Identify novel links between microglial TREM2 signalling and tau propagation that suggest repurposable drug targets

In microglia with TREM2 deficiency (R47H/T66M variants or low CSF sTREM2 <2000 pg/mL indicating impaired TREM2 function), BTK inhibition with acalabrutinib will reduce pathogenic exosome-mediated tau propagation by 35-50% as measured by CD63+/AT8+ exosomal particles, by intercepting compensatory BTK-dependent membrane remodeling and cytoskeletal pathways (CDC42/RAC) that are upregulated when TREM2-SYK phagocytic signaling fails, while preserving CSF1R-mediated microglial survival signals; this would create a TREM2-deficiency-selective therapeutic window, validated by demonstrating efficacy only in BIN1 rs7561528 risk carriers (where 20-43% of genetic effects operate through sTREM2 pathways) and requiring tau PET propagation velocity as primary endpoint with exosomal tau species characterized by phospho-specific (AT8) and conformational (MC1) immunocapture normalized to total extracellular vesicle counts.

In AD patients with TREM2 R47H variant or CSF sTREM2/p-tau181 ratio below median (indicating impaired TREM2 paracrine neuroprotection), combined treatment with low-dose fasudil (20mg BID, titrated from 10mg to minimize hypotension) and sub-therapeutic lithium (300mg daily targeting 0.3-0.5 mEq/L) will replicate the sTREM2-transgelin-2-RhoA-ROCK-GSK3β neuroprotective axis reducing CSF p-tau181/t-tau ratio by 25-35% at 9 months, while co-administered TREM2 agonist antibody AL002 enhances microglial phagocytic clearance of existing tau aggregates (distinct cellular target), creating complementary mechanisms addressing neuronal tau production (kinase inhibition) and microglial tau removal (phagocytosis enhancement); this would require demonstration in a safety-enriched population (excluding cerebral amicrohemorrhages >4 on MRI, orthostatic hypotension, eGFR <45) with intensive monitoring (biweekly BP/lithium levels months 0-3, then monthly), using tau PET SUVr reduction in Braak III-IV regions as co-primary endpoint to validate aggregate clearance independent of CSF biomarker confounds, and BIN1 rs7561528 genotype as exploratory stratification variable to test whether genetic effects mediated through sTREM2 pathways predict pharmacological response to sTREM2-mimetic intervention.

In ApoE4/4 homozygous AD patients (n=120, enriched population representing ~15% of AD where TREM2-independent pathogenic pathways predominate per PMID:36368315), low-dose pexidartinib (200mg BID, 50% of approved oncology dose targeting ~30-40% CSF1R occupancy and partial activated microglia reduction rather than complete ablation) combined with OLT1177 (NLRP3 inhibitor, 1000mg BID, completed Phase 2 safety in heart failure NCT03534297) will reduce tau PET propagation velocity by 40-60% over 12 months compared to placebo by selectively suppressing NLRP3 inflammasome-mediated IL-1β/IL-18 neurotoxicity (TREM2-independent pathway per PMID:40938771) while partially depleting hyperactivated disease-associated microglia that exhibit ApoE4-dependent lipid metabolic dysfunction (PMID:40149001), preserving remaining microglial TREM2-dependent phagocytic capacity; this would require rigorous safety monitoring (weekly LFTs months 0-2, biweekly months 3-6, monthly thereafter; automatic discontinuation for ALT >3× ULN; exclusion of baseline liver disease, CAA >4 microhemorrhages, concurrent hepatotoxic/QT-prolonging drugs) and validation that the mechanism is ApoE-genotype-selective by demonstrating minimal efficacy (<15% tau PET velocity reduction) in ApoE3/3 control arm (n=40) where TREM2-dependent pathways dominate and would not be targeted by this combination, with CSF sTREM2 stability confirming preserved TREM2 pathway function in partially depleted microglial populations.