Abstract
The microtubule-associated protein tau (MAPT) H1 haplotype is the strongest genetic risk factor for corticobasal degeneration (CBD). However, the specific H1 subhaplotype association is not well defined, and it is not clear whether any MAPT haplotypes influence severity of tau pathology or clinical presentation in CBD. Therefore, in the current study we examined 230 neuropathologically confirmed CBD cases and 1312 controls in order to assess associations of MAPT haplotypes with risk of CBD, severity of tau pathology (measured as semi-quantitative scores for coiled bodies, neurofibrillary tangles, astrocytic plaques, and neuropil threads), age of CBD onset, and disease duration. After correcting for multiple testing (P < 0.0026 considered as significant), we confirmed the strong association between the MAPT H2 haplotype and decreased risk of CBD (Odds ratio = 0.26, P = 2 × 10−12), and also observed a novel association between the H1d subhaplotype and an increased CBD risk (Odds ratio = 1.76, P = 0.002). Additionally, although not statistically significant after correcting for multiple testing, the H1c haplotype was associated with a higher risk of CBD (Odds ratio = 1.49, P = 0.009). No MAPT haplotypes were significantly associated with any tau pathology measures, age of CBD onset, or disease duration. Though replication will be important and there is potential that population stratification could have influenced our findings, these results suggest that several MAPT H1 subhaplotypes are primarily responsible for the strong association between MAPT H1 and risk of CBD, but that H1 subhaplotypes are unlikely to play a major role in driving tau pathology or clinical features. Our findings also indicate that similarities in MAPT haplotype risk-factor profile exist between CBD and the related tauopathy progressive supranuclear palsy, with H2, H1d, and H1c displaying associations with both diseases.
Highlights
Corticobasal degeneration (CBD) is a rare and progressive neurodegenerative disorder, with an estimated prevalence of approximately 6 cases per 100,000 people [12]
After correcting for the 19 haplotypes that were examined (P < 0.0026 considered as significant), the H2 haplotype was strongly associated with a decreased risk of CBD (OR = 0.26, 95% Confidence interval (CI): 0.18–0.38, P = 2 × 10−12), while the H1d subhaplotype was associated with increased CBD risk (OR = 1.76, 95% CI: 1.22–2.52, P = 0.002)
When evaluating associations of microtubule-associated protein tau (MAPT) haplotypes with coiled bodies (CB), neurofibrillary tangles (NFT), astrocytic plaques (AP), and neuropil threads (NT) overall tau pathology scores in CBD cases (Table 3), no associations survived correction for multiple testing
Summary
Corticobasal degeneration (CBD) is a rare and progressive neurodegenerative disorder, with an estimated prevalence of approximately 6 cases per 100,000 people [12]. Patients with CBD can present with a variety of clinical features which overlap with other neurodegenerative. Valentino et al acta neuropathol commun (2020) 8:218 disorders, including progressive supranuclear palsy (PSP), Alzheimer’s disease (AD), and frontotemporal dementia (FTD), which makes clinical diagnosis challenging [2, 5, 12]. While PSP and CBD are both primary 4R-tauopathies, tau pathology occurs disproportionately in forebrain structures in CBD and in hindbrain structures in PSP, both regions are affected in both disorders [12, 18]
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