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Associations between inflammatory markers and change in cognitive endpoints

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Associations between inflammatory markers and change in cognitive endpoints

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Content Copyright 2024 Yuhan Zhang
Associations between inflammatory markers and change in cognitive endpoints
By
Yuhan Zhang
A Thesis Presented to the
FACULTY OF THE USC KECK SCHOOL OF MEDICIEN
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirement for the Degree
MASTER OF SCIENCE
(BIOSTATISTICS)
May 2024

ii
Table of Contents
List of Tables…………………………………………………...…………………….…………………..iii
List of Figures…………………………………………………...…………………….………………….vi
Abstract…………………………………………………………………………………………..………..1
Chapter One: Introduction…………………………………………………...…………………….…….3
Chapter Two: Methods……………………………………………………………………..…………....4
Chapter Three: Statistical Analysis……………………………………………………………………10
Chapter Four: Results…………………………………………………………………………..….…..12
Univariate analysis…………………………..…………………………………………………12
Multivariable analysis…………………………………………………………………………..15
Chapter Five: Discussion…………………………………………………………………………..…..19
References…………………………………………………………………………………...…...……..20

iii
List of Tables
Table1. Participant characteristics at baseline…………………………………………………..27
Table 2. Associations of global cognition change with inflammation variables: ELITE
Postmenopausal Women (N = 565) ………………………………………………….………..…30
Table 3. Associations of verbal memory change with inflammation variables: ELITE
Postmenopausal Women (N = 565) ……………………………………………….…………..…32
Table 4. Associations of executive function change with inflammation variables: ELITE
Postmenopausal Women (N = 565) …………………………………………………………...…34
Table 5. Associations of visual memory change with inflammation variables: ELITE
Postmenopausal Women (N = 565) ……………………………………………………….…..…36
Table 6. Associations of global cognition change with inflammation variables: NAPS
Postmenopausal Women (N = 141) …………………………………………………………...…38
Table 7. Associations of verbal memory change with inflammation variables: NAPS
Postmenopausal Women (N = 141) ………………………………………………….…………..40
Table 8. Associations of executive function change with inflammation variables: NAPS
Postmenopausal Women (N = 141) ……………………………………………….………..……42
Table 9. Associations of visual memory change with inflammation variables: NAPS
Postmenopausal Women (N = 141) …………………………………………………….…..……44
Table 10. Associations of global cognition change with inflammation variables: NAPS Men
(N = 88) ……………………………………………………………………………………………...46

iv
Table 11. Associations of verbal memory change with inflammation variables: NAPS Men (N
= 88) …….………………………………………………………………………………….………..48
Table 12. Associations of executive function change with inflammation variables: NAPS Men
(N = 88) ….…………………………………………………………………………………………..50
Table 13. Associations of visual memory change with inflammation variables: NAPS Men (N
= 88) ………………………………………………………………………………………….……...52
Table 14. Associations of global cognition change with inflammation variables: Combined
ELITE and NAPS Postmenopausal Women (N = 704) …………………………….…………..54
Table 15. Associations of verbal memory change with inflammation variables: Combined
ELITE and NAPS Postmenopausal Women (N = 704) …………………………….…………..55
Table 16. Associations of executive function change with inflammation variables: Combined
ELITE and NAPS Postmenopausal Women (N = 704) ………………………………….……..56
Table 17. Associations of visual memory change with inflammation variables: Combined
ELITE and NAPS Postmenopausal Women (N = 704) ………………………………………...57
Table 18. Robust associations of global cognition change with inflammation variables:
ELITE Postmenopausal Women (N = 565) ………………………………………………..……58
Table 19. Robust associations of verbal memory change with inflammation variables: ELITE
Postmenopausal Women (N = 565) ……………………………………………………...………60
Table 20. Robust associations of executive function change with inflammation variables:
ELITE Postmenopausal Women (N = 565) ……………………………………………..………62

