Plasma Amyloid as Prescreener for the Earliest Alzheimer Pathological Changes

Abstract

Objective: We investigated the association of plasma amyloid beta (Abeta)40, Abeta42, and total tau (tTau) with the presence of Alzheimer pathological changes in cognitively normal individuals with subjective cognitive decline (SCD).

Methods: We included 248 subjects with SCD (61 ± 9 years, 42% female, Mini-Mental State Examination = 28 ± 2) from the SCIENCe project and Amsterdam Dementia Cohort. Subjects were dichotomized as amyloid abnormal by cerebrospinal fluid (CSF) and positron emission tomography (PET). Baseline plasma Abeta40, Abeta42, and tTau were measured using Simoa technology. Associations between plasma levels and amyloid status were assessed using logistic regression analyses and receiver operating characteristic analyses. Association of plasma levels with risk of clinical progression to mild cognitive impairment (MCI) or dementia was assessed using Cox proportional hazard models.

Results: Fifty-seven (23%) subjects were CSF-amyloid abnormal. Plasma Abeta42/Abeta40 ratio and plasma Abeta42 alone, but not tTau, identified abnormal CSF-amyloid status (plasma ratio: area under the curve [AUC] = 77%, 95% confidence interval [CI] = 69-84%; plasma Abeta42: AUC = 66%, 95% CI: 58-74%). Combining plasma ratio with age and apolipoprotein E resulted in AUC = 83% (95% CI = 77-89%). The Youden cutoff of the plasma ratio gave a sensitivity of 76% and specificity of 75%, and applying this as a prescreener would reduce the number of lumbar punctures by 51%. Using PET as outcome, a comparable reduction in number of PET scans would be achieved when applying the plasma ratio as prescreener. In addition, low plasma ratio was associated with clinical progression to MCI or dementia (hazard ratio = 2.0, 95% CI = 1.4-2.3).

Interpretation: Plasma Abeta42/Abeta40 ratio has potential as a prescreener to identify Alzheimer pathological changes in cognitively normal individuals with SCD. Ann Neurol 2018;84:656-666.

Figure 1

Scatterplots of plasma and cerebrospinal fluid (CSF) markers. Scatterplots present the correlation of the plasma marker concentrations (A, B) and the correlation of plasma marker concentrations with CSF marker concentrations (C– H). Triangles = total study population; open circles = subjects with normal CSF amyloid status (ie, CSF amyloid beta [Abeta]42 concentration > 813pg/ml); closed circles = subjects with abnormal CSF amyloid status (ie, CSF Abeta42 concentration ≤ 813pg/ml). tTau = total tau.

Figure 2

Receiver operating characteristic (ROC) curves discriminating cerebrospinal fluid (CSF)‐amyloid abnormal from amyloid normal subjects in the nondemented subjects with subjective cognitive decline based on plasma amyloid beta (Abeta)42, plasma ratio Abeta42/Abeta40, and multivariate models including age and apolipoprotein E (APOE) ε4 status. Pink = plasma Abeta42/Abeta40 ratio, APOE ε4 carriership and age; orange = APOE ε4 carriership and age; green = plasma Abeta42/Abeta40 ratio; blue = plasma Abeta42; yellow = 50% reference line.

Figure 3

For visualization of prescreening potential in a 2‐step diagnostics process, prevalence of cerebrospinal fluid (CSF) amyloid abnormality in our cohort (A) and the Youden cutoff of the plasma Abeta42/Abeta40 ratio in our cohort extracted from the receiver operating characteristic (ROC) coordinates table (B; cutoff = 45, sensitivity = 76%, specificity = 75%) were applied. Numbers were extrapolated so that a hypothetical total of 100 CSF‐amyloid abnormal subjects would be identified. Plasma Abeta42/Abeta40 ratio was multiplied by 1,000 prior to ROC analysis.

Figure 4

Heat maps showing predicted probability of being cerebrospinal fluid (CSF)‐amyloid abnormal based on plasma amyloid beta (Abeta)42/Abeta40 ratio and age when stratified for apolipoprotein E (APOE) ε4 carriership. Probabilities are presented as percentages. Red lines indicate the Youden cutoff of plasma Abeta42/Abeta40 ratio. Plasma Abeta42/Abeta40 ratio was multiplied by 1,000 prior to analysis. Heat maps were constructed using a logistic regression predictor formula with constant = −0.879 and betas (B)s B(age) = 0.082, B(plasma Abeta42/Abeta40 ratio) = −0.131, and B(APOE ε4 carriership) = 1.202. Age and plasma ratios were entered as continuous variables, and APOE ε4 carriership as a dichotomous variable with 0 = noncarrier and 1 = carrier.

Figure 5

Kaplan–Meier survival analysis graphically presenting cognitive decline to or Alzheimer disease (AD) dementia upon follow‐up with low (orange), medium (green), or high (blue) baseline plasma Abeta42 (left) or plasma Abeta42/Abeta40 ratio (right). cum = cumulative.