Cerebrospinal fluid tau and ptau(181) increase with cortical amyloid deposition in cognitively normal individuals: implications for future clinical trials of Alzheimer's disease

Abstract

Alzheimer's disease (AD) pathology is estimated to develop many years before detectable cognitive decline. Fluid and imaging biomarkers may identify people in early symptomatic and even preclinical stages, possibly when potential treatments can best preserve cognitive function. We previously reported that cerebrospinal fluid (CSF) levels of amyloid-beta(42) (Abeta(42)) serve as an excellent marker for brain amyloid as detected by the amyloid tracer, Pittsburgh compound B (PIB). Using data from 189 cognitively normal participants, we now report a positive linear relationship between CSF tau/ptau(181) (primary constituents of neurofibrillary tangles) with the amount of cortical amyloid. We observe a strong inverse relationship of cortical PIB binding with CSF Abeta(42) but not for plasma Abeta species. Some individuals have low CSF Abeta(42) but no cortical PIB binding. Together, these data suggest that changes in brain Abeta(42) metabolism and amyloid formation are early pathogenic events in AD, and that significant disruptions in CSF tau metabolism likely occur after Abeta(42) initially aggregates and increases as amyloid accumulates. These findings have important implications for preclinical AD diagnosis and treatment.

Figures

Figure 1. Cortical amyloid as detected by PET PIB and fluid biomarkers in CDR 0 participants (n = 189) as a function of age

Levels of

1. cortical amyloid are positively correlated with age in this CDR 0 cohort,

2. The level of CSF Aβ38 is not correlated with age,

3. nor is CSF Aβ40.

4. CSF Aβ42 is negatively correlated with age.

5. Positive correlations with age are observed for CSF tau,

6. CSF ptau181 and

7. plasma Aβ1–40.

8. Plasma Aβ1–42 is not correlated with age in this cohort.

Figure 2. Cortical amyloid as detected by PET PIB and its relationship to CSF Aβ in CDR 0 participants (n = 189)

A. A high percentage (84%) of participants with low PIB values (MCBP < 0.18) had high CSF Aβ42 levels (mean (SD) = 705 pg/ml (211)) whereas the vast majority of participants (86%) in the cohort who had high PIB binding (MCBP ≥ 0.18) had low CSF Aβ42 (mean (SD) = 362 pg/ml (115)). Horizontal lines represent the group means, and these means are statistically different from each other (asterisk, p < 0.0001). B. Relationship between CSF Aβ42 levels and cortical amyloid. Most participants had low MCBP values. The vast majority (86%) of participants with MCBPs ≥ 0.18 had low CSF Aβ42 levels. These CDR 0 participants are hypothesized to have preclinical AD. The box outlined by dashed lines identifies the 28 individuals who have low cortical PIB binding (MCBP < 0.18) with low CSF Aβ42. There is a linear relationship between CSF Aβ42 and the amount of cortical amyloid although CSF Aβ42 appears to drop and then stay low as the amyloid load increases. C. MRI (left) and PET PIB (right) images of a representative low PIB (MCBP = 0.0270) CDR 0 participant (top panel), a high PIB (MCBP = 0.7790) CDR 0 participant (middle panel), and a high PIB (MCBP = 0.7812) CDR > 0 participant (bottom panel). The amount of cortical PIB binding (yellow-red corresponds to high binding) in the high PIB CDR 0 participant and the high PIB CDR > 0 participant is comparable, whereas there is only background PIB binding (green) in white matter tracks in the low PIB CDR 0 participant. D,E. No relationship between CSF Aβ40 (D) and CSF Aβ38 (E) levels and cortical amyloid was observed in this cognitively normal cohort (r = −0.0287, p = 0.6963; r = 0.06851, p = 0.3515, respectively). F. A negative correlation was found between cortical amyloid and the CSF Aβ38/Aβ42 ratio. All Pearson correlation coefficients are corrected for age. n.s., not significant.

Figure 3. Cortical amyloid as detected by PET PIB and its relationship to plasma Aβ42 and Aβ40 species in CDR 0 participants (n = 189)

No relationship was observed between mean cortical PIB binding and plasma

1. Aβ1–40 (r = −0.0724, p = 0.3234),

2. Aβx–40 (r = 0.04583, p = 0.5323),

3. Aβ1–42 (r = −0.1015, p = 0.1658) or

4. Aβx–42 (r = −0.03869, p = 0.5981). Five participants had levels of plasma Aβx–42 below the level of detection so they are represented as having 0 pg/ml. All Pearson correlation coefficients are corrected for age. n.s., not significant.

Figure 4. Cortical amyloid as detected by PET PIB and its relationship to CSF tau and ptau181 and the ratios of CSF tau/Aβ42 and ptau181/Aβ42 in CDR 0 participants (n = 189)

A linear relationship is observed between the amount of cortical amyloid and

1. the levels of CSF tau

2. the levels of CSF ptau181

3. the ratios of CSF tau/Aβ42 and

4. the ratios of the ptau181/Aβ42. The correlations between the CSF tau(s)/Aβ42 ratios and MCBP remain significant even when the statistical outlier (high PIB, high ratio) is omitted from the analysis (tau/Aβ42, r = 0.74227, p < 0.0001; ptau181/Aβ42, r = 0.73510, p < 0.0001). All Pearson correlation coefficients are corrected for age.