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Table 21. Robust associations of visual memory change with inflammation variables: ELITE
Postmenopausal Women (N = 565) ………………………………………………………...……64
Table 22. Multivariable associations of global cognition change with inflammation variables:
ELITE Postmenopausal Women (N = 565) …………………………………………………..…66
Table 23. Multivariable associations of executive function change with inflammation
variables: ELITE Postmenopausal Women (N = 565) …………………………………………67
Table 24. Multivariable associations of visual memory change with inflammation variables:
ELITE Postmenopausal Women (N = 565) ……………………………………………..………68
Table 25. Multivariable associations of global cognition change with inflammation variables:
NAPS postmenopausal women (N = 141) ………………………………………………………69
Table 26. Multivariable associations of verbal memory change with inflammation variables:
NAPS postmenopausal women (N = 141) ………………………………………………………70
Table 27. Multivariable associations of global cognition change with inflammation variables:
NAPS Men (N = 88) ……………………………………………………………………………..…71
Table 28. Multivariable associations of global cognition change with inflammation variables:
Combined ELITE and NAPS Postmenopausal Women (N = 704) ……………………………72
Table 29. Multivariable associations of executive function change with inflammation
variables: Combined ELITE and NAPS Postmenopausal Women (N = 704) ………….……73
Table 30. Multivariable associations of visual memory change with inflammation variables:
Combined ELITE and NAPS Postmenopausal Women (N = 704) ……………………………7

vi
List of Figures
Figure 1: Lowess plot of associations of global cognition change with inflammation variables:
ELITE Postmenopausal Women (N = 565)………………………………………………………75
Figure 2. Lowess plot of associations of verbal memory change with inflammation variables:
ELITE Postmenopausal Women (N = 565)………………………………………………………76
Figure 3. Lowess plot of associations of executive function change with inflammation
variables: ELITE Postmenopausal Women (N = 565)……………………………………….…77
Figure 4. Lowess plot of associations of visual memory change with inflammation variables:
ELITE Postmenopausal Women (N = 565)….………………………………………..…………78
Figure 5. Lowess plot of associations of global cognition change with inflammation variables:
NAPS Postmenopausal Women (N = 141).……..………………………………………….……79
Figure 6. Lowess plot of associations of verbal memory change with inflammation variables:
NAPS Postmenopausal Women (N = 141)………………………………………………………80
Figure 7. Lowess plot of associations of executive function change with inflammation
variables: NAPS Postmenopausal Women (N = 141)………………………………………..…81
Figure 8. Lowess plot of associations of visual memory change with inflammation variables:
NAPS Postmenopausal Women (N = 141)………………………………………………………82
Figure 9. Lowess plot of associations of global cognition change with inflammation variables:
NAPS Men (N = 88)……………………………………………………………………...…………83
Figure 10. Lowess plot of associations of verbal memory change with inflammation
variables: NAPS Men (N = 88)…………………………………………………………….………84

vii
Figure 11. Lowess plot of associations of executive function change with inflammation
variables: NAPS Men (N = 88)…………………………..……………………………………..…85
Figure 12. Lowess plot of associations of visual memory change with inflammation variables:
NAPS Men (N = 88) ………………………………..………………………………………………86
Figure 13. Lowess plot of associations of global cognition change with inflammation
variables: Combined ELITE and NAPS Postmenopausal Women (N = 704) ….……………87
Figure 14. Lowess plot of associations of verbal memory change with inflammation
variables: Combined ELITE and NAPS Postmenopausal Women (N = 704) …………….…88
Figure 15. Lowess plot of associations of executive function change with inflammation
variables: Combined ELITE and NAPS Postmenopausal Women (N = 704)……………..…89
Figure 16. Lowess plot of associations of visual memory change with inflammation variables:
Combined ELITE and NAPS Postmenopausal Women (N = 704)…………………….………90

1
Abstract
Objective
Accumulating evidence has linked inflammation (an immune response to injury, pathogens, irritants, or
oxidative stress) to decline in cognitive performance and elevated risk of dementia. The
pathophysiological pathways for neurodegenerative diseases like dementia are not fully understood.
However, current evidence has highlighted the involvement of various inflammatory processes in the
brain, which play a crucial role in pathologies of many diseases such as dementia, stroke, and traumatic
brain injury. We aimed to analyze the association between inflammation markers and change in cognition
endpoints in participants from two randomized clinical trials who were aged 55-73 years.
Methods
This is a post-hoc analysis using the data collected in two completed clinical trials. The Early vs Late
Intervention Trial with Estradiol (ELITE) was a single-center, randomized, double-blinded, placebocontrolled trial that tested whether time since menopause modifies the effect of estradiol therapy on
specified health outcomes, including progression of subclinical atherosclerosis and cognition. The
Nattokinase Atherothrombotic Prevention Study (NAPS) was a single-center, randomized, doubleblinded, placebo-controlled trial that tested whether daily nattokinase supplementation reduces
progression of subclinical atherosclerosis. A combined dataset was based on harmonized common
variables, including E-selectin, P-selectin, ICAM-1, VCAM-1, IL-1β, IL-10, MCP-1, and TNF-α, from ELITE
and NAPS trials. Inflammation variables were composite measures derived from a neuropsychological
test battery. The primary outcome for this analysis was 2.5-year change in cognitive endpoints in the
ELITE trial and 3-year change in cognitive endpoints in NAPS trial. Associations between inflammation
markers measured at baseline (prior to randomization) and change in cognitive performance were
analyzed with linear regression models. Associations between inflammation markers and 2.5-3-year
change in cognitive endpoints were analyzed with multivariable linear regression models adjusted for age,
race, education level, and baseline cognition.

