Research ArticleNEUROSCIENCE

Association of naturally occurring antibodies to β-amyloid with cognitive decline and cerebral amyloidosis in Alzheimer’s disease

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Science Advances  01 Jan 2021:
Vol. 7, no. 1, eabb0457
DOI: 10.1126/sciadv.abb0457
  • Fig. 1 Plasma and CSF levels of NAbs targeting different domains of Aβ in the Chongqing cohort.

    (A to D) Comparison of plasma levels of (A) NAbs-Aβ1–12, (B) NAbs-Aβ7–18, (C) NAbs-Aβ19–30, and (D) NAbs-Aβ25–36 between CN (n = 91) and AD (n = 91). Unpaired t test. (E to H) Comparison of CSF levels of (E) NAbs-Aβ1–12, (F) NAbs-Aβ7–18, (G) NAbs-Aβ19–30, and (H) NAbs-Aβ25–36 between CN (n = 40) and AD (n = 40). Unpaired t test. * denotes nominal significance only at P < 0.05. ** denotes nominal significance only at P < 0.01. *** denotes significance at the Bonferroni correction at P < 0.001. † denotes less than Bonferroni-corrected α.

  • Fig. 2 Plasma levels of NAbs targeting different domains of Aβ in the AIBL cohort.

    (A to D) Comparison of plasma levels of (A) NAbs-Aβ1–12, (B) NAbs-Aβ7–18, (C) NAbs-Aβ19–30, and (D) NAbs-Aβ25–36 between the Aβ-PET (n = 210) and Aβ-PET+ (n = 150) subjects. Unpaired t test. (E to H) Comparison of plasma levels of (E) NAbs-Aβ1–12, (F) NAbs-Aβ7–18, (G) NAbs-Aβ19–30, and (H) NAbs-Aβ25–36 among the Aβ-PET CN (n = 210), Aβ-PET+ CN (n = 120), and Aβ-PET+ AD (n = 30) groups. One-way analysis of variance (ANOVA). N.S. denotes no statistical difference. * denotes nominal significance only at P < 0.05. ** denotes nominal significance only at P < 0.01. *** denotes significance after Bonferroni correction at P < 0.001. † denotes less than Bonferroni-corrected α.

  • Fig. 3 Correlations between plasma levels of NAbs targeting different domains of Aβ and load of Aβ deposition in the brain at baseline in the AIBL cohort.

    Fit lines are shown for the correlations between plasma levels of (A) NAbs-Aβ1–12, (B) NAbs-Aβ7–18, (C) NAbs-Aβ19–30, and (D) NAbs-Aβ25–36 and the centiloid score. The shaded areas represent the 95% confidence interval. Spearman correlation analysis. * denotes nominal significance only at P < 0.05. *** denotes significance after Bonferroni correction at P < 0.001. † denotes less than Bonferroni-corrected α.

  • Fig. 4 Correlations between plasma levels of NAbs targeting different domains of Aβ and cognitive function at baseline in the AIBL cohort.

    (A to D) Fit lines are shown for the correlations between plasma levels of (A) NAbs-Aβ1–12, (B) NAbs-Aβ7–18, (C) NAbs-Aβ19–30, and (D) NAbs-Aβ25–36 and PACC in different subgroups. (E to H) Fit lines are shown for the correlations between plasma levels of (E) NAbs-Aβ1–12, (F) NAbs-Aβ7–18, (G) NAbs-Aβ19–30, and (H) NAbs-Aβ25–36 and EM in different subgroups. The shaded areas represent the 95% confidence interval. Spearman correlation analysis. N.S. denotes no statistical difference. ** denotes nominal significance only at P < 0.01. *** denotes significance after Bonferroni correction at P < 0.001. † denotes less than Bonferroni-corrected α.

  • Fig. 5 Linear mixed-effects model plots for plasma levels of NAbs targeting different domains of Aβ and speed of cognitive decline in the AIBL cohort.

    The plots have been separated for APOE ε4 allele status given its effect on both PACC score and the biomarkers. Fit lines are shown for the relationships between plasma levels of (A) NAbs-Aβ1–12, (B) NAbs-Aβ7–18, (C) NAbs-Aβ19–30, and (D) NAbs-Aβ25–36 and speed of PACC decline in different subgroups.

  • Table 1 Correlations of NAbs-Aβ with the rate of PACC decline in the total cohort and the Aβ-PET+ subgroup.

    Note: Linear mixed models with adjustment of age, gender, education level, and APOE ε4 genotype.

