Abstract:
INTRODUCTION:MAPT encodes for tau, the predominant component of neurofibrillary tangles that are neuropathological hallmarks of Alzheimer's disease (AD). Genetic association of MAPT variants with late-onset AD (LOAD) risk has been inconsistent, although insufficient power and incomplete assessment of MAPT haplotypes may account for this. METHODS:We examined the association of MAPT haplotypes with LOAD risk in more than 20,000 subjects (n-cases = 9,814, n-controls = 11,550) from Mayo Clinic (n-cases = 2,052, n-controls = 3,406) and the Alzheimer's Disease Genetics Consortium (ADGC, n-cases = 7,762, n-controls = 8,144). We also assessed associations with brain MAPT gene expression levels measured in the cerebellum (n = 197) and temporal cortex (n = 202) of LOAD subjects. Six single nucleotide polymorphisms (SNPs) which tag MAPT haplotypes with frequencies greater than 1% were evaluated. RESULTS:H2-haplotype tagging rs8070723-G allele associated with reduced risk of LOAD (odds ratio, OR = 0.90, 95% confidence interval, CI = 0.85-0.95, p = 5.2E-05) with consistent results in the Mayo (OR = 0.81, p = 7.0E-04) and ADGC (OR = 0.89, p = 1.26E-04) cohorts. rs3785883-A allele was also nominally significantly associated with LOAD risk (OR = 1.06, 95% CI = 1.01-1.13, p = 0.034). Haplotype analysis revealed significant global association with LOAD risk in the combined cohort (p = 0.033), with significant association of the H2 haplotype with reduced risk of LOAD as expected (p = 1.53E-04) and suggestive association with additional haplotypes. MAPT SNPs and haplotypes also associated with brain MAPT levels in the cerebellum and temporal cortex of AD subjects with the strongest associations observed for the H2 haplotype and reduced brain MAPT levels (β = -0.16 to -0.20, p = 1.0E-03 to 3.0E-03). CONCLUSIONS:These results confirm the previously reported MAPT H2 associations with LOAD risk in two large series, that this haplotype has the strongest effect on brain MAPT expression amongst those tested and identify additional haplotypes with suggestive associations, which require replication in independent series. These biologically congruent results provide compelling evidence to screen the MAPT region for regulatory variants which confer LOAD risk by influencing its brain gene expression.
journal_name
Alzheimers Res Therjournal_title
Alzheimer's research & therapyauthors
Allen M,Kachadoorian M,Quicksall Z,Zou F,Chai HS,Younkin C,Crook JE,Pankratz VS,Carrasquillo MM,Krishnan S,Nguyen T,Ma L,Malphrus K,Lincoln S,Bisceglio G,Kolbert CP,Jen J,Mukherjee S,Kauwe JK,Crane PK,Haines JL,doi
10.1186/alzrt268subject
Has Abstractpub_date
2014-07-01 00:00:00pages
39issue
4issn
1758-9193pii
alzrt268journal_volume
6pub_type
杂志文章abstract:INTRODUCTION:Depression and psychosis are two of the most severe neuropsychiatric symptoms (NPS) in dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). Both NPS have negative effects on cognitive performance and life expectancy. The current study aimed to investigate and compare monoaminergic etiologies betwe...
journal_title:Alzheimer's research & therapy
pub_type: 杂志文章
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doi:10.1186/s13195-019-0552-6
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journal_title:Alzheimer's research & therapy
pub_type: 杂志文章,评审
doi:10.1186/alzrt142
更新日期:2012-10-17 00:00:00
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journal_title:Alzheimer's research & therapy
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journal_title:Alzheimer's research & therapy
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doi:10.1186/s13195-016-0170-5
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journal_title:Alzheimer's research & therapy
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doi:10.1186/s13195-017-0326-y
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journal_title:Alzheimer's research & therapy
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doi:10.1186/s13195-017-0329-8
更新日期:2018-01-09 00:00:00
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journal_title:Alzheimer's research & therapy
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doi:10.1186/alzrt7
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abstract:BACKGROUND:Blood-based biomarkers for Alzheimer's disease (AD) are highly needed in clinic practice. So far, the gold standards for AD diagnosis are brain neuroimaging and beta-amyloid peptide, total tau, and phosphorylated tau in cerebrospinal fluid (CSF); however, they are not attractive for large-scale screening. Bl...