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Results
A total of 565 postmenopausal women were included in the ELITE dataset. In NAPS, there were 141
women and 88 men. In the combined dataset, 704 participants were included. Based on the ELITE trial,
baseline IL-1β (P-value = 0.019) was positively associated with 2.5-year change in global cognition, and
baseline IL-6 (P-value = 0.0028) was inversely associated with 2.5-year change in global cognition.
Baseline VEGF-A (P-value = 0.028) was positively with 2.5-year change in executive function, and
baseline IL-6 (P-value = 0.0033) and baseline TNF-α (P-value = 0.016) was inversely associated with 2.5-
year change in executive function. Baseline E-selectin (P-value = 0.036) was positively associated with
2.5-year change in visual memory, and baseline IFNγ (P-value = 0.018) was inversely associated with
2.5-year change in visual memory. Based on the NAPS trial including postmenopausal women, baseline
E-selectin (P-value = 0.048) was inversely associated with 3-year change in global cognition. Baseline
PIGF (P-value = 0.024) was inversely associated with 3-year change in verbal memory. Based on the
NAPS trial including men, baseline IL-8 (P-value = 0.012) was positively associated with 3-year change in
global cognition. Based on the combined dataset, baseline TNF-α was inversely associated with 2.5-3-
year change in global cognition (P-value = 0.0030) and executive function (P-value = 0.011). Baseline Eselectin (P-value = 0.014) was positively associated with 2.5-3-year change in visual memory, and
baseline VCAM-1 (P-value = 0.023) and baseline TNF-α (P-value = 0.0090) was inversely associated with
3-year change in visual memory.
Conclusions
Our results suggest that TNF-α and IL-6 were inflammation markers that showed in general inverse
associations with changes in various aspects of cognitive performance over a 2.5-3-year period in healthy
cognitively intact older adults.

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Chapter One: Introduction
Alzheimer’s disease (AD), a type of cognitive and age-related disorder, is the most frequent progressive
neuropsychiatric dementing disorder [1]. Almost 10% of U.S. adults ages 65 and older have dementia,
while another 22% adults have mild cognitive impairment [2]. The current diagnostic standards rely on
clinical manifestations of cognitive dysfunction and impaired daily activities. However, these indicators
may not be sufficiently sensitive to identify early stages of the disease [3]. In the beginning stages of AD,
cognitive changes are often too subtle to be recognized by patients, family, friends, and experienced
physicians [4]. As such, AD poses significant challenges for early detection and intervention, particularly
when in initial stages.
There is evidence that circulating inflammatory markers are elevated prior to onset of cognitive
impairment characteristic of AD [5,6,7]. Although various studies have investigated the role of
inflammation markers in AD, including the involvement of cytokines such as IL-1, IL-6, and TNF-α [9], the
relationship between inflammation markers and change in cognitive endpoints is complex.2
Unraveling the intricate relationship between inflammation markers and change in cognitive endpoints is
essential for developing effective diagnostic approaches and interventions aimed at mitigating the onset
and progression of AD. In this study, we used longitudinal cognitive datasets from two clinical trials to
assess association of circulating inflammatory biomarkers measured at baseline with change in cognitive
endpoints including global cognition, verbal memory, executive function, and visual memory measured
over a 2.5 to 3-year follow-up.

