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. 2024 Jun;20(6):4159-4173.
doi: 10.1002/alz.13835. Epub 2024 May 15.

Associations among plasma, MRI, and amyloid PET biomarkers of Alzheimer's disease and related dementias and the impact of health-related comorbidities in a community-dwelling cohort

Marc D Rudolph  1 , Courtney L Sutphen  1 , Thomas C Register  1 , Christopher T Whitlow  1 , Kiran K Solingapuram Sai  1 , Timothy M Hughes  1 , James R Bateman  1 , Jeffrey L Dage  2 , Kristen A Russ  2 , Michelle M Mielke  1 , Suzanne Craft  1 , Samuel N Lockhart  1
Affiliations

Associations among plasma, MRI, and amyloid PET biomarkers of Alzheimer's disease and related dementias and the impact of health-related comorbidities in a community-dwelling cohort

Marc D Rudolph et al. Alzheimers Dement. 2024 Jun.

Abstract

Introduction: We evaluated associations between plasma and neuroimaging-derived biomarkers of Alzheimer's disease and related dementias and the impact of health-related comorbidities.

Methods: We examined plasma biomarkers (neurofilament light chain, glial fibrillary acidic protein, amyloid beta [Aβ] 42/40, phosphorylated tau 181) and neuroimaging measures of amyloid deposition (Aβ-positron emission tomography [PET]), total brain volume, white matter hyperintensity volume, diffusion-weighted fractional anisotropy, and neurite orientation dispersion and density imaging free water. Participants were adjudicated as cognitively unimpaired (CU; N = 299), mild cognitive impairment (MCI; N = 192), or dementia (DEM; N = 65). Biomarkers were compared across groups stratified by diagnosis, sex, race, and APOE ε4 carrier status. General linear models examined plasma-imaging associations before and after adjusting for demographics (age, sex, race, education), APOE ε4 status, medications, diagnosis, and other factors (estimated glomerular filtration rate [eGFR], body mass index [BMI]).

Results: Plasma biomarkers differed across diagnostic groups (DEM > MCI > CU), were altered in Aβ-PET-positive individuals, and were associated with poorer brain health and kidney function.

Discussion: eGFR and BMI did not substantially impact associations between plasma and neuroimaging biomarkers.

Highlights: Plasma biomarkers differ across diagnostic groups (DEM > MCI > CU) and are altered in Aβ-PET-positive individuals. Altered plasma biomarker levels are associated with poorer brain health and kidney function. Plasma and neuroimaging biomarker associations are largely independent of comorbidities.

Keywords: dementias; neuroimaging; plasma biomarkers.

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Conflict of interest statement

The authors declare the following financial interests/personal relationships, which may be considered as potential competing interests: Marc Rudolph, Courtney Sutphen, Thomas Register, Christopher Whitlow, Kiran Solingapuram Sai, Timothy Hughes, and Kristen Russ have no conflicts of interest to disclose. James R. Bateman and Samuel N. Lockhart receive funding from the NIH and Alzheimer's Association. Dage is an inventor on patents or patent applications of Eli Lilly and Company relating to the assays, methods, reagents, and/or compositions of matter for p‐tau assays. Dage has served as a consultant or on advisory boards for Eisai, Abbvie, Genotix Biotechnologies Inc., Gates Ventures, Karuna Therapeutics, AlzPath Inc., and Cognito Therapeutics, Inc., and received research support from ADx Neurosciences, Fujirebio, AlzPath Inc., Roche Diagnostics, and Eli Lilly and Company in the past 2 years. Dage has received speaker fees from Eli Lilly and Company. Dage is a founder and advisor for Monument Biosciences. Dage has stock or stock options in Eli Lilly and Company, Genotix Biotechnologies, AlzPath Inc., and Monument Biosciences. Michelle Mielke consults for or serves on advisory boards for Biogen, Eisai, Lilly, Merck, Roche, and Siemens Healthineers. Suzanne Craft reports disclosures for vTv Therapeutics, T3D Therapeutics, Cyclerion Inc., and Cognito Inc. Author disclosures are available in the supporting information.

Figures

FIGURE 1
FIGURE 1
Unadjusted group comparisons of plasma and neuroimaging measures by diagnostic status. Note that levels of plasma and neuroimaging biomarkers are compared across diagnostic groups (unadjusted; Dx: blue = CU; green = MCI; red = DEM). Aβ, amyloid beta; BVOL, brain volume (adjusted for intracranial volume); CU, cognitively unimpaired; DEM, dementia; DWI, diffusion weighted imaging; Dx, diagnosis; FA, fractional anisotropy; FW, freewater; GFAP, glial fibrillary acidic protein; MCI, mild cognitive impairment; NfL, neurofilament light; NODDI, neurite orientation dispersion and density imaging; PLASMA SUM = sum Z‐scored composite of NfL, GFAP, Aβ42/40, and p‐tau181; WMH, log‐transformed global white matter hyperintensity volume.
FIGURE 2
FIGURE 2
Unadjusted linear relationships between plasma and neuroimaging biomarkers. Note that unadjusted bivariate associations between plasma and neuroimaging markers are presented. r2 statistics and p values represent lines of best fit (solid black line) for the full sample of participants (irrespective of consensus diagnosis). Plasma‐neuroimaging associations, stratified by clinical diagnosis, are provided for comparison (blue = CU; green = MCI; red = DEM). Plasma biomarkers are most strongly associated with Aβ‐PET deposition. Adj, linear models adjusted for comorbidities (eGFR, BMI); Aβ, amyloid beta; BVOL, brain volume (adjusted for intracranial volume); CU, cognitively unimpaired; DEM, dementia; base, baseline unadjusted models; DWI, diffusion weighted imaging; Dx, diagnosis; FA, fractional anisotropy; FW, free water; GFAP, glial fibrillary acidic protein; MCI, mild cognitive impairment; NfL, neurofilament light; NODDI, neurite orientation dispersion and density imaging; SUVr, standardized uptake volume ratio; WMH, log‐transformed global white matter hyperintensity volume; F‐Adj, adjusted models plus additional covariates (age, sex, race, education, APOE ε4 status, medications); F‐Adj*, fully adjusted models plus clinical diagnosis.
See this image and copyright information in PMC

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