Low‑Dose Interleukin‑2 Expands Regulatory T Cells and Modulates Biomarkers in Mild–Moderate Alzheimer’s Disease: Phase 2a Randomized Trial Shows Safety and Promising Signals

Highlights

– Low‑dose subcutaneous IL‑2 (1 x 10^6 IU/day for 5 days) administered every 4 weeks (IL‑2 q4wks) was safe and well tolerated in people with mild–moderate Alzheimer’s disease (AD).

– IL‑2 q4wks significantly expanded circulating regulatory T cells (Tregs) and increased Foxp3 mean fluorescent intensity (MFI), with enhanced suppressive function versus placebo.

– IL‑2 q4wks produced favorable shifts in multiple plasma inflammatory mediators (reduced CCL2, CCL11, IL‑15; increased IL‑4, CCL13) and increased CSF Aβ42 (p = 0.045 vs placebo) on Day 148; CSF NfL remained stable versus a rise in placebo (p = 0.060).

– The trial identified a signal toward slower cognitive decline by ADAS‑Cog at week 22 (p = 0.061) supporting larger, longer studies.

Background: disease burden and rationale

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, accumulation of amyloid‑β (Aβ) and tau pathology, synaptic loss, and neuroinflammation. Inflammation and dysfunctional immune regulation have emerged as central contributors to disease progression and are increasingly viewed as actionable therapeutic targets. Regulatory T cells (Tregs) are key immune modulators that suppress excessive inflammation and maintain homeostasis. Prior work has documented compromised Treg numbers and/or function in AD, a shift toward pro‑inflammatory peripheral and central immune profiles, and associations between immune dysregulation and clinical progression.

Low‑dose interleukin‑2 (IL‑2) preferentially expands Tregs in vivo and has been investigated in several autoimmune and inflammatory disorders as a strategy to restore immune regulation. Translating this approach to AD seeks to reduce maladaptive inflammation, protect neurons from immune‑mediated injury, and potentially influence core AD pathobiology.

Study design

This report describes a phase 2a, randomized, double‑blind, placebo‑controlled trial (ClinicalTrials.gov NCT06096090) enrolling 38 participants with mild to moderate AD. Participants were randomized to one of three arms: IL‑2 q4wks (n = 9), IL‑2 q2wks (n = 10), or placebo (n = 19). The IL‑2 regimen consisted of subcutaneous injections at a dose of 1 × 10^6 IU/day for five consecutive days, repeated either every 4 weeks or every 2 weeks, over a 21‑week treatment period followed by 9 weeks of observation.

Primary endpoints were safety and tolerability — incidence and severity of adverse events (AEs). Secondary endpoints assessed immunologic pharmacodynamics: changes in Treg frequency and suppressive function, and Foxp3 MFI. Exploratory endpoints included longitudinal measurement of 45 plasma inflammatory mediators, cerebrospinal fluid (CSF) AD biomarkers (Aβ42, neurofilament light chain [NfL]), and clinical scales including the ADAS‑Cog.

Key findings

Safety and tolerability

All 38 participants completed the trial. There were no serious adverse events or deaths reported. Both IL‑2 dosing schedules were generally well tolerated. The absence of serious safety signals in this older, AD cohort supports feasibility of short courses of low‑dose IL‑2 in this population, though larger samples are required to define uncommon adverse events and long‑term safety.

Immunologic effects: Treg expansion and function

Both IL‑2 q4wks and q2wks increased circulating Treg numbers and enhanced suppressive activity relative to baseline and placebo. Notably, IL‑2 q4wks produced superior increases in Treg percentage and Foxp3 MFI compared with the q2wks regimen. These readouts indicate not only quantitative expansion but also phenotypic strengthening of the Treg compartment (higher Foxp3 expression), which correlates with suppressive capacity in mechanistic studies.

Peripheral inflammatory mediators

Longitudinal profiling of 45 plasma inflammatory markers revealed that IL‑2 q4wks had the most pronounced effects on several mediators implicated in neuroinflammation and AD. Specifically, IL‑2 q4wks decreased CCL2 (MCP‑1), CCL11 (eotaxin‑1), and IL‑15 while increasing IL‑4 and CCL13. These shifts suggest a dampening of monocyte/chemokine‑driven inflammatory recruitment (CCL2, CCL11) and a tilt toward anti‑inflammatory or regulatory cytokine milieu (IL‑4). IL‑15 reduction may reflect decreased cytotoxic or pro‑inflammatory lymphocyte activation. The pattern is biologically plausible for a Treg‑mediated modulation of peripheral immune tone that could impact central immunity indirectly.

CSF biomarkers

On Day 148, IL‑2 q4wks recipients showed a significant increase in CSF Aβ42 compared with placebo (p = 0.045). Interpretation requires nuance: in symptomatic AD, low CSF Aβ42 is classically interpreted as sequestration into brain amyloid aggregates. A rise in CSF Aβ42 after an immunomodulatory therapy could plausibly reflect enhanced clearance of soluble Aβ species from brain to CSF, reduced deposition, or altered equilibrium between compartments. Additional corroboration with amyloid PET would be needed to firmly conclude clearance of parenchymal amyloid.

