Plasma biomarkers of Alzheimer’s disease predict cognitive decline and could improve clinical trials in the cognitively unimpaired elderly

Abstract

Plasma biomarkers of amyloid, tau, and neurodegeneration (ATN) need to be characterized in cognitively unimpaired (CU) elderly indviduals. We therefore tested if plasma measurements of amyloid-β (Aβ)42/40, phospho-tau217 (P-tau217), and neurofilament light (NfL) together predict clinical deterioration in 435 CU individuals followed for an average of 4.8 ±1.7 years in the BioFINDER study. A combination of all three plasma biomarkers and basic demographics best predicted change in the cognition (Pre-Alzheimer’s Clinical Composite; R2=0.14, 95% CI [0.12-0.17]; P<0.0001) and subsequent AD dementia (AUC=0.82, 95% CI [0.77-0.91], P<0.0001). In a simulated clinical trial, a screening algorithm combining all three plasma biomarkers would reduce the required sample size by 70% (95% CI [54-81]; P<0.001) with cognition as trial endpoint, and by 63% (95% CI [53-70], P<0.001) with subsequent AD dementia as trial endpoint. Plasma ATN biomarkers show usefulness in cognitively unimpaired populations and could make large clinical trials more feasible and cost-effective.

Plasma pTau-217 in preclinical Alzheimer’s disease

“…Plasma biomarkers have potential for prescreening AD biomarker positive participants in clinical trials. 3 To that end, our results are encouraging, as we observed strong relationships between plasma pTau 217 and concurrent brain imaging biomarkers of AD, with an AUC of approximately 0.91 for identifying PiB+ participants, and 0.95 for identifying those who were MK+. These values are similar to those seen for the easier task of discriminating AD A𝛽𝛽 + from CU A𝛽𝛽 − groups, and are high compared to other reports describing cognitively unimpaired elderly groups in AIBL, 11 MCSA, 24 and BioFINDER.…”

“…Although similar relationships have been found in older groups, our report establishes such relationships with biomarkers measured in late midlife. 3, 23, 24 Given the interest in establishing valid surrogate outcomes for AD pharmaceutical research, 47 our findings may inform the trial design in which the fitness of plasma pTau 217 for that purpose is evaluated.…”

“…1,2 The utility and convenience of an accurate blood test has clear implications for accelerating and improving clinical research and practice. [1][2][3][4] Several candidate markers exist including massspectrometry [5][6][7] and immunoassay 8 measured A𝛽𝛽 42 and A𝛽𝛽 40 and their ratio, and phosphorylated tau at threonine 217 (pTau 217 ), 9 181 (pTau 181 ), 10 and other phosphorylated sites, 11 as well as non-specific markers of neurodegeneration and astrogliosis, including neurofilament light (NfL) 12,13 and glial fibrillary acidic protein (GFAP). [14][15][16] Recently, interest has turned to pTau 217 , as cerebrospinal fluid levels increase early in autosomal dominant AD 17 and better discriminate AD from non-AD subgroups of cognitively impaired adults, compared to pTau 181 .…”

“…In this same cohort, baseline pTau 217 levels affected cognitive change. 3 In the Australian Imaging, Biomarker & Lifestyle study (AIBL), among CU adults (mean age=75), a twofold increase in levels of the pTau 217 + marker in A𝛽𝛽 + compared to A𝛽𝛽 − was recently reported, 11 although the correlation between this biomarker and A𝛽𝛽 centiloids was relatively weaker in CU than in AD and MCI, perhaps due to restriction of range (𝜌𝜌 = 0.64 vs. 0.45). In the Mayo Clinic Study of Aging, among CU adults (mean age=79), a smaller fold increase of 0.49 was reported in A𝛽𝛽 + compared to A𝛽𝛽 − .…”