CSF progranulin increases in the course of Alzheimer's disease and is associated with sTREM2 (2018)
Figure 7

Figure 7. Association of CSF PGRN with AD core CSF biomarkers in late-onset AD (ADNI)

Scatter plots representing the associations of CSF PGRN with CSF sTREM2 and each of the AD CSF core biomarkers (T-tau, P-tau181P and Aβ1−42) in healthy controls (blue; A, D, G and J), Alzheimer's continuum (red; B, E, H and K) and 'suspected non-Alzheimer's pathophysiology (SNAP)' groups (green; C, F, I and L). Each point depicts the value of CSF PGRN and the corresponding biomarker of a subject and the solid lines indicate the regression line and the 95% confidence interval (CI) for each of the groups. The standardized regression coefficients (β) and the P-values are shown and were computed using a linear model adjusting for age, gender and APOE ε4. The sample contained some outliers (defined as 3 SDs below or above the group mean) of the CSF core markers of AD, the analysis including these outliers yielded similar results (Appendix Table S8). The Aβ1-42 values used for the associations test are those based on an extrapolation curve since the upper technical limit is 1700pg/ml. We also tested the associations with Aβ1-42 values truncated at the upper technical limit and the result was similar.

Abbreviations: Aβ1-42: amyloid-β 42; T-tau: total tau; P-tau: tau phosphorylated at Threonine 181; SNAP: suspected non-Alzheimer's pathophysiology.

Tables:

Table 1. DIAN participants' characteristics

Autosomal Dominant Alzheimer's disease

(DIAN study)

Non-carriers (NC)

(n = 85)

Mutation carriers (MC)

(n = 130)

P-value

(group effect)

Data are expressed as mean (M) and standard deviation (SD) or percentage (%), as appropriate. Pearson's Chi-square tests were used for the group comparisons of categorical variables and two-sample independent t tests to compare continuous variables.

*Significant differences. The P-values indicated in the last column refer to the group effects in these tests.

†CSF core biomarkers in DIAN were measured using the Luminex bead-based multiplexed xMAP technology (INNO-BIA AlzBio3, Innogenetics).

‡CSF PGRN differences were assessed by a linear model adjusted for age, gender and APOE ε4 status (see main text).

§Cognitive status was defined by the clinical dementia rating (CDR) score (0, cognitively normal; 0.5, very mild; 1, mild; 2, moderate; 3, severe dementia).

¶In NC participants, the mutation present in their family is shown.

Abbreviations: Aβ1-42: amyloid-β 42; AD, Alzheimer disease; APOE, apolipoprotein E; APP, amyloid precursor protein; CSF, cerebrospinal fluid; EYO, estimated years from expected symptom onset; MMSE, Mini-Mental State Examination; PSEN1, presenilin 1; PSEN2, presenilin 2; P-tau181P, tau phosphorylated at threonine 181; T-tau, total tau; y, years.

Table 2. CSF PGRN estimates (pg/ml) in MCs and NCs as a function of EYO

Mean estimated levels of CSF PGRN were obtained by a lineal model including gender, mutation status, EYO and the interaction between mutation status and EYO as covariates (see statistics section and Appendix Table S2). For each EYO, the group difference, 95% CI and the P-value for the two-sample independent t test is reported. Participants with EYO > +20 (1 NC and 2 MC) were excluded from the analysis. The same analysis including the PGRN outliers and those participants with an EYO > +20 yielded identical results (Appendix Table S3). Differences are calculated from unrounded values. *Significant difference.

Abbreviations: CI, confidence interval.

Table 3. Classification of ADNI participants based on their biomarker profile and clinical stage

CDR = 0

(cognitively unimpaired)

CDR = 0.5

(very mild dementia)

CDR = 1

(mild dementia)

Healthy controls

n = 128

Preclinical AD A+/TN-

n = 56

Preclinical AD A+/TN+

n = 48

AD CDR = 0.5

n = 289

AD CDR = 1

n = 81

ADNI participants were classified based on their CSF biomarker profile and their clinical stage, which yielded 12 different categories. Columns depict the clinical stage (C) as defined by the clinical dementia rating (CDR) scale. Rows depict the biomarker profiles. Each of the three biomarkers groups (A/T/N) were binarized into positive or negative (+/-). T and N were merged to simplify the classification and TN- indicates that both T and N biomarkers are normal and TN+ indicates that T and/or N biomarkers are abnormal.

