Lipocalin-2 is an acute phase protein that has been suggested to have a significant proinflammatory role in Alzheimer’s disease (AD). However, whether circulating lipocalin-2 is involved in the pathogenesis of AD during the preclinical stage, where there is amyloid-beta (Aβ) and tau pathology but no significant cognitive decline, is not known.

Cognitively normal (Clinical Dementia Rating of 0) volunteers from the Healthy Aging & Senile Dementia and Adult Children Study (Missouri, USA) with body mass index < 30, fasting plasma and cerebrospinal fluid (CSF) samples were included in this cross-sectional study. Preclinical AD was defined by previously established CSF criteria (preclinical AD: 20 men, 18 women; control: 45 men, 73 women). Plasma lipocalin-2 levels were measured by a commercially available immunoassay (MilliporeSigma).

Plasma lipocalin-2 levels were significantly higher in preclinical AD subjects compared to control subjects (preclinical AD: 82.0 ± 23.7 ng/mL, control: 71.5 ± 20.0 ng/mL, p = 0.007). There were no significant differences in plasma lipocalin-2 levels between male and female subjects or between apolipoprotein E ε4 carriers and non-carriers (p > 0.05). After adjusting for age, plasma lipocalin-2 levels were negatively correlated with CSF Aβ₄₂ levels (β = -0.22, p = 0.006) but not with CSF tau or p-tau levels (p > 0.05).

These results suggest that circulating levels of lipocalin-2 are altered in the earliest stages of AD and are directly associated with established biomarkers of AD pathology. Although the findings need verification in additional cohorts and the underlying molecular mechanisms defined, these findings may lead to the development of lipocalin-2 and associated pathways as novel biomarkers and therapeutic targets of AD at its earliest stages.