The interplay between triggering receptor expressed on myeloid cells 2 (TREM2) and low-density lipoprotein receptor-related protein 1 (LRP1) is critical for amyloid-beta (Aβ) clearance in Alzheimer’s disease (AD). Current therapeutic strategies targeting this axis can be broadly divided into two pharmacological approaches: indirect induction via metabolic modulation (e.g., ACAT1 inhibition) and direct functional restoration of LRP1. While ACAT1 inhibition effectively upregulates LRP1, recent findings suggest that this effect is mechanistically coupled to ADAM10/17-mediated shedding of TREM2. This raises a critical pharmacological dilemma: balancing the benefit of LRP1 upregulation against the reduction of cell-surface TREM2. While TREM2 shedding may represent a functional shift from membrane-bound sensing to soluble Aβ clearance rather than a simple loss of function, cell-surface TREM2 signaling remains essential for Aβ sensing and microglial fitness in the long term. Conversely, strategies focusing on the direct restoration of LRP1 transport achieve robust Aβ clearance but face challenges regarding delivery specificity. Integrating emerging evidence on lipid droplet–driven microglial dysfunction and membrane fluidity, this article discusses the trade-offs of these strategies and proposes that preserving surface TREM2 signaling while enhancing LRP1 activity is key to long-term therapeutic efficacy. Clinical evidence from the INVOKE-2 trial further supports the need for combination strategies targeting both TREM2 signaling and LRP1-mediated clearance.
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