sTREM2 is associated with amyloid‐related p‐tau increases and glucose hypermetabolism in Alzheimer's disease

Abstract

Microglial activation occurs early in Alzheimer's disease (AD) and previous studies reported both detrimental and protective effects of microglia on AD progression. Here, we used CSF sTREM2 to investigate disease stage‐dependent drivers of microglial activation and to determine downstream consequences on AD progression. We included 402 patients with measures of earliest beta‐amyloid (CSF Aβ1‐42) and late‐stage fibrillary Aβ pathology (amyloid‐PET centiloid), as well as sTREM2, p‐tau181, and FDG‐PET. To determine disease stage, we stratified participants into early Aβ‐accumulators (Aβ CSF+/PET−; n = 70) or late Aβ‐accumulators (Aβ CSF+/PET+; n = 201) plus 131 controls. In early Aβ‐accumulators, higher centiloid was associated with cross‐sectional/longitudinal sTREM2 and p‐tau181 increases. Further, higher sTREM2 mediated the association between centiloid and cross‐sectional/longitudinal p‐tau181 increases and higher sTREM2 was associated with FDG‐PET hypermetabolism. In late Aβ‐accumulators, we found no association between centiloid and sTREM2 but a cross‐sectional association between higher sTREM2, higher p‐tau181 and glucose hypometabolism. Our findings suggest that a TREM2‐related microglial response follows earliest Aβ fibrillization, manifests in inflammatory glucose hypermetabolism and may facilitate subsequent p‐tau181 increases in earliest AD.

Functional Correlates of Microglial and Astrocytic Activity in Symptomatic Sporadic Alzheimer’s Disease: A CSF/18F-FDG-PET Study

“…This finding contrasts with previous literature showing a link between sTREM-2 and FDG-PET signal in AD patients with Mild Cognitive Impairment (MCI). Biel and colleagues reported that sTREM-2 positively associates with FDG-PET hypermetabolism in patients with CSF findings of amyloidopathy but negative amyloid-PET, while, in case of amyloid-PET positivity—reflecting higher levels of fibrillary Aβ—sTREM-2 associates with hypometabolism instead [ 33 ]. Nevertheless, this discrepancy could be due to our limited sample size and to the different clinical and AT profiles of our cohort.…”

“…Previous works also investigated the relationship between measures of cerebral glucose consumption and some markers of neuroinflammation, focusing especially on pre-symptomatic or very early AD, highlighting the presence of higher 18 F-FDG-PET uptake in relation to neuroinflammatory processes in early AD [ 31 , 32 , 33 ]. We aimed to implement these findings by evaluating a cohort of symptomatic patients diagnosed with sporadic AD, by exploring possible correlations between regional hypometabolism of 18 F-FDG-PET and changes in CSF biomarkers of microglial and astrocytic reactivity (sTREM-2, GFAP and β-S100).…”

Microglial Reactivity Correlates with Presynaptic Loss Independent of β‐Amyloid and Tau

“…[19][20][21] Elevated CSF sTREM2 was also related to attenuated brain atrophy, glucose hypometabolism, and cognitive decline. 19,[21][22][23][24] However, one recent study reported the accelerated effects of CSF sTREM2 and microglial activation on future tau deposition. 25 Supporting this, CSF sTREM2 has also been linked to Aβ-related tau aggregates.…”

“…25 Supporting this, CSF sTREM2 has also been linked to Aβ-related tau aggregates. 24,26 Together, the roles of TREM2-dependent and PGRN-dependent microglial reactivity in the course of AD remain controversial.…”

“…Accumulating evidence from human and animal models showed that higher CSF sTREM2 and microglial activation were associated with reduced Aβ and tau deposition 19–21 . Elevated CSF sTREM2 was also related to attenuated brain atrophy, glucose hypometabolism, and cognitive decline 19,21–24 . However, one recent study reported the accelerated effects of CSF sTREM2 and microglial activation on future tau deposition 25 .…”