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. 2022 Jan 13;14(1):9.
doi: 10.1186/s13195-021-00955-9.

Plasma Lipocalin 2 in Alzheimer's disease: potential utility in the differential diagnosis and relationship with other biomarkers

Peter Hermann #  1 , Anna Villar-Piqué #  2   3 , Matthias Schmitz  4   5 , Christian Schmidt  4 , Daniela Varges  4 , Stefan Goebel  4 , Timothy Bunck  4 , Hanna Lindemann  4 , Carla Bogner  4 , Isabel Santana  6 , Inês Baldeiras  6 , Joachim Riggert  7 , Inga Zerr #  4   5 , Franc Llorens #  4   2   3
Affiliations

Plasma Lipocalin 2 in Alzheimer's disease: potential utility in the differential diagnosis and relationship with other biomarkers

Peter Hermann et al. Alzheimers Res Ther. .

Abstract

Background: Lipocalin-2 is a glycoprotein that is involved in various physiological and pathophysiological processes. In the brain, it is expressed in response to vascular and other brain injury, as well as in Alzheimer's disease in reactive microglia and astrocytes. Plasma Lipocalin-2 has been proposed as a biomarker for Alzheimer's disease but available data is scarce and inconsistent. Thus, we evaluated plasma Lipocalin-2 in the context of Alzheimer's disease, differential diagnoses, other biomarkers, and clinical data.

Methods: For this two-center case-control study, we analyzed Lipocalin-2 concentrations in plasma samples from a cohort of n = 407 individuals. The diagnostic groups comprised Alzheimer's disease (n = 74), vascular dementia (n = 28), other important differential diagnoses (n = 221), and healthy controls (n = 84). Main results were validated in an independent cohort with patients with Alzheimer's disease (n = 19), mild cognitive impairment (n = 27), and healthy individuals (n = 28).

Results: Plasma Lipocalin-2 was significantly lower in Alzheimer's disease compared to healthy controls (p < 0.001) and all other groups (p < 0.01) except for mixed dementia (vascular and Alzheimer's pathologic changes). Areas under the curve from receiver operation characteristics for the discrimination of Alzheimer's disease and healthy controls were 0.783 (95%CI: 0.712-0.855) in the study cohort and 0.766 (95%CI: 0.627-0.905) in the validation cohort. The area under the curve for Alzheimer's disease versus vascular dementia was 0.778 (95%CI: 0.667-0.890) in the study cohort. In Alzheimer's disease patients, plasma Lipocalin2 did not show significant correlation with cerebrospinal fluid biomarkers of neurodegeneration and AD-related pathology (total-tau, phosphorylated tau protein, and beta-amyloid 1-42), cognitive status (Mini Mental Status Examination scores), APOE genotype, or presence of white matter hyperintensities. Interestingly, Lipocalin 2 was lower in patients with rapid disease course compared to patients with non-rapidly progressive Alzheimer's disease (p = 0.013).

Conclusions: Plasma Lipocalin-2 has potential as a diagnostic biomarker for Alzheimer's disease and seems to be independent from currently employed biomarkers.

Keywords: Alzheimer’s disease; Biomarker; Dementia; Lipocalin 2; Neutrophil gelatinase-associated Lipocalin; Plasma.

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Conflict of interest statement

PH, CS, DV, SG, TB, HL, and CB have nothing to disclose. AVP is recipient of a postdoctoral grant of the Beatriu de Pinós program (2018-BP-00129) from the Ministry of Business and Knowledge of the Government of Catalonia, co-funded by the EU Horizon 2020 program under an MSCA grant agreement (801370). MS received funds from the Alzheimer Forschung Initiative (AFI, project no. 20026). IS received an institutional pharma grant (Roche) for a project of investigation on Multiple Sclerosis 2021 and consultations fees for speakers bureau and educational events from Roche, Biogen, and Merck; attended American Academy of Neurology; is supported by Roche; and is Member of the EAN Pannel in dementia Portuguese National Ethics committee. IB is funded by Grupo de Estudos de Envelhecimento Cerebral e Demencia, Sanofi-Genzyme, Fundação Ciência e Tecnologia - FCT, and received honoraria from Merck S.A. JR is funded by the EU grant for blood donation of reconvalescence plasma after COVID19-infection. FL received funding from the ADDF (Alzheimer’s Drug Discovery Foundation, grant 201810-2017419 related to this work) and is recipient of research grants from the Instituto de Salud Carlos III (Institute of Health Carlos III, ISCIII) from the Government of Spain (grants CP16/00041 and PI19/00144). IZ received funding from the ADDF (Alzheimer’s Drug Discovery Foundation, grant 201810-2017419) and the Robert Koch Institute through funds from the German Federal Ministry of Health (grant no. 1369–341).