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Chapter Two: Methods
ELITE
Design and setting
The Early vs Late Intervention Trial with Estradiol (ELITE) was a single-center, randomized, double-blind,
placebo-controlled trial in which serial carotid artery measurements were obtained by B-mode ultrasound
to test whether time since menopause modifies the effect of estradiol therapy on progression of
subclinical atherosclerosis measured as carotid artery intima-media thickness (CIMT) and cognition.
Participants were allocated randomly, with a 1:1 ratio, to either receive oral 17β-estradiol (1 mg daily) or
placebo; randomization was stratified by early postmenopause (<6 years since menopause) and late
postmenopause (≥10 years since menopause). Additional stratification factors considered for
randomization were baseline CIMT (<0.75 or ≥0.75 mm) and hysterectomy status (yes or no).
Postmenopausal women with a uterus were additionally assigned sequential micronized progesterone (45
mg) as a 4% vaginal gel or matched placebo gel, one daily application for 10 days each 30 days.
Standard protocol approvals, registrations, and participant consents
The study was approved by Institutional Review Board of the University of Southern California and
monitored by an independent External Data and Safety Monitoring Board. Participants provided written
informed consent. The protocol is registered at clinicaltrials.gov (NCT00114517).
Participants
Healthy women, without clinical evidence of cardiovascular disease (CVD) and diabetes mellitus, were
enrolled in two groups based on postmenopausal stage: early postmenopause, defined as within 6 years
of the final menstrual period or surgical menopause, and late postmenopause, defined as 0 years or more
beyond natural or surgical menopause. Postmenopausal status was determined by absence of vaginal
bleeding for a minimum of 6 months (natural menopause) or bilateral oophorectomy (surgical
menopause), along with serum estradiol levels below 25 pg/mL.

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ELITE exclusion criteria were as follows: indeterminate time since menopause; fasting plasma triglyceride
level >500 mg/dL (5.65 mmol/L); diabetes mellitus or fasting serum glucose >140 mg/dL; serum
creatinine >2.0 mg/dL (177 mmol/L); diastolic blood pressure >110 mmHg or systolic blood pressure >160
mmHg; untreated thyroid disease; liver disease; life-threatening disease with a prognosis of less than 5
years; history of deep vein thrombosis or pulmonary embolism; history of breast cancer; current
postmenopausal hormone therapy within 1 month of screening.
Trial Follow-up
Recruitment initially entailed a 3-year recruitment phase followed by 2 to 5 years of randomly assigned
estradiol therapy or placebo. Participants were evaluated monthly at a specialized research clinic for the
first 6 months and then every other month until the trial was completed (refer to the Supplementary
Appendix). The trial was extended by 2.5 years to collect additional data, which included results from
cardiac computed tomography (calcium and coronary artery lesions) conducted upon completion of the
randomly assigned treatment or placebo. A total of 596 women (92.3% of the total randomization)
finished follow-up ultrasonographic examinations.
Assessment of Cognition
The trial extension allowed for a third cognitive assessment as participants completed the trial. The
median (IQR) duration of follow-up among randomized participants was 57.6 months (IQR 39.6-66
months Cognitive assessment was determined with a comprehensive neuropsychological battery that
focused on standardized tests sensitive to age-related changes. See Combined Dataset section below for
details of the cognitive measures.
Inflammatory biomarkers
In the ELITE dataset, inflammation markers included Endothelial-selectin (E-selectin), Platelet-selectin (Pselectin), Intercellular Adhesion Molecule-1 (ICAM-1), Vascular Cell Adhesion Molecule-1 (VCAM-1),
Interleukin-1 beta (IL-1β), Interleukin-10 (IL-10), Monocyte Chemoattractant Protein-1 (MCP-1), Tumor
Necrosis Factor-alpha (TNF-α), Macrophage Inflammatory Protein-1 alpha (MIP-1α), Interleukin-1 alpha

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(IL-1α),), Interferon-gamma (IFNγ), Interleukin-6 (IL-6), Interleukin-8 (IL-8), and Vascular Endothelial
Growth Factor-A (VEGF-A).
The cytokines and inflammatory biomarkers were measured using validated ELISA kits from R&D
Systems (Minneapolis, MN). The assays used in our previous experiences [20-23] have shown adequate
sensitivity and precision to measure the proposed analytes, which include IL-1a, IL-1β, IL-6, IL-8, IL-10,
INF-γ, MCP-1, MIP-1a, TNF-α, sICAM-1, sVCAM-1, VEGF, E-selectin, and P-selectin.
NAPS
Design and setting
The Nattokinase Atherothrombotic Prevention Study (NAPS) was a single-center, randomized, doubleblinded, placebo-controlled trial that tested whether daily nattokinase supplementation in healthy
postmenopausal women and men reduces progression of subclinical atherosclerosis, measured as CIMT
and carotid arterial stiffness (CAS) from serial carotid artery B-mode ultrasound. Eligible and participants
were randomly assigned in a 1:1 ratio to receive either oral nattokinase at a dosage of 2,000 fibrinolytic
units daily or matching placebo. Blocked randomization with a block size of 4 was used and stratification
was based on baseline CIMT categorized as <0.75 mm or ≥0.75 mm.
Standard protocol approvals, registrations, and patient consents
The trial was approved by the Institutional Review Board of the University of Southern California and is
registered on clinicaltrials.gov (NCT02080520). All participants provided written informed consent and an
independent External Data Safety and Monitoring Board oversaw participant safety and trial conduct.
Participants
Healthy postmenopausal women and men without clinical evidence of CVD or diabetes mellitus were
included in the trial. Specific inclusion criteria were age 55 years and older and postmenopausal female
(no uterine bleeding for >6 months) and men. Exclusion criteria included: clinical signs, symptoms or
personal history of CVD; diabetes mellitus or fasting serum glucose >140 mg/dL; plasma

