PSEN2 variants might be as frequent as (or more frequent than) 
presenilin 1, for example, in German populations which are influenced by Volga 
German heritage. Variants in AD genes were also associated with rare phenotypes 
such as frontal AD or primary progressive aphasia, demonstrating the need to 
screen AD genes in frontotemporal dementia-like phenotypes.