Molecular Biomarkers in a Cohort of Middle-Aged African Americans and Caucasians with a Family History of Alzheimer’s Disease Open Access

Abstract

Background: African Americans (AAs) have a higher prevalence of Alzheimer’s disease (AD) than Caucasians (CCs). AAs are at a higher risk for other chronic health problems that, in combination with genetics, inflammation, and other psychosocial factors, could contribute to the onset of AD. AD neuropathological cascade starts in middle-age, many years before the diagnosis of clinical dementia, making this an optimal target for intervention. Investigating whether molecular biomarkers differ in AAs and CCs may suggest racial differences in biological mechanisms that contribute to AD pathogenesis.

Method: Participants were middle-aged AAs and CCs who are at high risk for AD due to a parent history of AD. Study visits included lumbar puncture for cerebrospinal fluid (CSF) collection, blood draw, and cognitive testing. The primary outcomes were AD biomarkers (amyloid-β, total tau, and hyperphosphorylated tau), markers of inflammation, markers of the renin-angiotensin system, and a novel CSF marker of capillary dysfunction, soluble platelet-derived growth factor receptor-β (sPDGFRβ).

Result: 30 AAs and 50 CCs were enrolled. Participants were middle-aged (59.1 ± 6.8) and well-educated 85% completed college). 83.3% were AAs were female compared with 56.0% of CCs. Systolic blood pressure (126.4 mmHg) suggests an overall healthy sample that did not differ by race. Compared to CCs, AAs had lower levels of CSF T-tau, P-tau, and sPDGFRβ. AAs had higher levels of IL-7, MCP-1, MDC, CRP, and SAP, and lower levels of VCAM-1 in blood, and lower levels MMP-2, IL-7, and VCAM-1 in CSF. After multiple linear regression adjusted for age, gender, race, and education, we found that higher CSF sPDGFRβ was associated with higher CSF T-tau, P-tau, MMP-2, IL-8, TIMP-1, TIMP-2 and VCAM-1 and higher CSF ACE-1 activity was associated with lower plasma IL-9 level and higher CSF IL-7 level.

Conclusion: The results of this study suggest that AAs had lower tau burden than CCs. AAs also had lower levels in three CSF markers that are related to Blood-brain barrier (BBB) dysfunction, MMP-2, VCAM-1, and sPDGFRβ, which point to racial differences in BBB integrity. This, in turn, could lead to race-dependent AD pathological mechanisms.

Table of Contents

1 Introduction....................8

1.1 Alzheimer’s Disease..........8

1.2 Racial Disparities in Alzheimer’s Disease..........9

1.3 Established Alzheimer’s Disease Biomarkers..........11

1.4 Markers of Inflammation..........13

1.5 Markers of Capillary Dysfunction..........15

1.6 Markers of the Renin Angiotensin System..........17

1.7 Rationale..........18

2 Methods....................20

2.1 Participants..........20

2.2 CSF and Blood Collection and Analysis..........20

2.3 Cognitive Testing..........23

2.4 Statistical Analysis..........23

3 Results....................25

4 Discussion....................27

5 Tables and Figures....................35

Table 1: Demographic Characteristics..........35

Table 2: Cognitive Testing..........36

Table 3: Core AD Biomarkers..........37

Table 4: Markers of Inflammation..........38

Table 5: ACE Activity and sPDGFRβ Level..........39

Table 6: Adjusted Correlation between CSF sPDGFRβ and Core AD Biomarkers..........40

Table 7: Adjusted Correlation between CSF sPDGFRβ and CSF Inflammatory Markers..........41

Table 8: Adjusted Correlation between CSF ACE-1 and Inflammatory Markers..........42

Figure 1: AAs had lower T-tau and P-tau levels compared to CCs..........43

Figure 2: AAs had lower CSF sPDGFRβ level compared to CCs..........44

Figure 3: Relationships between CSF sPDGFRβ and CSF Core AD Biomarkers..........45

Figure 4: Relationships between CSF sPDGFRβ and CSF Inflammatory Markers..........46

Figure 5: Relationships between CSF ACE-1 Activity and Inflammatory Markers..........47

6 References....................48

About this Honors Thesis

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School	Emory College
Department	Neuroscience and Behavioral Biology
Degree	B.S.
Submission	Honors Thesis
Language	English
Research Field	Biology, Molecular Biology, Neuroscience
Keyword	blood–brain barrier inflammation biomarker Alzheimer's disease renin–angiotensin system tau
Committee Chair / Thesis Advisor	Whitney Wharton, Emory University
Committee Members	Andrew Kazama, Emory University Kristen Frenzel, Emory University Sudeshna Paul, Emory University

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