Reduced serum AHR agonistic activity reflects amyloid dysregulation in AT1 subtypes of Alzheimer’s disease

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor linking environmental signals to immune regulation and neurodegeneration. While AHR agonists exert protective effects in Alzheimer’s disease (AD) models, their relevance in humans remains unclear. We investigated AHR agonistic activity in serum and cerebrospinal fluid (CSF) across AT1-defined AD subtypes and its association with amyloid beta (Aβ) metabolism. We measured AHR agonistic activity using a luciferase reporter assay in serum and cerebrospinal fluid (CSF) from 138 individuals (113 non-demented, 25 demented) classified by CSF Aβ1-42, Aβ1-42/Aβ1-40 ratio and pTau181 into four AT1 groups: A + T1 + (AD), A + T1- (isolated decrease of Aβ1-42/Aβ1-40 or Aβ1-42), A-T1 + (isolated tau pathology/PASSED), and A-T1- (biomarker-negative controls). Serum AHR agonistic activity was significantly reduced in biomarker-positive individuals compared to controls (Δ z-score = 2.25, 95% CI [1.33, 3.17], p < 0.001), with the most pronounced reductions observed in two distinct phenotypes: non-demented A-T1 + individuals (z-score = -2.33, 95% CI [-3.26, -1.40]) and A + T1 + patients with preserved CSF Aβ1-42 despite pathological Aβ1-42/Aβ1-40 ratios (p = 0.006 compared to A + T1 + with pathological Aβ1-42). Serum AHR activity correlated negatively with CSF Aβ1-40 (ρ = -0.31, p < 0.001) and Aβ1-42 (ρ = -0.20, p = 0.021) across all participants. The relationship between pTau181 and serum AHR activity showed significant effect modification by amyloidopathy (A) (interaction p < 0.0001): negative in A- individuals (β = -0.54, p < 0.0001) but positive at high pTau181 levels in A + cases (β = 0.12, p = 0.025). CSF AHR activity showed no significant differences between AT1 groups. Peripheral AHR agonistic activity is reduced in early and atypical AD phenotypes and correlates with amyloid peptides Aβ1-42 and Aβ1-40 in CSF. The amyloid status-dependent reversal of pTau181-AHR associations suggests distinct regulatory mechanisms across AT1 groups.