Characterizing plasma biomarkers of Alzheimer’s Disease in aging marmosets and genetically engineered PSEN1 mutation carriers.

Abstract

AbstractBackgroundAlzheimer’s Disease (AD) is a progressive disease that presents as a continuum evolution from preclinical AD to mild cognitive impairment and, ultimately, dementia. The phenotypic characterization of AD was unified under a biological construct research framework supported by the National Institutes on Aging and Alzheimer’s Association (NIA‐AA). This framework, referred to as ATN, is based on the presence of biomarkers for amyloid (Aβ, A), pathologic tau (T), and neurodegeneration (N). The present studies aimed to establish normative values of these biomarkers in our colony of outbred marmosets from infancy through aged individuals and compare them to the values from our population of marmosets genetically engineered with early onset familial mutations in the PSEN1 gene.MethodPlasma (EDTA) and fibroblast media from skin biopsies were evaluated using MesoScale Discovery (MSD) Aβ peptide panel 4G8 ELISA and Human Neurofilament L (NfL) per the manufacturer’s protocols for each kit.ResultThere was a significant increase in the plasma Aβ42:40 ratio in PSEN1 mutation carriers relative to age‐ and sex‐matched wild‐type (WT) controls, which was also observed in culture media generated from fibroblasts of the same individuals. Longitudinal analysis of plasma Aβ revealed consistent levels in WT controls across multiple samplings with persistent increases in PSEN1 carriers. An increase in Nfl was observed in aging WT marmosets relative to young subjects.ConclusionWe have optimized the detection of plasma biomarkers for amyloid and NfL in marmosets and established normative values within our colony. Importantly, these results demonstrate the sensitivity and validity of these reagents for tracking plasma Aβ longitudinally across the marmoset lifespan. Other clinically utilized commercially available reagents are in the process of being optimized and validated to enable an analogous marmoset ATN. Pilot studies are ongoing evaluating the potential of pTau plasma biomarkers as part of the longitudinal assessments. The application of the NIA‐AA Research Framework to marmosets will attain a more accurate characterization and understanding of the etiological sequence of events that lead to AD development, in line with the currently used framework in AD patients.