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MAPT

The MAPT gene encodes microtubule-associated protein tau which is widely expressed throughout the central nervous system and forms characteristic aggregates in several neurodegenerative diseases [42]. Mutations in MAPT lead to frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) [43], while common variation in the MAPT gene is associated with the development of atypical parkinsonian syndromes, including progressive supranuclear palsy and corticobasal degeneration [44, 45]. There are two common extended haplotypes that incorporate the MAPT gene, H1 and H2, which are differentiated by a 900-kb genomic inversion. Association studies have now shown that the more common MAPT H1 haplotype is not only overrepresented in patients with PD but influences PD cognitive phenotype [28, 46]. In the Cam- PalGN cohort, MAPT H1/H1 haplotype was associated with a strikingly increased rate of age- dependent cognitive decline over the first 3.5 years from diagnosis, as measured by rate of change in MMSE score; during this period, all subjects who developed dementia were H1 homozygotes [46]. After 10 years’ follow-up of the same cohort, MAPT H1/H1 haplotype emerged as one of the key predictors of dementia after adjustment for age (HR 3.08) (Fig. 17.2) [28].

The association between MAPT H1 haplotype and dementia in PD has been replicated in a cross-sectional study of 102 patients [47]. Another study based on a prospective cohort of patients with established PD did not demonstrate any influence of H1 haplotype on global decline

Kapla n-Meier curve illustrating the cumulative probability of remaining free of dementia stratified by MAPT genotype in an incident pD cohort

Fig. 17.2 Kapla n-Meier curve illustrating the cumulative probability of remaining free of dementia stratified by MAPT genotype in an incident pD cohort (campaiGN) followed for up to 10 years from diagnosis [28].

Reproduced from The campaign study of parkinson's disease: 10-year outlook in an incident population-based cohort, Williams-Gray CH, Mason SL, Evans JR, et al, 84, 1258-64, ©2013 with permission from BMJ publishing Group Ltd.

measured using the Mattis Dementia Rating Scale, but reported a detrimental effect of MAPT H1 haplotype specifically on tests of memory [38]. Our own cross-sectional functional MRI study of 37 PD patients without dementia (unpublished data discussed further in the subsection ‘Nondopaminergic networks’) likewise found that H1 homozygotes had impaired visual recognition memory function compared with H2 haplotype carriers, implicating MAPT haplotype as a modulator of cognitive function that relies on the integrity of posterior cortical brain circuitry.

Evidence from post-mortem studies supports the concept that the MAPT H1 haplotype produces its cognitive effects by driving Lewy body pathology. In a study of 22 cases of dementia with Lewy bodies (DLB), matched for demographics and clinical variables, total Lewy body counts and a-synuclein deposits were significantly higher in the H1/H1 group (n = 12) than in the H2 carriers (n = 10) with no difference in Alzheimer’s-type pathology [48]. In addition, in a post-mortem series of 762 cases with AD, Lewy body diseases, and vascular pathology, the MAPT H1 haplotype was associated with increased cortical Lewy body counts in frontal and parietal cortices but reduced Alzheimer’s-type changes [49].

The mechanism by which MAPT impacts on protein aggregation in PD remains unclear, but the relative transcription of tau isoforms with three or four microtubule-binding domains (three- or four-repeat tau) has been shown to be altered in PD [50], and MAPT H1 or H1 subhaplotypes are associated with increased expression of total tau or of four-repeat tau [51-53]. Our own study [29] demonstrated that the H1 haplotype was associated with a 20% increase in four-repeat tau transcription in PD brains. Tau itself can interact and synergistically promote fibrilization of a-synuclein, the core component of Lewy bodies [54], and these proteins have been found to co-localize in brains with Lewy body pathology [55]. Interestingly, while variation in the a-synuclein gene (SNCA) has not been consistently linked to dementia outcome, an early follow-up of the CamPaIGN cohort revealed that the MAPT and SNCA risk alleles interacted to further increase the rate of early cognitive decline, supporting the concept of a synergistic pathological link between these proteins in vivo [46].

 
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