Abstract

Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD) are the two most common neurodegenerative diseases leading to early onset dementia (< 65 years). Mutations in the amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) genes cause a proportion of familial early-onset AD (eoAD), while the microtubule-associated protein tau (MAPT) and progranulin (PGRN) mutations have been identified in FTLD patients. Only a few PSEN1 and APP mutations have previously been found in Finnish AD patients, and one MAPT mutation in a FTLD family, while the role of PGRN in Finnish FTLD patients is unknown. Increasing evidence suggests that mitochondrial dysfunction and oxidative stress also play an important role in neurodegenerative diseases.

The aim here was to investigate the genetics of eoAD and FTLD in the population of the province of Northern Ostrobothnia, Finland. Sequencing analysis of the APP, PSEN1 and PSEN2 genes was performed to determine whether mutations in these genes could be detected. The MAPT and PGRN genes were analysed in the FTLD patients by sequencing and MAPT haplotypes were determined. The contributions of mtDNA and its maintenance enzymes to eoAD and FTLD were studied by comparing the frequencies of mtDNA haplogroups and their clusters between the patient groups and controls and by screening for the five common POLG1 mutations (T251I, A467T, P587L, W748S, Y955C), two common mtDNA mutations (m.3243A>G, m.8344A>G) and mutations in the PEO1 and ANT1 genes.

This is the first report of a significant association between the mtDNA haplogroup cluster IWX and FTLD. The H2 MAPT haplotype was also associated with FTLD in our cohort. No significant differences in the frequencies of the mtDNA haplogroups were observed between the eoAD patients and controls, nor were there any pathogenic mutations detected in the genes analysed.

The findings suggest that possession of the mtDNA haplogroup cluster IWX and the H2 MAPT haplotype may be possible risk factors for FTLD in our cohort. The absence of any pathogenic mutations in the MAPT, PGRN, APP or PSEN genes in our series, together with the previous reports of only a few mutations found in this region, supports a minor role for these genes in the aetiology of eoAD and FTLD in Northern Ostrobothnia and indicates that this population may have its own genetic features. There may be other, still unknown genetic factors to be discovered, that explain familial diseases in the region.