    Parameterβ (SE) unadjustedP values (unadjusted)β (SE) adjustedP values (adjusted)
    Total cohort
    NAbs-Aβ1–12Biomarker−1.52 (0.36)3.23 × 10−5*−0.903 (0.325)0.00576
    NAbs-Aβ7–18Biomarker−0.834 (0.378)0.0279−0.369 (0.332)0.267
    NAbs-Aβ13–24Biomarker0.355 (0.269)0.1880.558 (0.232)0.0166
    NAbs-Aβ19–30Biomarker2.32 (0.393)8.14 × 10−9*1.89 (0.345)8.07 × 10−8*
    NAbs-Aβ25–36Biomarker2.62 (0.394)1.17 × 10−10*2.28 (0.343)1.19 × 10−10*
    NAbs-Aβ31–42Biomarker0.288 (0.606)0.6351.02 (0.523)0.051
    NAbs-Aβ1–42Biomarker−0.245 (0.179)0.172−0.117 (0.155)0.451
    NAbs-Aβ1–12Time0.03 (0.019)0.1160.0227 (0.019)0.234
    NAbs-Aβ7–18Time0.016 (0.0187)0.3940.0167 (0.0187)0.373
    NAbs-Aβ13–24Time−0.00526 (0.0167)0.7522.51 × 10−5 (0.017)0.999
    NAbs-Aβ19–30Time−0.0256 (0.0311)0.412−0.0053 (0.0312)0.866
    NAbs-Aβ25–36Time0.0291 (0.0316)0.3580.0504 (0.0316)0.113
    NAbs-Aβ31–42Time−0.0147 (0.011)0.18−0.00896 (0.011)0.415
    NAbs-Aβ1–42Time−0.0136 (0.0192)0.479−0.0084 (0.0193)0.663
    NAbs-Aβ1–12Biomarker × Time−0.181 (0.059)0.00248−0.139 (0.059)0.0198
    NAbs-Aβ7–18Biomarker × Time−0.13 (0.0573)0.0249−0.114 (0.0573)0.0484
    NAbs-Aβ13–24Biomarker × Time−0.0481 (0.0415)0.248−0.0474 (0.0415)0.254
    NAbs-Aβ19–30Biomarker × Time0.00985 (0.0645)0.879−0.0248 (0.0647)0.702
    NAbs-Aβ25–36Biomarker × Time−0.109 (0.0642)0.0916−0.143 (0.0642)0.0269
    NAbs-Aβ31–42Biomarker × Time−0.0875 (0.0855)0.307−0.0943 (0.0856)0.272
    NAbs-Aβ1–42Biomarker × Time−0.0112 (0.0251)0.656−0.0109 (0.0252)0.667
    Aβ-PET+ group
    NAbs-Aβ1–12Biomarker−1.96 (0.659)0.00341−1.71 (0.603)0.00514
    NAbs-Aβ7–18Biomarker−1.21 (0.707)0.088−0.694 (0.643)0.282
    NAbs-Aβ13–24Biomarker0.831 (0.497)0.09661.18 (0.439)0.00801
    NAbs-Aβ19–30Biomarker3.7 (0.747)1.65 × 10−6*3.02 (0.694)2.32 × 10−5*
    NAbs-Aβ25–36Biomarker3.77 (0.765)1.82 × 10−6*3.38 (0.694)2.41 × 10−6*
    NAbs-Aβ31–42Biomarker−0.28 (1.23)0.8210.211 (1.1)0.848
    NAbs-Aβ1–42Biomarker−0.259 (0.372)0.487−0.112 (0.333)0.736
    NAbs-Aβ1–12Time−0.0098 (0.0582)0.867−0.0183 (0.0576)0.751
    NAbs-Aβ7–18Time0.0199 (0.0537)0.7110.0177 (0.0533)0.74
    NAbs-Aβ13–24Time−0.11 (0.042)0.00985−0.102 (0.0416)0.0159
    NAbs-Aβ19–30Time−0.287 (0.0877)0.00128*−0.273 (0.0864)0.00187*
    NAbs-Aβ25–36Time0.0209 (0.0887)0.8140.0237 (0.0872)0.786
    NAbs-Aβ31–42Time−0.0929 (0.0298)0.00225−0.0895 (0.0296)0.00295
    NAbs-Aβ1–42Time0.0578 (0.047)0.2210.0557 (0.0466)0.233
    NAbs-Aβ1–12Biomarker × Time−0.282 (0.177)0.114−0.248 (0.175)0.159
    NAbs-Aβ7–18Biomarker × Time−0.362 (0.155)0.0212−0.35 (0.154)0.0248
    NAbs-Aβ13–24Biomarker × Time0.0435 (0.0967)0.6540.0246 (0.0961)0.799
    NAbs-Aβ19–30Biomarker × Time0.433 (0.195)0.02730.402 (0.191)0.0369
    NAbs-Aβ25–36Biomarker × Time−0.259 (0.196)0.187−0.262 (0.192)0.175
    NAbs-Aβ31–42Biomarker × Time−0.00977 (0.266)0.971−0.034 (0.264)0.898
    NAbs-Aβ1–42Biomarker × Time−0.205 (0.0561)0.000357*−0.201 (0.0558)0.000426*

    *Less than Bonferroni-corrected α. (α = 0.002). P < 0.05 were expressed as boldface.

    Supplementary Materials

    • Supplementary Materials

      Association of naturally occurring antibodies to β-amyloid with cognitive decline and cerebral amyloidosis in Alzheimer’s disease

      Yu-Hui Liu, Jun Wang, Qiao-Xin Li, Christopher J. Fowler, Fan Zeng, Juan Deng, Zhi-Qiang Xu, Hua-Dong Zhou, James D. Doecke, Victor L. Villemagne, Yen Ying Lim, Colin L. Masters, Yan-Jiang Wang

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