Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) are the two mostcommon neurodegenerative diseases leading to early onset dementia (<65 years). Mutations inthe amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) genes causea 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 fewPSEN1 and APP mutations have previously been found in Finnish AD patients, and one MAPTmutation 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 animportant role in neurodegenerative diseases.
The aim here was to investigate the genetics of eoAD and FTLD in the population of theprovince of Northern Ostrobothnia, Finland. Sequencing analysis of the APP, PSEN1 and PSEN2genes was performed to determine whether mutations in these genes could be detected. The MAPTand PGRN genes were analysed in the FTLD patients by sequencing and MAPT haplotypes weredetermined. The contributions of mtDNA and its maintenance enzymes to eoAD and FTLD werestudied by comparing the frequencies of mtDNA haplogroups and their clusters between thepatient 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 IWXand FTLD. The H2 MAPT haplotype was also associated with FTLD in our cohort. No significantdifferences in the frequencies of the mtDNA haplogroups were observed between the eoADpatients 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 MAPThaplotype may be possible risk factors for FTLD in our cohort. The absence of any pathogenicmutations in the MAPT, PGRN, APP or PSEN genes in our series, together with the previousreports of only a few mutations found in this region, supports a minor role for these genes in theaetiology of eoAD and FTLD in Northern Ostrobothnia and indicates that this population mayhave its own genetic features. There may be other, still unknown genetic factors to be discovered,that explain familial diseases in the region.