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triglycerides >500 mg/dL; uncontrolled hypertension (systolic blood pressure >160 mmHg or diastolic
blood pressure >110 mmHg); uncontrolled tachycardia or irregular heart rate (i.e., atrial fibrillation);
untreated thyroid disease; renal insufficiency (serum creatinine >2.0 mg/dL); life threatening illness with
prognosis <5 years; current use of lipid-lowering medication; current use of food supplements containing
soy, soy protein, isoflavone or other phytoestrogens; sensitivity or allergy to soy or nuts; regular use of
aspirin or other antiplatelet medication; use of anticoagulants; or, bleeding diatheses or tendencies.
Trial follow-up
Recruitment was based on a planned 2-year recruitment period and 3 years of randomized treatment.
Following randomization, each participant was followed every month for the first 6 months, then every 3
months for 36 months. A total of 234 randomized participants (88% of the total randomized) completed at
least one carotid artery ultrasound follow-up visit.
Assessment of Cognition
Cognitive outcomes were evaluated at baseline, and around 3 years after randomization. Cognitive
assessment determined at the 1.5-year midpoint was not used in this study. The median (IQR) duration of
trial follow-up among randomized participants was 36.1 months (IQR 35.7-36.3 months) [13]. See
Combined Dataset section below for details of the cognitive measures.
Inflammatory biomarkers
In the NAPS dataset, inflammation markers included Endothelial-selectin (E-selectin), Platelet-selectin (Pselectin), Intercellular Adhesion Molecule-1 (ICAM-1), Vascular Cell Adhesion Molecule-1 (VCAM-1),
Interleukin-1 beta (IL-1β), Interleukin-10 (IL-10), Monocyte Chemoattractant Protein-1 (MCP-1), Tumor
Necrosis Factor-alpha (TNF-α), Interleukin-8 (IL-8), Placental Growth Factor (PIGF), Very Late Antigen-4
(VLA-4), Cluster of Differentiation 11b (CD11b), and Cluster of Differentiation 14 (CD14).
MCP-1, IL-8, TNF-α, and IL-10 were assessed using ELISA kits from R&D Systems (Minneapolis, MN)
and measured in plasma with a FLUOstar Omega microplate reader (BMG Labtech, Cary, NC) at

8
wavelengths of 540 or 570 nm [14,15]. PIGF, a key molecule in angiogenesis and vasculogenesis
belonging to the VEGF-A sub-family, was assessed in plasma using an ELISA kit from R&D Systems and
the same microplate reader [16]. ICAM-1, VCAM-1, E-selectin, and P-selectin were also measured in
plasma with ELISA kits from R&D Systems and the FLUOstar Omega microplate reader at appropriate
wavelengths [17,18].
Furthermore, cluster differentiation (CD)11b, CD14, and veryVLA-4 expressed on
monocytes/macrophages isolated from whole blood were analyzed via cell fluorescence using the BD
Fluorescence-Activated Cell Sorting (FACS) system from Becton, Dickinson and Company (Franklin
Lakes, NJ) [19]. FACS values for CD11b and CD14 were reported as a percentage of cells positive for
the respective activation marker on monocytes/macrophages' cell surface [19]. The expression of VLA-4
on the cell surface of monocytes/macrophages was measured by binding of a phycoerythrin-conjugated
monoclonal antibody and quantified using FACS; VLA-4 expression was reported in relative fluorescence
units (RFU) [19].
Combined dataset (ELITE and NAPS women).
A combined dataset was created, which included harmonized common variables from ELITE and NAPS
trials. Participants in ELITE were all postmenopausal women, while participants in NAPS contained both
postmenopausal women and men. In the combined dataset, common variables from ELITE and for
postmenopausal women from NAPS were combined, which means data for men from NAPS were
excluded from the combined analysis. While ELITE included cognition change over 2.5 years, NAPS
included change over 3 years; no transformation of cognition endpoints was performed due to the slight
differences in the time over which cognitive change was assessed.
In both ELITE and NAPS, the same cognitive data were collected, and cognitive composite scores
determined. Cognitive outcomes were assessed at baseline at median of 2.5-year (median 2.54, IQR
2.51–2.69) after randomization in the ELITE, while in NAPS, assessments were conducted at baseline at
median of 3.0-year (median 3.01, IQR 3.00-3.03) after randomization. Cognitive outcomes were

