Abstract
A coding missense mutation (rs3747742) in triggering receptor expressed on myeloid cell-like 2 (TREML2) has been recently proposed as an important protective factor against Alzheimer’s disease (AD). However, the link between TREML2 and AD pathology remains unclear. Therefore, we explored the association of TREML2 rs3747742 with cognitive function, neuroimaging biomarkers and cerebrospinal fluid (CSF) biomarkers related to AD, including CSF total-tau (T-tau), phosphor-tau (P-tau), and amyloid-β (Aβ1-42). As for cognitive function, related cognitive scores of Clinical Dementia Rating Sum of Boxes (CDRSB), Alzheimer’s Disease Assessment Scale-cognitive section 11 (ADAS-cog 11), Mini-Mental State Examination (MMSE), and Rey Auditory-Verbal Learning Test (RAVLT) were extracted. We used a multiple linear regression model to examine the association of TREML2 rs3747742 with the baseline variables. Furthermore, we also calculated the change rate of above variables influenced by TREML2 rs3747742 via applying a mixed-effects model over a 4-year follow-up. In this analysis, a total of 1,306 individuals from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database were included. Finally, we observed that only in AD patients, but not in normal controls or mild cognitive impairment (MCI) individuals, TREML2 rs3747742 exhibited a strong association with CSF total-tau levels at baseline (β = -22.1210, p = 0.0166) and 4-year follow-up (β = -0.3961, p = 0.0115). Furthermore, no associations were found with CSF Aβ1-42 levels, P-tau levels, neuroimaging biomarkers and cognitive function neither for baseline variables nor for longitudinal data. Thus, this study indicated that TREML2 mediated the risk of AD through influencing AD-related neurodegeneration (abnormal T-tau levels) but not P-tau levels and Aβ pathology.
Highlights
Characterized by intracellular tau neurofibrillary tangles and extracellular amyloid-β (Aβ) plaques, Alzheimer’s disease (AD) is the most prevalent age-dependent dementia, accompanied by deteriorating cognitive function (Hardy and Selkoe, 2002; Jiang et al, 2012)
We examined the association of a missense mutation in triggering receptor expressed on myeloid cell-like 2 (TREML2) with cerebrospinal fluid (CSF) proteins, neuroimaging biomarkers and cognitive function among the total participants as well as three clinically diagnosed groups at baseline
We found that total participants (β = −0.1548, p = 0.0096) (Table 2) and AD patients (β = −0.3961, p = 0.0115) with C allele (CC, TC) showed a slower rate of change in CSF T-tau levels than TT allele carriers after controlling for age, gender, education and APOEε4 status (Figure 1B), but no associations were found with CSF Aβ1−42 levels, CSF P-tau levels, neuroimaging biomarkers and cognitive function (Table 2 and Supplementary Table 1)
Summary
Characterized by intracellular tau neurofibrillary tangles and extracellular amyloid-β (Aβ) plaques, Alzheimer’s disease (AD) is the most prevalent age-dependent dementia, accompanied by deteriorating cognitive function (Hardy and Selkoe, 2002; Jiang et al, 2012). AD has been suggested as a multifactorial disorder, and the role of genetics in AD pathology has been accepted widely (Querfurth and LaFerla, 2010; Jiang et al, 2012; Karch et al, 2014). Many biomarkers such as cerebrospinal fluid (CSF) Aβ1−42 and tau proteins have emerged as intermediate phenotype. This study is the first one designed to analyze the role of TREML2 rs3747742 in the pathogenesis of AD by examining the relation of rs3747742 with CSF proteins, neuroimaging biomarkers and cognitive function in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database
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