Abstract
Plasma biomarkers related to amyloid, tau, and neurodegeneration (ATN) show great promise for identifying these pathological features of Alzheimer’s Disease (AD) as shown by recent clinical studies and selected autopsy studies. We have evaluated ATN plasma biomarkers in a series of 312 well-characterized longitudinally followed research subjects with plasma available within 5 years or less before autopsy and examined these biomarkers in relation to a spectrum of AD and related pathologies. Plasma Aβ42, Aβ40, total Tau, P-tau181, P-tau231 and neurofilament light (NfL) were measured using Single molecule array (Simoa) assays. Neuropathological findings were assessed using standard research protocols. Comparing plasma biomarkers with pathology diagnoses and ratings, we found that P-tau181 (AUC = 0.856) and P-tau231 (AUC = 0.773) showed the strongest overall sensitivity and specificity for AD neuropathological change (ADNC). Plasma P-tau231 showed increases at earlier ADNC stages than other biomarkers. Plasma Aβ42/40 was decreased in relation to amyloid and AD pathology, with modest diagnostic accuracy (AUC = 0.601). NfL was increased in non-AD cases and in a subset of those with ADNC. Plasma biomarkers did not show changes in Lewy body disease (LBD), hippocampal sclerosis of aging (HS) or limbic-predominant age-related TDP-43 encephalopathy (LATE) unless ADNC was present. Higher levels of P-tau181, 231 and NfL predicted faster cognitive decline, as early as 10 years prior to autopsy, even among people with normal cognition or mild cognitive impairment. These results support plasma P-tau181 and 231 as diagnostic biomarkers related to ADNC that also can help to predict future cognitive decline, even in predementia stages. Although NfL was not consistently increased in plasma in AD and shows increases in several neurological disorders, it had utility to predict cognitive decline. Plasma Aβ42/40 as measured in this study was a relatively weak predictor of amyloid pathology, and different assay methods may be needed to improve on this. Additional plasma biomarkers are needed to detect the presence and impact of LBD and LATE pathology.
Highlights
Pathological processes underlying Alzheimer’s Disease (AD) include the aggregation of β-amyloid (A) and tau (T) proteins and progressive neurodegeneration (N), which can be combined into an ATN framework for diagnosis and staging of disease [15].Denis S
We examined plasma biomarkers in other common age-related pathologies that can cause dementia, including two key pathologic features of limbic-predominant age-related TDP-43 encephalopathy (LATE): Hippocampal sclerosis (HS) which has been assessed on all cases) and abnormal hippocampal TDP-43 accumulation of LATE, and Lewy body disease (LBD)
When we modeled the relationship between DRS score decline and baseline plasma phosphorylated tau (P-tau) or neurofilament light (NfL) biomarkers in all subjects with AD pathology (Fig. 6b–d), we found that cognitive decline was steeper in patients with high baseline plasma P-tau181 (> 3.64 pg/mL) or P-tau231 (> 10.5 pg/mL) levels than in those with low levels of these plasma biomarkers
Summary
Pathological processes underlying Alzheimer’s Disease (AD) include the aggregation of β-amyloid (A) and tau (T) proteins (forming plaques and tangles, respectively) and progressive neurodegeneration (N), which can be combined into an ATN framework for diagnosis and staging of disease [15]. Several studies have examined plasma biomarkers against neuropathology findings noted at autopsy and have found concordance between higher P-tau levels and tangle burden. We examine the central plasma biomarkers that relate to the ATN framework in a large series of patients followed at a single research center who had neuropathologic evaluation of their brains at autopsy. We examine the relationship between plasma biomarkers and cognitive change
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
