Role of MAPT mutations and haplotype in frontotemporal lobar degeneration in Northern Finland

Frontotemporal lobar degeneration (FTLD) is a clinically and neuropathologically heterogeneous group of neurodegenerative disorders affecting the frontal and/or temporal lobes and causing changes in personal and social conduct, disinhibition and progressive changes in language. The main clinical syndromes are frontotemporal dementia (FTD), semantic dementia (SD) and progressive non-fluent aphasia (PA).[1] FTLD can be divided neuropathologically into diseases with tau-positive inclusions and diseases with tau-negative and ubiquitin-positive inclusions.[2] A positive family history is present in 30–50% of FTLD cases.[3, 4] Mutations in microtubule-associated protein tau (MAPT), progranulin (PGRN) and charged multi-vesicular body protein 2B (CHMP2B) are associated with the autosomal dominant form of the disease. [5‐9]

Mutations in MAPT are associated with tau-positive neuropathology and occur in familial FTLD in frequencies that vary in the range 5–50% between populations.[3, 10‐15] Several polymorphisms throughout the MAPT gene are in complete linkage disequilibrium with each other and are inherited as two separate haplotypes, H1 and H2. The predominant haplotype, H1, has been found to be associated with sporadic tauopathies, [16‐18] and also to have a faint association with FTLD.[19, 20] However, in some studies the H2 haplotype has also been found to be associated with FTLD.[15, 21]

The aim of this work was to investigate the frequency of MAPT mutations in Finnish patients with FTLD and to examine the association between the MAPT haplotypes and FTLD. We sequenced exons 1, 2 and 9–13 of MAPT in 59 Finnish patients with FTLD and analysed the MAPT haplotypes in these patients, 122 patients with early onset Alzheimer's disease (eoAD, age at onset before 65 years) and 198 healthy middle-aged controls.

We sequenced exons 1, 2 and 9–13 of the MAPT gene in 59 Finnish patients with FTLD and analysed MAPT haplotypes in these patients, 122 patients with eoAD and 198 middle-aged healthy controls. No pathogenic MAPT mutations were found in the patients with FTLD.

We detected seven polymorphic sites which have previously been found to be associated with the H2 haplotype (Table 1), but did not find any novel polymorphisms in the H2 haplotype. The previously described Thr39Thr, P270P, Exon10 -47 and Exon11 +90, Exon11 +104 polymorphisms were found to be associated with the H1 allele (Table 2), in addition to a novel polymorphism Exon13 +67delAAT, which was found in 10 H1 alleles of patients with FTLD. One H1/H1 homozygous patient was also homozygous for the Exon13 +67delAAT polymorphism. The frequencies of Exon13 +67delAAT were 9.5% among the FTLD patients with the H1 allele, 8.5% in the whole FTLD group, 5.9% in the AD patients and 3.2% in healthy controls. Results of a neuropathological examination were available for one man with this polymorphism, who had had FTLD with ALS (amyotrophic lateralis sclerosis), for six years with onset at the age of 59 years. These results revealed tau-negative, ubiquitin-positive FTLD and motor neuron disease.

The frequencies of the H2 allele were 11.0% in the patients with FTLD and 9.8% in those with eoAD, as opposed to 5.3% in the controls (Table 3). Thus the frequencies of the H2 allele and the genotypes H1/H2 + H2/H2 were significantly increased in the FTLD patients relative to the controls (Table 3 and Table 4), and they also showed a significant increase among the patients with eoAD. The H2 allele was clustered with the familial form of FTLD, so that a positive family history was found in 58% of the FTLD cases with the H1/H2 or H2/H2 genotype (Fisher's exact test, P = 0.011). The H2 allele was not associated with onset of the disease at an earlier age, the age at onset being 56.0 ± 6.7 years (mean ± SD) in the H1/H2 or H2/H2 carriers, and 59.2 ± 6.5 years in the H1/H1 carriers (P = 0.138).

