Abstract
Background: rs9357347 located at the triggering receptor expressed on myeloid cells (TREM) gene cluster could increase TREM2 and TREM-like transcript 1 (TREML1) brain gene expression, which is considered to play a protective role against Alzheimer’s disease (AD).Objectives: To investigate the role of rs9357347 in AD pathogenesis by exploring the effects of rs9357347 on AD specific biomarkers.Methods: This study analyzed the association of rs9357347 with AD-related cerebrospinal fluid (CSF) and neuroimaging markers from 201 cognitively normal (CN) older adults, 349 elders with mild cognitive impairment (MCI), and 172 elders with AD dementia from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). We next analyzed the association in 259 amyloid-β positive (Aβ+) elders and 117 amyloid-β negative (Aβ-) elders (Aβ+: CSF Aβ1-42 ≤ 192 pg/ml; Aβ-: CSF Aβ1-42 > 192 pg/ml). Associations were tested using multiple linear regression models at baseline. Furthermore, multiple mixed-effects models were used in a longitudinal study which lasted 4 years.Results: At baseline, we found that rs9357347 had association with CSF Aβ1-42 in CN group (β = 0.357, P = 0.009). In AD group, rs9357347 was associated with total tau (T-tau) level (β = -0.436, P = 0.007). Moreover, the strong influence exerted by rs9357347 on T-tau was also seen in Aβ+ group (β = -0.202, P = 0.036). In the longitudinal study, rs9357347 was also found to be associated with Aβ1-42 in CN group (β = 0.329, P = 0.023). In AD group, the mutation of rs9357347 was associated with slower accumulation of T-tau (β = -0.472, P = 0.002) and tau phosphorylated at threonine 181 [P-tau 181 (β = -0.330, P = 0.019)]. Furthermore, the obvious influence exerted by rs9357347 on T-tau was also seen in Aβ+ group (β = -0.241, P = 0.013).Conclusion: This study suggested that rs9357347 reduced the risk of AD by modulating both amyloid-β pathology and neuronal degeneration.
Highlights
Alzheimer’s disease (AD) is a complex polygenetic disease characterized by the presence of extracellular deposits of the amyloid-β1−42 (Aβ1−42) and intracellular twisted strands of the tau protein (Alzheimer’s Association, 2011)
At baseline, we found that rs9357347 had association with cerebrospinal fluid (CSF) Aβ1−42 in cognitively normal (CN) group (β = 0.357, P = 0.009)
In AD group, the mutation of rs9357347 was associated with slower accumulation of total tau (T-tau) (β = −0.472, P = 0.002) and tau phosphorylated at triggering receptor expressed on myeloid cells (TREM) Gene and Neuronal Degeneration threonine 181 [P-tau 181 (β = −0.330, P = 0.019)]
Summary
Alzheimer’s disease (AD) is a complex polygenetic disease characterized by the presence of extracellular deposits of the amyloid-β1−42 (Aβ1−42) and intracellular twisted strands of the tau protein (Alzheimer’s Association, 2011). The triggering receptor expressed on myeloid cells (TREM) gene cluster on chromosome 6p21.11 has been identified as significantly associated gene region with AD (Karch et al, 2014). Carrasquillo et al (2017) re-analyzed whole genome and exome sequencing data to test which common AD-related variants within the TREM gene cluster influence AD through gene expression. The locus was demonstrated to influence TREML1 and TREM2 expression in the temporal cortex (Ford and McVicar, 2009). They found that only TREM2 and TREML1 had reliable expression in the brain region. The current study was to test associations of rs9357347 with AD-related cerebrospinal fluid (CSF) and neuroimaging markers in the population from Alzheimer’s Disease Neuroimaging Initiative (ADNI)
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