CSF NfL, a marker of neuroaxonal injury, increased by 217 pg/ml in the placebo arm but remained stable in the IL‑2 q4wks group (p = 0.060 IL‑2 q4wks vs placebo), a near‑significant finding that signals potential neuroprotective effects of Treg expansion through reduction of immune‑mediated axonal injury.

Clinical outcomes

The adjusted mean change from baseline in ADAS‑Cog at week 22 favored IL‑2 q4wks with a trend toward slower progression versus placebo (p = 0.061). Although not reaching conventional statistical significance, the directionality across biomarkers, immunologic endpoints, and cognition provides a coherent biological signal warranting confirmation.

Expert commentary: interpretation, mechanisms, and limitations

Interpretation. This phase 2a trial demonstrates that intermittent low‑dose IL‑2 is safe in the studied AD cohort, expands and functionally augments Tregs, modulates peripheral inflammatory mediators, and produces biomarker and clinical signals consistent with disease modification hypotheses. The coherence across immune, biochemical, and cognitive measures strengthens biological plausibility.

Putative mechanism. Low‑dose IL‑2 preferentially stimulates the high‑affinity IL‑2 receptor expressed on Tregs (CD25hi), promoting Treg survival, proliferation, and suppressive function. Restored peripheral immune regulation may reduce trafficking of pro‑inflammatory monocytes and lymphocytes into the CNS, decrease microglial activation, and mitigate downstream neuronal injury. Changes in chemokines such as CCL2 and CCL11 are consistent with reduced recruitment of peripheral inflammatory cells; increased IL‑4 may reflect a shift toward type‑2/regulatory responses.

Why q4wks > q2wks? The superior performance of the q4wks schedule could reflect homeostatic dynamics of Treg induction and contraction: pulse dosing with recovery intervals might allow more durable reprogramming of the Treg compartment, whereas shorter repeat intervals could favor transient expansion without phenotypic maturation. Pharmacodynamic modeling and mechanistic immunophenotyping in future studies could clarify optimal scheduling.

Limitations. Key limitations include small sample size (n = 38), especially within active arms, which reduces power and increases risk for type I/II errors. Multiple exploratory biomarker comparisons raise the possibility of false positives; the CSF Aβ42 finding (p = 0.045) and near‑significant NfL and ADAS‑Cog results require replication. Study duration was relatively short for disease‑modifying claims; AD pathology evolves over years, so longer follow‑up is necessary to assess durable effects on clinical progression and imaging biomarkers. The trial population and inclusion/exclusion criteria may limit generalizability, particularly to patients with comorbidities or later‑stage disease. The absence of amyloid or tau PET limits interpretation of CSF changes in relation to parenchymal pathology.

Implications and next steps

These results justify a larger, adequately powered randomized trial with several design considerations: longer treatment and follow‑up (≥12–18 months), stratification by baseline amyloid/tau burden (ideally PET or CSF profiles), incorporation of imaging biomarkers (amyloid and tau PET, volumetric MRI), more granular immunophenotyping (Treg subsets, trafficking markers), and careful safety monitoring in older adults with comorbidities. Dose‑finding and schedule optimization studies could identify regimens that maximize durable Treg function with minimal dosing burden. Combination approaches (e.g., IL‑2 with anti‑amyloid or anti‑tau therapies) could be considered if IL‑2 proves to modulate downstream neuroinflammation effectively while disease‑specific agents address proteinopathy.

Conclusion

In this phase 2a randomized trial, intermittent low‑dose IL‑2 administered every 4 weeks was safe, expanded and functionally strengthened regulatory T cells, altered plasma inflammatory mediators in a direction consistent with reduced pro‑inflammatory tone, increased CSF Aβ42, stabilized CSF NfL relative to placebo, and produced a favorable trend in cognitive decline. While preliminary, these convergent signals support further investigation of Treg‑targeted immunotherapy in AD through larger and longer trials with multimodal biomarker endpoints.

Funding and trial registration

Trial registration: ClinicalTrials.gov Identifier: NCT06096090, Registration Date: 10‑17‑2023. Funding sources are reported in the original publication (Faridar et al., Alzheimers Res Ther. 2025).

References

Faridar A, Gamez N, Li D, Wang Y, Boradia R, Thome AD, Zhao W, Beers DR, Thonhoff JR, Nakawah MO, Román GC, Volpi JJ, Toledo JB, George M, Davis CS, Pascual B, Grundman M, Masdeu JC, Appel SH. Low‑dose interleukin‑2 in patients with mild to moderate Alzheimer’s disease: a randomized clinical trial. Alzheimers Res Ther. 2025 Jul 4;17(1):146. doi: 10.1186/s13195-025-01791-x. PMID: 40615880; PMCID: PMC12231701.

Additional foundational literature on low‑dose IL‑2 and Treg therapy in human disease can be found in the clinical immunology and translational medicine literature; readers are referred to the primary trial report above for full methods, safety tables, and supplementary analyses.