TREM2 Associations with Concomitant Pathology in Alzheimer’s Disease
Winfree, Rebecca Lynn
Differential expression of both Triggering Receptor Expressed on Myeloid Cells-2 (TREM2) and its soluble fragment have been linked to Alzheimer’s disease (AD) risk in animal models and humans. The TREM2 pathway represents an opportune window into innate immune function and microglial dynamics in AD due to its preferential expression on microglia in brain and roles in immune homeostasis. And TREM2 is currently a nominated AD therapeutic target with active drug development. However, studies assessing TREM2 expression in AD have been largely focused on associations between TREM2 levels and parenchymal Aβ burden. Whereas possible associations between TREM2 levels and other concomitant neuropathology, particularly between cerebrovascular health outcomes, remains largely unexplored. This is despite several lines of preclinical evidence linking TREM2 to mechanisms of neurovascular unity integrity. This research sought to comprehensively examine regional TREM2 associations with autopsy measures of cerebrovascular disease and concomitant AD neuropathology (Aim 1). Also, to deconvolve the biological correlates associated with archetypal soluble TREM2 elevation in early AD (Aim 2). Lastly, after establishing the contributions of various AD inflammatory markers to variance in sTREM2 levels in CSF, it was explored whether or not known genetic regulators of CSF sTREM2 levels in the membrane-spanning 4-domains subfamily A (MS4A) modify these biomarkers associations (Aim 3). In summary, this work highlights multiple novel pathways associated with the TREM2 pathway in aging and AD, subsequently expanding the understanding of microglial dynamics in disease as well as the understanding of CSF sTREM2 as a complementary biomarker in adding and AD.