Abstract
BackgroundThe Apolipoprotein E ε4 allele (i.e. ApoE4) is the strongest genetic risk factor for sporadic Alzheimer’s disease (AD). TREM2 (i.e. Triggering receptor expressed on myeloid cells 2) is a microglial transmembrane protein brain that plays a central role in microglia activation in response to AD brain pathologies. Whether higher TREM2-related microglia activity modulates the risk to develop clinical AD is an open question. Thus, the aim of the current study was to assess whether higher sTREM2 attenuates the effects of ApoE4-effects on future cognitive decline and neurodegeneration.MethodsWe included 708 subjects ranging from cognitively normal (CN, n = 221) to mild cognitive impairment (MCI, n = 414) and AD dementia (n = 73) from the Alzheimer’s disease Neuroimaging Initiative. We used linear regression to test the interaction between ApoE4-carriage by CSF-assessed sTREM2 levels as a predictor of longitudinally assessed cognitive decline and MRI-assessed changes in hippocampal volume changes (mean follow-up of 4 years, range of 1.7-7 years).ResultsAcross the entire sample, we found that higher CSF sTREM2 at baseline was associated with attenuated effects of ApoE4-carriage (i.e. sTREM2 x ApoE4 interaction) on longitudinal global cognitive (p = 0.001, Cohen’s f2 = 0.137) and memory decline (p = 0.006, Cohen’s f2 = 0.104) as well as longitudinally assessed hippocampal atrophy (p = 0.046, Cohen’s f2 = 0.089), independent of CSF markers of primary AD pathology (i.e. Aβ1–42, p-tau181). While overall effects of sTREM2 were small, exploratory subanalyses stratified by diagnostic groups showed that beneficial effects of sTREM2 were pronounced in the MCI group.ConclusionOur results suggest that a higher CSF sTREM2 levels are associated with attenuated ApoE4-related risk for future cognitive decline and AD-typical neurodegeneration. These findings provide further evidence that TREM2 may be protective against the development of AD.
Highlights
The Apolipoprotein E ε4 allele (i.e. Apolipoprotein 4 (ApoE4)) is the strongest genetic risk factor for sporadic Alzheimer’s disease (AD)
ApoE4-carriage is associated with more abnormal AD biomarkers and faster cognitive decline but not with changed CSF Soluble TREM2 (sTREM2) levels First, we assessed the association between ApoE4carriage, baseline CSF biomarkers, rates of cognitive decline and hippocampal atrophy
We found an association between ApoE4-carriage and both decreased baseline CSF-Aβ1–42 (F = 182.12, p < 0.001, Cohens D = 0.96, Fig. 1a, Supplementary Figure 1A for a stratification by diagnosis) and higher baseline p-tau181 levels (F = 110.53, p < 0.001, Cohens D = 0.76, Fig. 1b, Supplementary Figure 1B stratified by diagnosis), using Analysis of Covariance (ANCOVA) controlled for age, gender, education and diagnosis
Summary
The Apolipoprotein E ε4 allele (i.e. ApoE4) is the strongest genetic risk factor for sporadic Alzheimer’s disease (AD). TREM2 (i.e. Triggering receptor expressed on myeloid cells 2) is a microglial transmembrane protein brain that plays a central role in microglia activation in response to AD brain pathologies. ApoE4-carriers are at increased risk of developing primary AD pathology, cognitive decline and AD dementia [2, 5, 6]. Recent GWAS suggest that the brain’s immune response may modulate AD risk [13,14,15] This is supported by a 2–4-fold elevated odds ratio for AD in carriers of loss-of-function risk variants in the TREM2 gene (triggering receptor expressed on myeloid cells 2, i.e. in the brain preferentially expressed on microglia) [16]. TREM2-related microglial activation may attenuate downstream consequences of primary AD pathology and modulate ApoE4-related risk for AD symptoms and neurodegeneration
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