journal_title:Alzheimer's research & therapy
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journal_title:Alzheimer's research & therapy
pub_type: 杂志文章,多中心研究,随机对照试验
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更新日期:2017-03-23 00:00:00
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doi:10.1186/s13195-018-0398-3
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journal_title:Alzheimer's research & therapy
pub_type: 杂志文章,随机对照试验
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更新日期:2019-12-04 00:00:00
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journal_title:Alzheimer's research & therapy
pub_type: 杂志文章
doi:10.1186/s13195-015-0143-0
更新日期:2015-09-15 00:00:00
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journal_title:Alzheimer's research & therapy
pub_type: 杂志文章
doi:10.1186/s13195-018-0434-3
更新日期:2018-10-27 00:00:00
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journal_title:Alzheimer's research & therapy
pub_type: 杂志文章
doi:10.1186/s13195-014-0081-2
更新日期:2015-02-03 00:00:00
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journal_title:Alzheimer's research & therapy
pub_type: 杂志文章
doi:10.1186/s13195-018-0336-4
更新日期:2018-01-29 00:00:00
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journal_title:Alzheimer's research & therapy
pub_type: 杂志文章
doi:10.1186/s13195-019-0525-9
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journal_title:Alzheimer's research & therapy
pub_type: 社论
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更新日期:2012-01-16 00:00:00
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journal_title:Alzheimer's research & therapy
pub_type: 杂志文章,随机对照试验
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更新日期:2017-07-26 00:00:00
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journal_title:Alzheimer's research & therapy
pub_type: 杂志文章
doi:10.1186/alzrt131
更新日期:2012-07-11 00:00:00
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journal_title:Alzheimer's research & therapy
pub_type: 杂志文章
doi:10.1186/s13195-018-0353-3
更新日期:2018-02-26 00:00:00
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journal_title:Alzheimer's research & therapy
pub_type: 杂志文章
doi:10.1186/s13195-016-0179-9
更新日期:2016-03-16 00:00:00
abstract::Identification of therapeutic targets based on novel mechanistic studies is urgently needed for neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and prion disease. Multiple lines of evidence have emerged to suggest that inhibition of the stress-induced endoplasmic reticulum kinase PERK (pro...
journal_title:Alzheimer's research & therapy
pub_type: 杂志文章
doi:10.1186/alzrt260
更新日期:2014-05-29 00:00:00
abstract::Dementia with Lewy bodies (DLB) has become the second most common neurodegenerative dementia due to demographic ageing. Differential diagnosis is still troublesome especially in early stages of the disease, since there is a great clinical and neuropathological overlap primarily with Alzheimer's disease and Parkinson's...
journal_title:Alzheimer's research & therapy
pub_type: 杂志文章,评审
doi:10.1186/s13195-014-0072-3
更新日期:2014-10-16 00:00:00
abstract:BACKGROUND:Association between kidney dysfunction and dementia has been studied in western cohorts, but with inconsistent conclusions which may be due to the different measurements of kidney function. We aim to verify the hypothesis that lower levels of kidney function would be associated with increased risk of inciden...
journal_title:Alzheimer's research & therapy
pub_type: 杂志文章
doi:10.1186/s13195-020-00729-9
更新日期:2021-01-11 00:00:00
abstract:BACKGROUND:Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by neuropathologic changes involving beta-amyloid (Aβ), tau, neuronal loss, and other associated biological events. While levels of cerebrospinal fluid (CSF) Aβ and tau peptides have enhanced the antemortem detection of AD-specifi...
journal_title:Alzheimer's research & therapy
pub_type: 杂志文章,多中心研究
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更新日期:2018-09-25 00:00:00
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journal_title:Alzheimer's research & therapy
pub_type: 杂志文章
doi:10.1186/s13195-019-0496-x
更新日期:2019-05-17 00:00:00
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journal_title:Alzheimer's research & therapy
pub_type: 杂志文章
doi:10.1186/s13195-019-0477-0
更新日期:2019-03-21 00:00:00