Generalizability of tau and amyloid plasma biomarkers in Alzheimer's disease cohorts of diverse genetic ancestries

Abstract

Introduction: Plasma phosphorylated threonine 181 of tau (pTau181) and amyloid beta (Aβ) are biomarkers for differential diagnosis and preclinical detection of Alzheimer disease (AD). Given differences in AD risk across diverse populations, the generalizability of existing biomarker data is not assured.

Methods: In 2086 individuals of diverse genetic ancestries (African American, Caribbean Hispanic, and Peruvian), we measured plasma pTau181 and Aβ42/Aβ40. Differences in biomarkers between cohorts and clinical diagnosis groups and the potential discriminative performance of the two biomarkers were assessed.

Results: pTau181 and Aβ42/Aβ40 were consistent across cohorts. Higher levels of pTau181 were associated with AD, while Aβ42/Aβ40 had minimal differences. Correspondingly, pTau181 had a greater predictive value than Aβ42/Aβ40; however, the area under the curve differed between cohorts.

Discussion: pTau181 as a plasma biomarker for clinical AD is generalizable across genetic ancestries, but its predictive value may vary. Combining genomic and biomarker data from diverse individuals will increase understanding of genetic risk and refine clinical diagnoses.

Highlights: This is a diverse ancestry study of plasma biomarkers for AD. Plasma biomarkers were assessed in African Americans, Caribbean Hispanics, and Peruvians. Biomarker levels were consistent across the diverse cohorts. Plasma phosphorylated tau was higher in AD in all cohorts. Plasma biomarker findings in diverse cohorts largely generalize with existing European studies.

Keywords: Alzheimer's disease; amyloid; diverse ancestry; plasma biomarkers; tau.

FIGURE 1

Global genomic ancestry analysis. (A) Principal component analyses. Estimation of relationship to ancestral reference groups from HGDP: maroon = African, green = Amerindian, yellow = East Asian, blue = European, or each sample cohort: light green = Cuban American, violet = Peruvian, red = Puerto Rican, aqua = African American. (B) Ancestral admixture estimations. Each column on the x‐axis represents one participant. Colors in each vertical line represent the proportion of ancestral admixture. red = African, blue = European, green = Amerindian, yellow = East Asian. HGDP, Human Genome Diversity Project.

FIGURE 2

AD biomarker levels across ancestral groups African Americans, Peruvians, and Caribbean Hispanics. (A) pTau181 in CU. (B) pTau181 in AD. (C) Aβ42/Aβ40 in CU. (D) Aβ42/Aβ40 in AD. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. AD, Alzheimer's disease; CU, cognitively unimpaired; ns, not significant.

FIGURE 3

Plasma pTau181 comparison analysis. Comparisons of pTau181 concentration in clinical diagnosis statuses of AD, MCI, or CU in (A) overall combined cohort, (B) African Americans, (C) Peruvians, and (D) Caribbean Hispanics. Each point represents one individual's pTau181 measurement. Concentrations are shown as median ± interquartile range. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. AD, Alzheimer's disease; CU, cognitively unimpaired; MCI, mild cognitively impaired; ns, not significant.

FIGURE 4

Plasma Aβ42/Aβ40 ratio comparison analysis. Comparisons of Aβ42/Aβ40 ratio in clinical diagnosis statuses of AD, MCI, or CU in (A) overall combined cohort, (B) African Americans, (C) Peruvians, and (D) Caribbean Hispanics. Each point represents one individual's Aβ42/Aβ40 ratio. Ratios are shown as median ± interquartile range. *p < 0.05. AD, Alzheimer's disease; CU, cognitively unimpaired; MCI, mild cognitively impaired; ns, not significant.

FIGURE 5

pTau181 and Aβ42/Aβ40 ratio comparisons in African American plasma and serum analysis. Comparisons of pTau181 concentrations between serum and plasma in (A) CU and (B) AD. Aβ42/Aβ40 ratio between serum and plasma in (C) CU and (D) AD. Each point represents one individual's measurement. Concentrations are shown as median  ±  interquartile range. *p < 0.05, **p < 0.01, ****p < 0.0001. AD, Alzheimer's disease; CU, cognitively unimpaired.

FIGURE 6

Serum pTau181 and Aβ42/Aβ40 ratio comparison analysis. Comparisons of (A) pTau181 concentration and (B) Aβ42/Aβ40 ratio in clinical diagnosis statuses of AD, mild cognitively impaired, or CU in a subset of AA individuals for which plasma was not available. Each point represents one individual's measurement. Concentrations are shown as median ± interquartile range. ****p  < 0.0001. AA, African American; AD, Alzheimer's disease; CU, cognitively unimpaired; ns, not significant.

FIGURE 7

ROC curves of plasma and serum biomarkers for classification of AD status in (A) overall combined cohort, (B) Caribbean Hispanics, (C) Peruvians, (D) African Americans – plasma, (E) African Americans – serum. Red lines represent pTau181 alone, green lines Aβ42/Aβ40 ratio alone, and blue lines the combination of pTau181 and Aβ42/Aβ40 ratio. AD, Alzheimer's disease; ROC, receiver operating characteristic.