Plasma biomarkers for diagnosis of Alzheimer's disease and prediction of cognitive decline in individuals with mild cognitive impairment

Abstract

BackgroundThe last few years have seen major advances in blood biomarkers for Alzheimer's Disease (AD) with the development of ultrasensitive immunoassays, promising to transform how we diagnose, prognose, and track progression of neurodegenerative dementias.MethodsWe evaluated a panel of four novel ultrasensitive electrochemiluminescence (ECL) immunoassays against presumed CNS derived proteins of interest in AD in plasma [phosphorylated-Tau181 (pTau181), total Tau (tTau), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP)]. Two sets of banked plasma samples from the Massachusetts Alzheimer's Disease Research Center's longitudinal cohort study were examined: A longitudinal prognostic sample (n = 85) consisting of individuals with mild cognitive impairment (MCI) and 4 years of follow-up and a cross-sectional sample (n = 238) consisting of individuals with AD, other neurodegenerative diseases (OND), and normal cognition (CN).ResultsParticipants with MCI who progressed to dementia due to probable AD during follow-up had higher baseline plasma concentrations of pTau181, NfL, and GFAP compared to non-progressors. The best prognostic discrimination was observed with pTau181 (AUC = 0.83, 1.7-fold increase) and GFAP (AUC = 0.83, 1.6-fold increase). Participants with autopsy- and/or biomarker verified AD had higher plasma levels of pTau181, tTau and GFAP compared to CN and OND, while NfL was elevated in AD and further increased in OND. The best diagnostic discrimination was observed with pTau181 (AD vs CN: AUC = 0.90, 2-fold increase; AD vs. OND: AUC = 0.84, 1.5-fold increase) but tTau, NfL, and GFAP also showed good discrimination between AD and CN (AUC = 0.81–0.85; 1.5–2.2 fold increase).ConclusionsThese new ultrasensitive ECL plasma assays for pTau181, tTau, NfL, and GFAP demonstrated diagnostic utility for detection of AD. Moreover, the absolute baseline plasma levels of pTau181 and GFAP reflect cognitive decline over the next 4 years, providing prognostic information that may have utility in both clinical practice and clinical trial populations.

Comparison of plasma biomarkers and amyloid PET for predicting memory decline in cognitively unimpaired individuals

“…Studies that have been composed of persons with mild cognitive impairment (MCI), dementia, or combinations of impaired and CU individuals have shown the ability of plasma biomarkers to predict cognitive outcomes including, in some studies, person‐level prediction. 3 , 17 , 40 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 We recognize that biomarkers should have greater power to predict decline rates among individuals who are impaired at baseline and who are exhibiting more uniform cognitive decline in comparison to CU individuals.…”

Association of plasma biomarkers with cognition, cognitive decline, and daily function across and within neurodegenerative diseases: Results from the Ontario Neurodegenerative Disease Research Initiative

“… 8 , 9 , 38 , 42 , 43 , 44 , 45 , 46 As such, our broad results are in keeping with the idea that GFAP and NfL are not specific to a single neurodegenerative disease process, and support some neuropathological overlap across these diseases, especially in AD/MCI and PD. Other studies have also investigated the association of GFAP and NfL with cognition, albeit predominantly with screening tools of global cognition (e.g., Mini‐Mental State Examination [MMSE], MoCA), and have found elevated GFAP to be associated with worse baseline cognition or cognitive decline in AD/MCI, 10 , 47 PD or other synucleinopathies, 38 or FTD, 37 , 48 while others did not. 10 , 49 Similarly, studies have found elevated NfL to be associated with worse cognition or cognitive decline in AD/MCI, 8 , 10 , 42 , 50 PD or other synucleinopathies, 44 , 45 , 46 , 50 , 51 , 52 , 53 or FTD, 54 while others did not.…”

“… 10 , 49 Similarly, studies have found elevated NfL to be associated with worse cognition or cognitive decline in AD/MCI, 8 , 10 , 42 , 50 PD or other synucleinopathies, 44 , 45 , 46 , 50 , 51 , 52 , 53 or FTD, 54 while others did not. 10 , 47 , 48 , 49 , 53 , 55 …”

Towards early diagnosis of Alzheimer’s disease: advances in immune-related blood biomarkers and computational approaches

“…GFAP levels have recently been reported to be predictive of conversion of MCI to AD-dementia in several studies with steeper trends of conversion for cognitively abnormal groups ( 99 , 100 ) and were able to discriminate between MCI individuals who progressed to dementia and non-progressors ( 101 ). GFAP serum levels were also found to detect AD pathology in patients with MCI ( 99 ).…”