The MAPT H1 haplotype is associated with tangle-predominant dementia.
Tangle-predominant dementia (TPD) patients exhibit cognitive decline that is clinically similar to early to moderate-stage Alzheimer disease (AD), yet autopsy reveals neurofibrillary tangles in the medial temporal lobe composed of the microtubule-associated protein tau without significant amyloid-beta (Aβ)-positive plaques. We performed a series of neuropathological, biochemical and genetic studies using autopsy brain tissue drawn from a cohort of 34 TPD, 50 AD and 56 control subjects to identify molecular and genetic signatures of this entity. Biochemical analysis demonstrates a similar tau protein isoform composition in TPD and AD, which is compatible with previous histological and ultrastructural studies. Further, biochemical analysis fails to uncover elevation of soluble Aβ in TPD frontal cortex and hippocampus compared to control subjects, demonstrating that non-plaque-associated Aβ is not a contributing factor. Unexpectedly, we also observed high levels of secretory amyloid precursor protein α (sAPPα) in the frontal cortex of some TPD patients compared to AD and control subjects, suggesting differences in APP processing. Finally, we tested whether TPD is associated with changes in the tau gene (MAPT). Haplotype analysis demonstrates a strong association between TPD and the MAPT H1 haplotype, a genomic inversion associated with some tauopathies and Parkinson disease (PD), when compared to age-matched control subjects with mild degenerative changes, i.e., successful cerebral aging. Next-generation resequencing of MAPT followed by association analysis shows an association between TPD and two polymorphisms in the MAPT 3' untranslated region (UTR). These results support the hypothesis that haplotype-specific variation in the MAPT 3' UTR underlies an Aβ-independent mechanism for neurodegeneration in TPD.
Department of Pathology and Cell Biology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York 10032, USA.
Ismael
I
Santa-Maria
Aya
A
Haggiagi
Xinmin
X
Liu
Jessica
J
Wasserscheid
Peter T
PT
Nelson
Ken
K
Dewar
Lorraine N
LN
Clark
John F
JF
Crary
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D058227:Amyloidogenic Proteins / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D016009:Chi-Square Distribution; D003704:Dementia / Q000235:genetics* / Q000473:pathology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D016874:Neurofibrillary Tangles / Q000235:genetics* / Q000473:pathology / Q000648:ultrastructure; D012720:Severity of Illness Index; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D058227:Amyloidogenic Proteins; C054369:MAPT protein, human; D016875:tau Proteins