Only one patient, with a negative family history of neurological disorders, had the H2/H2 genotype. In this case progressive aphatic symptoms and changes in personality had started at the age of 52 years and by the end-stage of the disease he was completely aphatic and had evident extrapyramidal symptoms. He died at the age of 62 years. Neuropathological evaluation revealed marked atrophy in both the frontal and temporal lobes. Tau-pathology was widespread. Tangle-like, globose and granular neuronal inclusions were present in neocortex, other than occipitally, and in the hippocampal pyramidal and fascia dentata neurones, basal ganglia, substantia nigra, locus ceruleus and cerebellar dentate. Tau-positive neuropil threads were seen in the same areas and in the subcortical white matter, and some white matter glial cells were tau-positive. Beta-amyloid and synuclein were absent.

The ApoE4 allele was found in 42.4% of the FTLD patients and 63.1% of the eoAD patients, the latter frequency being significantly increased (P < 0.001), but the former less so (P = 0.049).

We analysed MAPT mutations and the role of the MAPT haplotype in 59 patients with FTLD in Northern Finland. A positive family history was found in 27% of these patients, but no pathogenic mutations in MAPT were detected. The relative frequency of MAPT mutations has varied previously between 0 and 50% depending on type of study, the area concerned and whether there has been a family history of the disease, [4, 10, 12‐14, 27, 28] although the differences in frequency may also be explained by varying methods of case ascertainment. The frequency is obviously higher in familial forms of FTLD, however, an effect that has been attributed to the founder mutation in France and the Netherlands.[4, 10, 12] Interestingly, very low frequencies of MAPT mutations have been reported in Sweden and Poland.[27, 28] The roots of the Finnish population reach back over 2000 years, but internal migration to Northern Ostrobothnia in the 16th century created a regional subisolate in the population of some 380000 inhabitants examined here,[29] which may explain the extremely low MAPT mutation frequency. On the other hand, the geographical variation may reflect differences in the prevalence of MAPT mutations between populations. Our data support the findings of very low frequencies of MAPT mutations in the Baltic countries.[27, 28]

We found that the H2 allele frequencies in patients with either FTLD or eoAD were two-fold compared with those in the controls, and that the frequencies of both the H2 allele and the H1/H2 + H2/H2 genotypes were significantly higher in both patient groups. The H2 allele in particular was associated with the familial form of FTLD. The H1 haplotype is the most common, having an allele frequency of about > 70% in European populations,[30] while the H2 haplotype has been associated with Caucasian ancestry, since Middle Eastern and European populations have frequencies of about 25%, the Finnish population about 8% and Central Asian populations about 5%, while the allele is essentially practically non-existent in other populations.[30] H1 has been associated with sporadic tauopathies, including Parkinson's disease,[16, 17] progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD),[18] and it also has a putative association with FTD.[19, 20] In particular, the H1c variant of the H1 haplotype has been linked with CBD, PSP and AD.[18, 31] Recently, however, the H2 haplotype has been found to increase the risk of familial FTD in an Italian population.[21] Two Belgian families with FTLD have been linked with the extended rare H2 haplotype and a PGRN mutation.[7, 15] However, no pathogenic mutations in PGRN were found in our cohort.[24] The H2 haplotype has also been reported to lower the age of onset of the disease,[32] but this finding could not be confirmed in the present study. Interestingly, this is the first study showing the association between the H2 haplotype and Alzheimer's disease.

The H2 haplotype is assumed to be an ancestral one and to manifest only minor variability,[18, 33] as confirmed here. A novel polymorphism Exon 13 +67 delAAT was found to be associated with the H1 allele and to have an increased frequency in patients with FTLD and eoAD, although it was also frequent in the controls, thus suggesting a non-pathogenic nature.

A significant association was found between the ApoE4 allele, the most important genetic risk factor for AD, and eoAD, and a similar association was also evident with FTLD. Increased frequency of the ApoE4 allele in patients with FTLD has also been reported previously,[32, 34] and it has also been found to increase the penetrance of dementia, since valosin-containing protein (VCP) is associated with FTD,[35] and to impair long-term memory functions and reduce parahippocampal perfusion in FTLD patients.[36]

We conclude that, although pathogenic MAPT mutations are rare in Northern Finland, the frequency of the H2 allele of MAPT is significantly increased in patients with FTLD and also in patients with eoAD. Either the H2 haplotype itself or other genetic variations associated with it may be a risk factor for FTLD and eoAD in the Finnish population.