9
standardized composites from neuropsychological test scores assessing global cognition, verbal memory,
executive function, and visual memory. Scores for global cognition were determined from 17 tests.
Composites were calculated as a weighted average of contributing tests. Global cognition was a weighted
average of all cognitive tests.
In ELITE, E-selectin, P-selectin, ICAM-1, VCAM-1, IL-1β, IL-10, MCP-1, TNF-α, IL-8, MIP-1α, IL-1α, IFNγ,
IL-6, VEGF-A. In NAPS, inflammation markers included E-selectin, P-selectin, ICAM-1, VCAM-1, IL-1β,
IL-10, MCP-1, TNF-α, IL-8, PIGF, VLA-4, CD11b, and CD14. In the combined dataset, E-selectin, Pselectin, ICAM-1, VCAM-1, IL-1β, IL-10, MCP-1, TNF-α, and IL-8 were included in the analyses as these
inflammation markers were common markers between ELITE and NAPS.
Therefore, association between each inflammation measure and cognitive endpoint was analyzed in four
groups of participants: (1) ELITE postmenopausal women, (2) NAPS postmenopausal women only, (3)
NAPS men only, and (4) combined postmenopausal women from ELITE and NAPS.

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Chapter Three: Statistical analysis
The qualitative characteristics of participants, including race, education level, annual income, and years
since menopause were analyzed using percentages. Quantitative characteristics, including age, height,
weight, body mass index (BMI), systolic blood pressure, and diastolic blood pressure were analyzed
using means and interquartile ranges. These analyses were conducted separately for ELITE
postmenopausal women, NAPS postmenopausal women, and NAPS men only.
General linear regression models were used to analyze associations between cognitive endpoints and
inflammation variables. The primary independent variables of interest consisted of baseline levels of
inflammation variables. Dependent variables of interest were changes in cognitive endpoints including
global cognition, verbal memory, executive function, and visual memory. In ELITE, change from baseline
for each cognitive endpoint was calculated at both post-randomization cognitive visits, which occurred at
about 2.5 years and 5 years after randomization. In NAPS, change from baseline for each cognitive
endpoint was calculated at both post-randomization cognitive visits, which occurred at about 1.5 and 3
years after randomization. The 2.5-year (median 2.54, IQR 2.51–2.69) ELITE and 3-year (median 3.01,
IQR 3.00-3.03) NAPS cognitive changes were included in the combined trials analysis. Covariates
included potential confounders of age, race, education level, randomized stratification variables, and
baseline values of the cognitive endpoints.
General linear regression is a powerful method to analyze associations between two variables if model
assumptions are satisfied. However, in ELITE, there were outliers in residual plots of the IL-6 and TNF-α
inflammation variables, which indicated violation of the assumption of normally distributed residuals in the
linear regression. To test sensitivity of the results with the presence of outliers, robust regression was
used as it reduces influence of outliers [12]. Results from robust analysis showed no meaningful
differences between parameter estimates and results for IL-6 and TNF-α (in comparison to the linear
regression models) with one exception. TNF-α was non-significantly positively associated with visual
memory change (p-value = 0.85) using the general linear regression model after adjusting for age, race,
education level, and baseline visual memory. However, in the robust regression, after adjusting for age,

11
race, education level, and baseline visual memory, TNF-α was non-significantly inversely associated with
visual memory change (p-value = 0.76). Given no strong evidence for rejection of the null hypothesis of
no association in both models, changes in directions of association between linear and robust regression
are not meaningful. See supplement appendix for descriptive tables for robust analysis (Tables 18-21). To
understand linearity of associations between inflammation markers and cognitive endpoints, lowess plots
of each inflammation markers against each cognitive measure were produced. There was a linear
relationship between each inflammation marker, and cognitive measure.
Multivariable analysis was used to compare to the linear regression model. In the multivariable analysis,
relationships between multiple independent variables and one dependent variable were analyzed. The
primary independent variables of interest consisted of inflammation variables with adjusted univariate
statistically significant association (P-value < 0.10) with each cognitive endpoint. Dependent variables of
interest were the repeatedly measured (baseline and follow-up) cognitive outcomes. Covariates included
potential confounders of age, race, education level, randomized stratification variables, and baseline
values of the cognitive endpoints. RStudio 2022.07.2 was used for analysis. A two-sided significance
level of 0.05 was used for all analyses.

