Plasma β-amyloid in Alzheimer's disease and vascular disease

Abstract

Implementation of amyloid biomarkers in clinical practice would be accelerated if such biomarkers could be measured in blood. We analyzed plasma levels of Aβ42 and Aβ40 in a cohort of 719 individuals (the Swedish BioFINDER study), including patients with subjective cognitive decline (SCD), mild cognitive impairment (MCI), Alzheimer's disease (AD) dementia and cognitively healthy elderly, using a ultrasensitive immunoassay (Simoa platform). There were weak positive correlations between plasma and cerebrospinal fluid (CSF) levels for both Aβ42 and Aβ40, and negative correlations between plasma Aβ42 and neocortical amyloid deposition (measured with PET). Plasma levels of Aβ42 and Aβ40 were reduced in AD dementia compared with all other diagnostic groups. However, during the preclinical or prodromal AD stages (i.e. in amyloid positive controls, SCD and MCI) plasma concentration of Aβ42 was just moderately decreased whereas Aβ40 levels were unchanged. Higher plasma (but not CSF) levels of Aβ were associated with white matter lesions, cerebral microbleeds, hypertension, diabetes and ischemic heart disease. In summary, plasma Aβ is overtly decreased during the dementia stage of AD indicating that prominent changes in Aβ metabolism occur later in the periphery compared to the brain. Further, increased levels of Aβ in plasma are associated with vascular disease.

Figure 1. Correlations between plasma and CSF Aβ and between plasma Aβ and [¹⁸F]flutemetamol SUVR.

(A–C) Plasma (Simoa immunoassay) and CSF (Euroimmun immunoassay) Aβ42 and Aβ40 were measured in a cohort of 719 individuals (174 SCI, 214 MCI, 57 AD patients and 274 controls). (D–F) Neuocortical amyloid deposition was measured using [¹⁸F]flutemetamol PET in a cohort of 340 individuals (103 SCI, 112 MCI patients and 125 controls). Correlation coefficients (r) and p-values are from Pearson’s correlation analysis. AD, Alzheimer’s disease; CSF, cerebrospinal fluid; SCD, subjective cognitive decline; MCI, mild cognitive impairment; PET, positron emission tomography; SUVR, standardized uptake value ratio.

Figure 2. Plasma and CSF Aβ in different diagnostic groups.

Plasma (A–C, Simoa immunoassay) and CSF (D–F, Euroimmun immunoassay) levels of Aβ42, Aβ40 and the Aβ42/Aβ40 ratio in patients with SCD (n = 174), MCI (n = 214), AD (n = 57) and controls (n = 274). Data are presented as mean ± 95% confidence interval (CI); p values are from univariate general linear models controlling for age and gender; statistical significance was set to p < 0.008 (0.05/6) to account for Bonferroni correction. AD, Alzheimer’s disease; CSF, cerebrospinal fluid; SCD, subjective cognitive decline; MCI, mild cognitive impairment.

Figure 3. Plasma and CSF Aβ in different diagnostic groups with pathological CSF signature.

Plasma (A–C, Simoa immunoassay) and CSF (D–F, Euroimmun immunoassay) levels of Aβ42, Aβ40 and the Aβ42/Aβ40 ratio in patients with SCD (n = 60), MCI (n = 121), AD (n = 53) and controls (n = 74) with pathological (P) CSF amyloid signature compared to controls with normal (N) CSF amyloid signature (n = 200). Data are presented as mean ± 95% confidence interval (CI); p values are from univariate general linear models controlling for age and gender; statistical significance was set to p < 0.005 (0.05/10) to account for Bonferroni correction. AD, Alzheimer’s disease; CSF, cerebrospinal fluid; SCD, subjective cognitive decline; MCI, mild cognitive impairment.

Figure 4. Effects of hypertension, ischemic heart disease and anti-hypertensive/cardio-protective medications on plasma Aβ.

Plasma levels of Aβ42, Aβ40 and the Aβ42/Aβ40 ratio (Simoa immunoassay) in patients with and without hypertension (n = 267 and n = 444, respectively), ischemic heart disease (n = 73 and n = 637, respectively), diabetes (n = 69 and n = 641, respectively) or anti-hypertensive/cardio-protective medications (n = 325 and n = 385, respectively). Data are presented as mean ± 95% confidence interval (CI); p values are from univariate general linear models controlling for age, gender and diagnosis; **p < 0.05; **p < 0.01; ***p < 0.001. IHD, ischemic heart disease.