Circulating Leptin in the Preclinical Stage of Alzheimer’s Disease (4065)

Objective: To determine if circulating leptin levels are altered in preclinical Alzheimer’s Disease (AD). Background: Weight loss is an early manifestation of AD that can precede the cognitive decline. Leptin is an adipocyte-derived hormone that is essential for regulating body weight. However, it is not known if leptin signaling is altered in individuals during the preclinical stage of AD, where there is Aβ and tau pathology but no significant cognitive decline. Design/Methods: Cognitively normal (Clinical Dementia Rating of 0) volunteers from two cohorts, 156 subjects (58% female) from St. Louis and 28 subjects (50% female) from Atlanta, with fasting plasma and cerebrospinal fluid (CSF) samples were included in this cross-sectional study. Preclinical AD was defined by previously established CSF criteria. Plasma leptin was measured by ELISA (R&D Systems). Results: St. Louis Cohort: In males, plasma leptin was significantly lower in preclinical AD compared to controls (control: 3.97 ± 1.61 ng/mL; preclinical AD: 2.83 ± 1.18 ng/mL, p=0.006). Plasma leptin was associated with CSF Aβ42 (β=0.41, p=0.001) but not CSF tau or p-tau181 (all p>0.05). In females, there was no significant difference in plasma leptin levels between preclinical AD and controls (p>0.05). Atlanta cohort: In males, there was a trend towards lower plasma leptin levels in preclinical AD compared to controls (p=0.17). In females, there was an insufficient number of preclinical AD subjects for analysis. Secondary analysis in this cohort showed that African Americans have significantly higher plasma leptin levels than Caucasians, suggesting leptin resistance may be a confounding factor for African Americans. Conclusions: These results suggest that alterations in leptin signaling may be caused by early Aβ pathology. Although these findings need verification in additional sufficiently powered cohorts and the mechanisms defined including any differences due to sex and race, these findings may provide key insights into the mechanisms underlying weight loss early in AD. Disclosure: Dr. Sha has nothing to disclose. Dr. Hu has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AARP, Locks Law Firm, Interpleader Law, and Roche Diagnostics USA. Dr. Hu has received research support from Avid Radiopharmaceuticals and Fujirebio US. Dr. Iadecola has nothing to disclose. Dr. Ishii has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Relias Media. Dr. Ishii holds stock and/or stock options in Regneron Pharmaceuticals.