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Chapter Four: Results
Characteristics of ELITE and NAPS participants are shown in Table 1 and include baseline characteristics
among 565 randomized postmenopausal women in ELITE, 141 women in NAPS, and 88 men in NAPS. A
total of 565 participants in ELITE had a mean (IQR) age of 60.0(55.0- 64.0) years, 141 postmenopausal
women in NAPS had a mean (IQR) age of 67.1(61.0- 73.0), and 88 men in NAPS had a mean (IQR) age
of 65.2(59.0-71.0). In ELITE, the sample was all postmenopausal women, primarily white (70% white,
30% non-white), and well-educated (68% reported a bachelor’s degree or higher). In NAPS women, the
sample was all postmenopausal women, primarily white (66.7% white, and 33.3% non-white), and welleducated (66.6% reported a bachelor’s degree or higher). In NAPS men, the sample was all men,
primarily white (77.3% white, 22.7% non-white), and well-educated (71.6% reported a bachelor’s degree
or higher).
Univariate analysis
ELITE Postmenopausal Women
Global Cognition: In unadjusted analyses, global cognition change was positively statistically significantly
associated with baseline E-selectin (p-value = 0.040) and inversely statistically significantly associated
with baseline IL-6 (p-value = 0.020). After adjusting for age, race, education level, and baseline global
cognition, baseline IL-1β (p-value = 0.020) was positively statistically significantly associated with global
cognition change. Baseline IL-6 (p value = 0.0030) was inversely statistically significantly associated with
global cognition change (Table 2).
Verbal Memory: In unadjusted analyses, verbal memory change was positively statistically significantly
associated with baseline E-selectin (p-value = 0.048) and IL-6 (p-value = 0.0011). After adjusting for age,
race, education level, and baseline verbal memory, there were no statistically significant associations
between verbal memory change and baseline inflammatory markers (Table 3).

13
Executive Function: In unadjusted analyses, executive function change was positively statistically
significantly associated with baseline VEGF-A (p-value = 0.040) and was inversely statistically
significantly associated with baseline IL-6 (p-value = 0.023). After adjusting for age, race, education level,
and baseline executive function, baseline VEGF-A (p-value = 0.039) was positively statistically
significantly associated with executive function change and baseline IL-6 (p-value = 0.0034) and TNF-α
(P-value = 0.033) were inversely statistically significantly associated with executive function change
(Table 4).
Visual Memory: In unadjusted analyses, visual memory change was positively statistically significantly
associated with baseline E-selectin (p-value = 0.045) and inversely statistically significantly associated
with baseline VCAM-1 (p-value = 0.011) and IFNγ (p-value = 0.024). After adjusting for age, race,
education level, and baseline visual memory, baseline IFNγ (p-value = 0.031) was inversely statistically
significantly associated with visual memory change (Table 5).
NAPS Postmenopausal Women
Verbal Memory: In unadjusted analyses, verbal memory change was inversely statistically significantly
associated with baseline PIGF (p-value = 0.025). After adjusting for age, race, education level, and
baseline verbal memory, baseline PIGF (p-value = 0.022) remained inversely statistically significantly
associated with verbal memory change (Table 7).
In unadjusted and adjusted analyses, there were no statistically significant associations between baseline
inflammatory markers and changes in global cognition, executive function, or visual memory and baseline
inflammatory markers (Table 6, Table 8 and Table 9).
NAPS Men
Global Cognition: In unadjusted analyses, global cognition change was positively statistically significantly
associated with baseline IL-8 (P-value = 0.0128) and TNF-α (p-value = 0.040). After adjusting for age,

