Higher CSF sTREM2 attenuates ApoE4-related risk for cognitive decline and neurodegeneration

Abstract

Background 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. 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. Methods We 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). Results Across 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. Conclusion Our 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.

Wild-type sTREM2 blocks Aβ aggregation and neurotoxicity, but the Alzheimer's R47H mutant increases Aβ aggregation

“…However, these authors did show that WT sTREM2 bound strongly to amyloid plaques ( 34 ), consistent with our results. Our studies provide a potential explanation of the clinical observation of slower rates of cognitive and clinical decline in patients with MCI or AD who have higher levels of sTREM2 in the CSF ( 20 , 21 ) and slower rates of amyloid deposition in healthy controls and MCI patients with higher sTREM2 levels in CSF ( 22 ). They also provide a potential explanation for the beneficial effects of infusing or expressing sTREM2 into the brain of mouse models of AD ( 16 ).…”

“…However, the CSF Aβ levels rise in the early symptomatic stages of AD and then decline again at later stages of AD (11,12). Fifth, mild cognitive impairment (MCI) and AD patients with higher sTREM2 levels in CSF have slower brain atrophy, cognitive decline, and clinical decline (20,21), consistent with sTREM2 inhibiting AD progression. Sixth, healthy controls and MCI patients with higher sTREM2 levels in CSF have slower progression of amyloid and tau deposition (22), consistent with sTREM2 inhibiting Aβ aggregation and subsequent tau pathology.…”

Association Between sTREM2, an Immune Biomarker of Microglial Activation, and Aging-Related Brain Volume Changes in Community-Dwelling Older Adults: A 7-Year Follow-Up Study

“…Based on our results, serum sTREM2 levels in the older adults might not be considered as a biomarker for predicting a decline in future cognitive functions or brain volume. Recently, it has been suggested that higher CSF sTREM2 attenuates risk for cognitive decline and TREM2 may be protective against the development of AD ( Franzmeier et al, 2020 ). Although measuring sTREM2 level in peripheral blood is less invasive and relatively easily, it might be necessary to analyze the relationship between the CSF sTREM2 levels and brain volume.…”

Wild-type sTREM2 blocks Aβ aggregation and neurotoxicity, while the Alzheimer’s R47H mutant does the opposite

“…Our studies are broadly congruent with previous research showing that knockout of TREM2 expression in APP mice, resulted in accelerated amyloid plaque seeding 17 , with increased protofibrillar halos and hotspots around these plaques 3,16,18 . Our studies provide a potential explanation of the clinical observation of slower rates of cognitive and clinical decline in patients with MCI or AD who have higher levels of sTREM2 in the CSF 20,21 , and slower rates of amyloid deposition in healthy controls and MCI patients with higher sTREM2 levels in CSF 22 . They also provide a potential explanation for the beneficial effects of infusing or expressing sTREM2 into the brain of mouse models of AD 16 .…”