The grey highlighting indicates the grouping used for comparisons in the main text. Light grey highlights the healthy controls (n = 128), middle grey the groups included in the Alzheimer's continuum (n = 474) and dark grey the suspected non-Alzheimer's pathophysiology (SNAP) group (n = 182). Bold text indicates the groups analysed in the main analysis, namely: 'healthy controls', 'Preclinical AD A+/TN-', 'Preclinical AD A+/TN+', 'AD CDR = 0.5' and 'AD CDR = 1'.

Abbreviations: A: amyloid-β biomarker status; AD: Alzheimer's disease; CDR: clinical dementia rating; N: neurodegeneration biomarker status; T: tau pathology biomarker status.

Table 4. ADNI participants' characteristics for the control and Alzheimer's continuum groups in ADNI

(n = 128)

Alzheimer's continuum

(n = 474)

(n = 56)

(n = 48)

(n = 289)

(n = 81)

Data are expressed as mean (M) and standard deviation (SD) or percentage (%), as appropriate. Pearson's Chi-square tests were used for the group comparisons of categorical variables and one-way ANOVA to compare continuous variables.

* Significant differences. The P-values indicated in the last column refer to the group effects in these tests.

†GRN rs5848 genotype was available in 77 'healthy controls' (60%), 38 'Preclinical AD A+/TN-' (68%), 29 'Preclinical AD A+/TN+' (60%), 154 'AD CDR = 0.5' (53%), and 54 'AD CDR = 1' (67%).

‡The CSF core biomarkers measurements were performed using the electrochemiluminiscence immunoassays, Total-tau CSF, phospho-tau(181P) CSF and Elecsys β-amyloid(1-42) CSF. The Elecsys β-amyloid(1-42) assay has an upper technical limit of 1700 pg/ml; the values above this limit were truncated to this value.

§CSF PGRN levels were log-transformed and assessed by a linear model adjusted for age, gender and APOE ε4 status (see main text).

Abbreviations: A: amyloid-β biomarker status; Aβ1-42: amyloid-β 42; AD, Alzheimer disease; APOE, apolipoprotein E; ADAS-Cog, Alzheimer's disease Assessment Scale - cognitive subscale; ADNI-Mem: ADNI memory composite score; ADNI-EF: ADNI executive function composite score; CDR: clinical dementia rating; CDR-SB: clinical dementia rating Sum of Boxes; CSF, cerebrospinal fluid; MMSE, Mini-Mental State Examination; N: neurodegeneration biomarker status; P-tau181P, tau phosphorylated at threonine 181; T: tau pathology biomarker status; T-tau, total tau; y, years.

Table 5. Associations of CSF PGRN with cognitive measures in the Alzheimer's continuum category (ADNI sample)

Model 1

(unadjusted)

Model 2

(adjusted by age, gender, APOE ε4 and education)

Model 3

(also adjusted by Aβ1-42 and T-tau)

Associations between CSF PGRN and cognitive measures were studied only in the participants of the Alzheimer's continuum (n = 474) and were assessed by three different linear regression models. The standardized regression coefficients (β) and the P-values are shown.

Note that higher levels of CSF PGRN are associated with worse cognitive performance in all tests investigated even when age, gender APOE ε4 status and education (model 2) are accounted. The associations still remain after adding Aβ1-42 and T-tau as added in the model (model 3) in all tests except in ADNI-Mem, MMSE and CDR-SB.

The analysis was performed excluding CSF PGRN outliers. The same analysis including these outliers yielded similar results (Appendix Table S6). There were 2 subjects without ADAS-Cog11 score and 6 subjects without ADAS-Cog13 scores.

*Significant differences.

Abbreviations: Aβ1-42: amyloid-β 42; ADAS-Cog, Alzheimer's disease Assessment Scale - cognitive subscale; ADNI-Mem: ADNI memory composite score; ADNI-EF: ADNI executive function composite score; CDR-SB: clinical dementia rating Sum of Boxes; MMSE, Mini-Mental State Examination; T-tau: total tau.

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