Relationship between the metabolic hormone response and plasma biomarkers of Alzheimer’s Disease and Related Dementias

Abstract

AbstractBackgroundInsulin resistance is a known risk factor for Alzheimer’s Disease and related dementias (ADRD). While the role of insulin on peripheral tissue is well understood, it’s effect on the brain remains unclear. Insulin and other gastrointestinal peptides can cross the blood‐brain barrier to form ligands in areas involved in metabolic response. Thus, it’s important to understand the relationship between systemic metabolic outcomes, such as meal‐stimulated hormone responses, and plasma biomarkers of ADRD.Method67 Participants (27 ADRD) completed a clinical and cognitive (Uniform Data Set 2.0) examination, meal tolerance test, and MRI scan. Cognitive scores were standardized to z‐scores and averaged to yield a global z‐score. EDTA plasma samples collected during the meal tolerance test were analyzed for glucose and insulin, and responses of peptide tyrosine tyrosine (PYY) and gastric inhibitory polypeptide (GIP) were analyzed in plasma from a subset of samples (n=53) containing DPP4 inhibitor. Further characterization of amyloid beta (Aβ42), pTau 181, Neurofilament light (NFL), and glial fibrillary acidic protein (GFAP) was performed using non‐fasted EDTA plasma on the Simoa HD‐X (Quanterix). We then assessed the relationship between the early metabolic and hormone responses to a mixed meal and baseline plasma ADRD biomarkers.ResultThe study sample consisted of 53.7% females and 43.3% APOE4 carriers with an average age of 74.9±6.3 and 16±3 years of education. All analyses were controlled for age and sex. Aβ42/pTau181, pTau 181, NFL, and GFAP were significantly elevated in ADRD compared to CH individuals (p<0.05) and tracked linearly with global cognitive z score (p=0.004, p<0.001, p<0.01, p=0.02, respectively). Linear regression revealed that both pTau 181 (β=0.334, p=0.009) and NFL (β=0.320, p=0.003) tracked significantly with the early PYY response (0‐30 minute), but not other metabolic responses, across the entire cohort. pTau181 and the Aβ42/pTau181 ratio each tracked significantly with global cognitive z score (p<0.001, p=0.01, respectively).ConclusionEarly PYY response to a mixed meal tracks with pTau181 and NFL, plasma biomarkers of ADRD neuropathology and neurodegeneration, respectively. The relationship between gut and brain biomarkers warrants additional study, and further characterization of cross‐sectional and longitudinal relationships with other meal‐related hormone responses is ongoing.