Lamivudine decreases a type I interferon cellular signature linked to viral sensing in people with mild cognitive impairment

Retrotransposon reactivation may drive neuro-inflammation and synaptic loss via type I interferon signaling. Lamivudine (3TC), a reverse transcriptase (RT) inhibitor that blocks retrotransposon RT activity, improved cognition in mouse models of accelerated ageing. Here, we evaluated whether 3TC reduces the inflammation from reactivated retrotransposons in individuals with mild cognitive impairment (MCI) due to Alzheimer’s disease (AD)—defined by CSF biomarkers or amyloid PET.

An ongoing single-center, open-label, self-controlled Phase 2a pilot trial enrolled 20 participants aged 55–90 to receive oral 3TC (300 mg/day) for 24 weeks (NCT06519357). Participants met NIA-AA criteria for MCI and were positive for CSF or PET biomarkers for AD. Exclusion criteria included other dementias or unstable medical or psychiatric conditions. Blood was collected during screening, at baseline, and at weeks 1, 4, 12, 24, and 48. Primary outcomes included measuring 10 type I interferon signaling genes (ISGs) via RT-PCR in PBMCs. Safety and tolerability were also evaluated.

Three participants did not complete treatment, but 3TC was safe and well tolerated in all cases. Changes up to week 12 in the 10 ISGs were measured by calculating significant negative slopes using a linear regression model. Of note, 47% of the participants had a statistically significant decrease in IFN-a and IFN-b, consistent with a reduced sensing of retrotransposon RT activity blocked by 3TC. Moreover, 20-15% had a significant reduction in MX1, IFHI1, OAS1, TLR7, and TLR3. About 12% showed reduced IP10, IRF7, and TREX1. In three patients, at least six genes were downregulated. RT-PCR at weeks 24 to 48, as well as quantification of neurocognitive plasma biomarkers, is underway.

3TC lowers IFN-a and IFN-b release in PBMCs from AD patients, potentially reducing immune inflammation driven by retrotransposon RT. Further work should address if a strategy based on 3TC, with higher brain-barrier penetrance than other antiretrovirals, could reduce brain inflammation.