Neuropathologic correlates of distinct plasma biomarker profiles in community-living older adults

Abstract There has been a rapid growth in research on peripheral fluid biomarkers for Alzheimer’s disease (AD) and AD-related dementias, because they are non-invasive, relatively inexpensive and easily accessible. The most commonly used plasma biomarkers include amyloid-β (Aβ), phosphorylated tau (p-tau), neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP). The extent to which distinct profiles of multiple plasma biomarkers correlate with common neuropathologies is unclear. Using clinicopathologic data from 405 community-dwelling older adults, we applied latent profile analysis to four plasma biomarkers, i.e. Aβ42/40 ratio, p-tau217, NfL and GFAP, and examined the correlates of the latent profiles with four degeneration measures: AD, Lewy bodies, limbic-predominant age-related TDP-43 encephalopathy (LATE) and hippocampal sclerosis; and five vascular measures: chronic macroscopic infarcts, microinfarcts, cerebral amyloid angiopathy, atherosclerosis and arteriosclerosis. On average, participants died at the age of 89, and blood samples for plasma biomarkers were measured 3.9 years before death. Over 75% were female, and 24% were non-Latino Black. We observed three distinct biomarker profiles. Profile 1, characterized by low p-tau217, low GFAP, low NfL and high Aβ42/40, represented most participants (55.6%), with better than average biomarker levels. Both Profile 2 and Profile 3 showed worse than average biomarker levels. Profile 2, representing 34.8% of the participants, was high in p-tau217 and GFAP. In contrast, Profile 3, representing 9.6% of the participants, was high in NfL and GFAP. Examination of neuropathologic correlates of these plasma biomarker profiles revealed that Profile 2 exemplifies older adults with a high burden of neurodegeneration; almost all participants (92.9%) in Profile 2 had a diagnosis of pathologic AD, and the group also had the highest percentage of participants with Lewy bodies (41.1%). In comparison, Profile 3 exemplifies older adults with more severe vascular conditions; participants in this group had the highest percentage of macroscopic infarcts (31.6%) and moderate or severe atherosclerosis (42.1%). Together, these findings suggest that common plasma biomarkers may exhibit profiles reflective of distinct pathophysiologic processes.