Race modifies the relationship between cognition and Alzheimer's disease cerebrospinal fluid biomarkers

Jennifer C Howell, Kelly D Watts, Monica W Parker, Junjie Wu, Alexander Kollhoff, Thomas S Wingo, Cornelya D Dorbin, Deqiang Qiu, William T Hu, Jennifer C Howell, Kelly D Watts, Monica W Parker, Junjie Wu, Alexander Kollhoff, Thomas S Wingo, Cornelya D Dorbin, Deqiang Qiu, William T Hu

Abstract

Background: African Americans have been reported to have a higher prevalence of Alzheimer's disease (AD) than Caucasians, but etiology-specific AD biomarkers have not been systematically analyzed in older African Americans. Coexisting cerebrovascular disease may also contribute to this increased prevalence. We hypothesized that cerebrospinal fluid (CSF) biomarkers of amyloid, neurodegeneration, and endothelial dysfunction would differ between older African Americans and Caucasians with normal cognition and cognitive impairment associated with AD.

Methods: We prospectively recruited 135 older Americans to undergo detailed clinical, neuropsychological, genetic, magnetic resonance imaging (MRI), and CSF analysis from 2013 to 2015 at Emory University (Atlanta, GA, USA). We compared levels of CSF markers for β-amyloid (Aβ42, Aβ40), total and phosphorylated tau (t-tau and p-tau181, respectively), endothelial dysfunction (soluble vascular cell adhesion molecule 1, soluble intercellular adhesion molecule 1), α-synuclein, and neurodegeneration (neurofilament light chain [NfL]), as well as MRI markers, for hippocampal atrophy and cerebrovascular disease (white matter hyperintensity [WMH] volume).

Results: Sixty-five older African Americans (average age, 69.1 years) and 70 older Caucasians (average age, 70.8 years) were included. After adjusting for demographic variables, AD risk alleles, and cognitive function, older African Americans had lower CSF levels of p-tau181 (difference of 7.4 pg/ml; 95% CI, 3.7-11.2 pg/ml; p < 0.001), t-tau (difference of 23.6 pg/ml; 95% CI, 9.5-37.7; p = 0.001), and Aβ40 (difference of 1.35 ng/ml; 95% CI, 0.29-2.42 ng/ml; p = 0.013) despite similar levels of Aβ42, NfL, WMH volume, and hippocampal volume. Cognitively impaired African Americans also had lower CSF t-tau/Aβ42 (difference of 0.255 per 1-SD change in composite cognition; 95% CI, 0.100-0.409; p = 0.001) and p-tau181/Aβ42 (difference of 0.076 per 1-SD change in composite cognition; 95% CI, 0.031-0.122; p = 0.001). These could not be explained by measured biomarkers of non-AD processes, but African Americans may be more susceptible than Caucasians to the cognitive effects of WMH.

Conclusions: Despite comparable levels of CSF Aβ42 and Aβ42/Aβ40, cognitive impairment in African Americans is associated with smaller changes in CSF tau markers but greater impact from similar WMH burden than Caucasians. Race-associated differences in CSF tau markers and ratios may lead to underdiagnosis of AD in African Americans.

Trial registration: ClinicalTrials.gov, NCT02089555 . Retrospectively registered on 14 March 2014.

Keywords: African American; Amyloid; Dementia; Endothelial dysfunction; Mild cognitive impairment; Tau.

Conflict of interest statement

Ethics approval and consent to participate

This study was approved by the Emory Institutional Review Board (number 66145). Informed consent was obtained from all subjects or their authorized representatives.

Consent for publication

Not applicable.

Competing interests

WTH has a patent (assignee, Emory University) on the use of CSF p/t-tau ratio in the evaluation of frontotemporal lobar degeneration, has received research support from Avid Pharmaceuticals, and has received travel support from Eli Lilly and Hoffman-La Roche. DQ has received research support from Medtronic and Siemens Healthcare.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Cerebrospinal fluid (CSF) levels of tau and amyloid markers in older African Americans and Caucasians according to cognitive function. Composite cognitive Z-scores are shown on the x-axis (lower score corresponds to worse cognitive function). African Americans (closed circles) had lower CSF levels of total tau (t-tau) (a), tau phosphorylated at threonine 181 (p-tau181) (b), and β-amyloid 1–40 (Aβ40) (d) than Caucasians (open circles). Raw values are shown, with dashed lines representing trends among Caucasians and solid lines representing trends among African Americans. The differences persisted after adjusting for age, sex, apolipoprotein E (APOE) and ABCA7 genotypes, and β-amyloid 1–42 (Aβ42) levels (c), which did not differ between the two groups. CSF biomarker t-tau/Aβ42 ratio was lower in African Americans than in Caucasians when there was cognitive impairment (e), but race did not have a significant effect on CSF biomarker Aβ42/Aβ40 (f)
Fig. 2
Fig. 2
Relationship between cerebrospinal fluid (CSF) soluble vascular cell adhesion molecule 1 (sVCAM-1) levels and other vascular markers according to race. In Caucasians (open circles), CSF sVCAM-1 levels strongly correlated with log-transformed white matter hyperintensity (WMH) volumes derived by magnetic resonance imaging (a, b) and the total number of peripheral vascular risk factors (c, d) whether a more (a, c) or less stringent (b, d) threshold was applied to identify subjects with no Alzheimer’s disease pathology. However, there was no such correlation in African Americans (closed circles). Aβ42 β-Amyloid 1–42, t-Tau Total tau

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