CSF sTREM2: Marking the tipping point between preclinical AD and dementia?

Biomarkers for Alzheimer's disease (AD) have improved our understanding of the temporal sequence of biological events that lead to AD dementia (Jack et al, ). AD is characterized neuropathologically by amyloid plaques comprised of the amyloid-β peptide and neurofibrillary tangles comprised of tau. Brain amyloid deposition, as evidenced by a decline in amyloid-β peptide 42 (Aβ42) in the cerebrospinal fluid (CSF) or by binding of amyloid PET ligands, is thought to be a key initiating event in AD and begins many years prior to the onset of dementia. A rise in CSF tau and phosphorylated tau in the setting of Aβ deposition appears to reflect neurodegeneration and also begins years prior to the onset of dementia but after Aβ deposition has begun to accumulate. Individuals with "preclinical AD," that is, normal cognition but abnormal AD biomarkers, have a much higher risk for developing AD dementia but may remain cognitively normal for years (Vos et al, 2013). While deposition of amyloid and formation of tau tangles are necessary for AD to occur, it is likely that additional events involving inflammation or other processes contribute to crossing the tipping point from preclinical AD to AD dementia. Current efforts are aimed at defining the biomarker(s) that best predict the transition from cognitive normality to abnormality. A biomarker that is closely associated with the onset of cognitive decline could help us to understand the biological events that connect amyloid deposition and tangle formation to cognitive decline and could have significant practical value in AD diagnosis and clinical trial design. Schindler and Holtzman highlight the work of Suarez-Calvet et al in this issue as they report that cerebrospinal fluid sTREM2 levels are associated with the onset of cognitive decline in Alzheimer's disease, a significant finding for AD diagnostics and drug trials.