Purpose The study investigates the effects of genetic factors on the pathology of Alzheimer's disease (AD) and Lewy body (LB) diseases, including Parkinson's disease and dementia with Lewy bodies.
Methods A multicentre autopsy series (762 brain samples) with AD, LB or vascular pathology was examined. The effects of the tau gene (MAPT) H1 haplotype, the H1 specific SNP rs242557, APOE and the α-synuclein gene (SNCA) 3′UTR SNP rs356165 on the burden of AD and LB pathology were assessed. Neurofibrillary tangles (NFTs) were counted in four brain regions, senile plaques in five and LBs in four. Braak NFT stage, brain weight and presence of vascular pathology were also documented.
Results MAPT H1 associated with lower counts of NFTs in the middle frontal (p<0.001) and inferior parietal (p=0.005) cortices, and also with lower counts of senile plaques in the motor cortex (p=0.001). Associations of MAPT H1 with increased LB counts in the middle frontal cortex (p=0.011) and inferior parietal cortex (p=0.033) were observed but were not significant after multiple testing adjustment. The APOE ε4 allele was strongly associated with overall Alzheimer type pathology (all p≤0.001). SNCA rs356165 and the MAPT H1 specific SNP rs242557 did not associate with AD or LB pathology.
Conclusion This study shows for the first time that MAPT H1 is associated with reduced Alzheimer type pathology which could have important implications for the understanding of disease mechanisms and their genetic determinants.
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CW and OAR contributed equally to this work.
Funding The Mayo Clinic is a Morris K Udall Parkinson's Disease Research Center of Excellence supported by the National Institute of Neurological Disorders and Stroke, NS072187. The Mayo Clinic brain bank for neurodegenerative disorders is supported by P01AG017216; Einstein Ageing Study, P01AG03949; Mayo Alzheimer's Disease Research Center, P50AG16754; State of Florida Alzheimer's Disease Initiative; and the Society for Progressive Supranuclear Palsy. Additional funding included the Pacific Alzheimer's Research Foundation (PARF) (grant C06-01).
Competing interests ZKW is partially funded by P01AG017216, R01NS057567, R01AG015866 and CIHR 121849. CW is supported by the Swiss National Science Foundation (PASMP3-123268/1). OAR is supported by P01AG017216 and the family of Carl and Susan Bolch. SP is currently employed by Biogen Idec Inc (Cambridge, Massachusetts, USA) and holds stock in this company.
Ethics approval Ethics approval was provided by the institutional review board committee of the Mayo Clinic as well as from all of the centres that collaborated in the study (detailed in the article).
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement All brains used in the study are stored at the Mayo Clinic and are directly accessible/available to the senior author (DWD). All pathology, genetic and statistic data are stored at the Mayo Clinic and directly accessible/available to CW, OAR, MGH and DWD. All available data have been used for publication.