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. 2019 Sep 6:11:646-653.
doi: 10.1016/j.dadm.2019.07.004. eCollection 2019 Dec.

Plasma lipocalin-2 levels in the preclinical stage of Alzheimer's disease

Emily Eruysal  1 , Lisa Ravdin  2 , Hooman Kamel  1   2 , Costantino Iadecola  1   2 , Makoto Ishii  1   2
Affiliations

Plasma lipocalin-2 levels in the preclinical stage of Alzheimer's disease

Emily Eruysal et al. Alzheimers Dement (Amst). .

Abstract

Introduction: Lipocalin-2 is an acute-phase protein with pleotropic functions that has been implicated in several diseases including Alzheimer's disease (AD). However, it is unknown if circulating lipocalin-2 levels are altered in the preclinical stage of AD, where AD pathology has accumulated but cognition remains relatively intact.

Methods: In this cross-sectional study, we used an immunoassay to measure plasma lipocalin-2 levels in cognitively normal (Clinical Dementia Rating 0) elderly individuals. 38 of 156 subjects were classified as preclinical AD by cerebrospinal fluid criteria.

Results: Plasma lipocalin-2 levels were higher in preclinical AD compared with control subjects and associated with cerebrospinal fluid amyloid-beta42 levels but not cerebrospinal fluid tau or phosphorylated-tau181 levels. Exploratory analyses revealed that plasma lipocalin-2 was associated with executive function but not episodic memory.

Discussion: Collectively, these results raise the possibility that circulating lipocalin-2 is involved early in AD pathogenesis and may represent an early blood biomarker of amyloid-beta pathology.

Keywords: Alzheimer's disease; Amyloid beta-Peptides; Biomarkers; Blood; Dementia; Immunoassay; Lipocalin; NGAL; Preclinical.

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Figures

Fig. 1
Fig. 1
Plasma lipocalin-2 levels in preclinical AD group are higher than the control group. Lipocalin-2 levels were measured in fasting plasma samples by a commercial immunoassay. (A) Using CSF Aβ42 only as a criterion, preclinical AD group had higher plasma lipocalin-2 levels than control group (plasma lipocalin-2: 71.5 ± 20 for control and 82.0 ± 23.7 ng/mL, P = .007, n = 118 control and 38 preclinical AD subjects). (B) Using all three CSF AD biomarkers (Aβ42, tau, and p-tau181), plasma lipocalin-2 levels in preclinical AD group were higher than the control group (plasma lipocalin-2: 71.5 ± 20 for control and 82.9 ± 25.1 ng/mL, P = .0196, n = 118 control and 22 preclinical AD subjects). All individual values are presented with bars for means and standard deviations. *P < .05 and **P < .01. Abbreviations: AD, Alzheimer's disease; Aβ, amyloid-beta; CSF, cerebrospinal fluid.
Fig. 2
Fig. 2
Association between plasma lipocalin-2 and CSF AD biomarkers. All subjects regardless of preclinical AD status were included in the analysis. (A) Plasma lipocalin-2 were significantly associated with CSF Aβ42 (age- and sex-adjusted, beta coefficient –0.213, P = .009). (B, C) However, plasma lipocalin-2 were not associated with CSF tau (age- and sex-adjusted, beta coefficient 0.0561, P = .46) or with CSF p-tau181 (age- and sex-adjusted, beta coefficient 0.018, P = .82). Scatterplots with individual values and unadjusted regression lines are shown. Abbreviations: AD, Alzheimer's disease; Aβ, amyloid-beta; CSF, cerebrospinal fluid.
Fig. 3
Fig. 3
Association between plasma lipocalin-2 and neuropsychological measures. All subjects regardless of preclinical AD status were included in the analysis. (A-D) Plasma lipocalin-2 levels were not associated with MMSE (age- and sex-adjusted, beta coefficient –0.0629, P = .42), WMS-R-LM I (age- and sex-adjusted, beta coefficient −0.0142, P = .46), WMS-R-LM II (age- and sex-adjusted, beta coefficient –0.0186, P = .831), and Trail Making A scores (age- and sex-adjusted, beta coefficient 0.145, P = .14). (E) Plasma lipocalin-2 levels were associated with Trail Making B scores (age- and sex-adjusted, beta coefficient 0.228, P = .014). Scatterplots with individual values and unadjusted regression lines are shown. Abbreviations: AD, Alzheimer's disease; MMSE, Mini–Mental State Examination; WMS-R-LM, Wechsler Memory Scale–Revised, Logical Memory.
Fig. 4
Fig. 4
Association between plasma lipocalin-2 and BMI. BMI was not associated with plasma lipocalin-2 (age- and sex-adjusted, beta coefficient, –0.0864; P = .27). All individuals regardless of preclinical AD status or sex were included. Scatterplots with individual values and unadjusted regression lines are shown. Abbreviations: AD, Alzheimer's disease; BMI, body mass index.
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