Longitudinal changes in Alzheimer's‐related plasma biomarkers and brain amyloid

Abstract

INTRODUCTIONUnderstanding longitudinal plasma biomarker trajectories relative to brain amyloid changes can help devise Alzheimer's progression assessment strategies.METHODSWe examined the temporal order of changes in plasma amyloid‐β ratio (), glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and phosphorylated tau ratios (, ) relative to 11C‐Pittsburgh compound B (PiB) positron emission tomography (PET) cortical amyloid burden (PiB−/+). Participants (n = 199) were cognitively normal at index visit with a median 6.1‐year follow‐up.RESULTSPiB groups exhibited different rates of longitudinal change in . Change in brain amyloid correlated with change in GFAP (r = 0.5, 95% CI = [0.26, 0.68]). The greatest relative decline in (−1%/year) preceded brain amyloid positivity by 41 years (95% CI = [32, 53]).DISCUSSIONPlasma may begin declining decades prior to brain amyloid accumulation, whereas p‐tau ratios, GFAP, and NfL increase closer in time.HIGHLIGHTS Plasma declines over time among PiB− but does not change among PiB+. Phosphorylated‐tau to Aβ42 ratios increase over time among PiB+ but do not change among PiB−. Rate of change in brain amyloid is correlated with change in GFAP and neurofilament light chain. The greatest decline in may precede brain amyloid positivity by decades.

Proteomic Indicators of Health Predict Alzheimer's Disease Biomarker Levels and Dementia Risk

“…Although the general patterns of protein-based risk factor associations with plasma and cortical Aβ were similar, the sample size for cortical Aβ was smaller, with considerably less statistical power to detect effects. Although prior studies suggest that plasma Aβ 42/40 is predictive of cortical Aβ PET positivity, 47 several studies-including one from our group 48 -show that plasma Aβ 42/40 declines prior to and is predictive of elevations in cortical Aβ (measured using PET). 49 Thus, given the cognitively normal sample, Aβ 42/40 may provide a more meaningful indicator of Aβ burden, particularly among this sample, where 71% of participants do not have elevations in cortical amyloid.…”

Modeling the temporal evolution of plasma p‐tau in relation to amyloid beta and tau PET

“…The assumption of a hypothetical common curve is an extension of prior work described by Jack et al 21,22 and has been similarly implemented in other recently described temporal modeling approaches. 20,23,25,27 In this study, we extended prior AFT models to accommodate five biomarker outcomes: Aβ PET meta-ROI, tau PET temporal meta-ROI, plasma p-tau217, plasma p-tau181, and GFAP. Aβ and tau PET were natural log-transformed to account for skewness.…”

“…16,17 Limited longitudinal modeling studies suggest that plasma p-tau181 and p-tau217 become abnormal around the same time or within several years after Aβ PET and precede changes in tau PET. [18][19][20] While these studies provide information on the timing of change in the population, they do not explain how plasma p-tau and PET biomarker changes are related on the individual level. Both are of interest.…”

“…to model these trajectories, 20,[23][24][25][26][27] and the approach our group has employed is an accelerated failure time (AFT) or non-linear mixedeffects model. 28 The AFT model differs from other approaches in that the primary result is the relative timing of biomarker progression on the individual level, whereas others model population-level change.…”

Plasma p‐tau217, p‐tau181, and NfL as early indicators of dementia risk in a community cohort: The Shanghai Aging Study

“…Previous studies found plasma p-tau217 and p-tau181 were associated with amyloid PET, 16,36,[41][42][43][44] and could distinguish Aβ+ from Aβ-, 11,14,16,23,36,[45][46][47][48] which implied that plasma p-tau reflected the brain amyloid pathology. Comparing to plasma p-tau181, p-tau217 could more accurately distinguish Aβ+ from Aβ-in community residents in the MCSA.…”