Figures

Fig. 1
Fig. 1
Plasma LCN2 in the differential diagnosis of dementia. Plasma LCN2 concentrations in diagnostic groups. Comparison of biomarker concentrations of diagnostic groups was performed with linear regression models; age and sex were included as covariates. Multiple comparisons were performed with Tukey contrasts. P-values are indicated above dot columns. Bars indicate mean and standard error of mean. MD group is presented for visualization purposes but excluded from data analyses due to the low number of cases. HC, healthy controls; ND-Dem, non-neurodegenerative neurological diseases with dementia syndrome; AD, Alzheimer’s disease; CJD, Creutzfeldt-Jakob disease; LBD, Lewy body diseases (dementia with Lewy bodies and Parkinson’s disease dementia); FTD, fronto-temporal dementia; and VaD, vascular dementia
Fig. 2
Fig. 2
Plasma LCN2 in AD and MCI cases of cohorts 1 and 2. A Plasma LCN2 concentrations in HC, MCI-AD, and AD of cohort 1. B Plasma LCN2 concentrations in HC, amnestic MCI, and AD of cohort 2. C Areas under the curve (AUC) from receiver operating characteristic with 95% confidence intervals (95% CI) and p-values from assessment of diagnostic accuracy in cohort 1 and 2. D Plasma LCN2 concentrations in HC, MCI-VCI, and VaD of cohort 1. Comparison of biomarker concentrations of diagnostic groups was performed with linear regression models; age and sex were included as covariates. Multiple comparisons were performed with Tukey contrasts. P-values are indicated above dot columns when significant. Bars (A, B, D) indicate mean and standard error of mean. HC, healthy controls; MCI (AD), mild cognitive impairment with positive biomarkers for AD-related pathology; AD, Alzheimer’s disease; MCI (amnestic), mild cognitive impairment with disturbance of memory function; MCI-VCI, mild vascular cognitive impairment; VaD, vascular dementia or major vascular cognitive impairment
Fig. 3
Fig. 3
Disease stage, clinical subtypes, APOE genotype, and white matter hyperintensities in AD in cohort 1. A Plasma LCN2 concentrations in AD patients with different biomarker characteristics. Group comparisons were performed with linear regression models; age and sex were included as covariates. Multiple comparisons were performed with Tukey contrasts. No significant differences were found. A+/−, positive/negative for decreased CSF Abeta 1-42 or Abeta 1-42/1-40 ratio; T+/−, positive/negative for increased CSF p-tau; N+, positive marker of neurodegeneration, either elevated CSF t-tau or medial temporal lobe atrophy on MRI. B Scatter plot of the association between Mini Mental Status Examination (MMSE) scores and plasma lipocalin 2 (LCN2) concentrations. Spearman coefficients (cc) with 95% confidence interval (CI) and corresponding p-values are indicated. C Plasma LCN2 concentrations in different APOE genotypes in the AD group. Comparison of biomarker concentrations was performed with linear regression models; age and sex were included as covariates. Multiple comparisons were performed with Tukey contrasts. No significant differences were found. D Plasma LCN2 in rapidly progressive Alzheimer’s disease (rpAD) and slowly progressive Alzheimer’s disease (spAD). For comparison between the two groups, a linear regression model including age and sex as covariates was applied; the corresponding p-value is indicated. Bars (B, C, and D) indicate mean and standard error of mean
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