14
race, education level, and baseline global cognition, baseline IL-8 (p-value = 0.0105) was positively
statistically significantly associated with global cognition change (Table 10).
Verbal Memory: In unadjusted analyses, verbal memory change was positively statistically significantly
associated with baseline TNF-α (p-value = 0.029). After adjusting for age, race, education level, and
baseline verbal memory, there were no statistically significantly associations between baseline
inflammation variables and verbal memory change (Table 11).
In unadjusted and adjusted analyses, there were no statistically significantly associations between
change in executive function or visual memory and baseline inflammation variables (Table 12).
Combined ELITE and NAPS Postmenopausal Women
Global Cognition: In unadjusted analyses, there were no statistically significantly associations between
global cognition change and baseline inflammation variables. After adjusting for age, race, education
level, and baseline global cognition, baseline MCP-1 (p-value = 0.032) and baseline TNF-α (p-value =
0.00024) were inversely statistically significantly associated with global cognition change (Table 14).
Verbal Memory: In unadjusted and adjusted analyses, there were no statistically significant associations
between verbal memory change and baseline inflammatory markers (Table 15).
Executive Function: In unadjusted analyses, there were no statistically significantly associations between
executive function change and baseline inflammation variables. After adjusting for age, race, education
level, and baseline executive functions, baseline P-selectin (p-value = 0.0096), baseline MCP-1 (P-value
= 0.032), and baseline TNF-α (p-value = 0.00023) were inversely statistically significantly associated with
executive function change (Table 16).
Visual Memory: In unadjusted analyses, visual memory change was positively statistically significantly
associated with baseline E-selectin (p-value = 0.036) and inversely statistically significantly associated
with baseline VCAM-1 (p-value = 0.0025) and baseline TNF-α (p-value = 0.0264). After adjusting for age,
race, education level, and baseline visual memory, baseline E-selectin (p-value = 0.0027) was positively

15
statistically significantly associated with visual memory change and baseline P-selectin (p-value =
0.0086), baseline VCAM-1 (p-value = 0.00015), MCP-1 (p-value = 0.00073), and baseline TNF-α (p-value
= 2.7e-06) were inversely statistically significantly associated with visual memory change (Table 17).
Multivariable analysis
ELITE Postmenopausal Women
Global Cognition: Based on Table 2, IL-1β, IL-6, and TNF-α were significantly associated with global
cognition change in the adjusted univariate inflammation measure analyses; these inflammation
measures were included in the multivariable model. After adjusting for age, race, education level, and
baseline global cognition, baseline IL-1β (P-value = 0.0192) was positively statistically significantly
associated with global cognition change. Baseline IL-6 (P-value = 0.00284) was inversely statistically
significantly associated with global cognition change in the multivariable analysis (Table 22).
Verbal Memory: Based on Table 3, there were no statistically significant associations between verbal
memory change and baseline inflammatory markers after adjustments of covariates.
Executive Function: Based on Table 4, IL-6, TNF-α, and VEGF-A were significantly associated with
executive function change in the adjusted univariate inflammation measure analyses; these inflammation
measures were included in the multivariable model. After adjusting for age, race, education level, and
baseline executive functions, baseline VEGF-A (P-value = 0.028) was positively statistically significantly
associated with executive functions change and baseline IL-6 (P-value = 0.0034) and baseline TNF-α (Pvalue = 0.015) were inversely statistically significantly associated with executive functions change in the
multivariable analysis (Table 23).
Visual Memory: Based on Table 5, E-selectin and IFNγ were significantly associated with visual memory
change in the adjusted univariate inflammation measure analyses; these inflammation measures were
included in the multivariable model. After adjusting for age, race, education level, and baseline visual
memory, baseline E-selectin (P-value = 0.0357) was positively statistically significantly associated with

16
visual memory change and baseline IFNγ (P-value = 0.0182) was inversely statistically significantly
associated with visual memory change in the multivariable analysis (Table 24).
NAPS Postmenopausal Women
Global Cognition: Based on Table 6, E-selectin was marginally significantly associated with global
cognition change in the adjusted univariate inflammation measure analyses, and was the only
inflammation variable in the multivariable model. After adjusting for age, race, education level, and
baseline global cognition, baseline E-selectin (P-value = 0.048) was inversely statistically significantly
associated with global cognition change in multivariable analysis (Table 25).
Verbal Memory: Based on Table 7, PIGF was significantly associated with verbal memory change in the
adjusted univariate inflammation measure analyses, and was the only inflammation variable in the
multivariable model. After adjusting for age, race, education level, and baseline verbal memory, baseline
PIGF (P-value = 0.022) was inversely statistically significantly associated with verbal memory change in
multivariable analysis (Table 26).
Executive Function: Based on Table 8, P-selectin was significantly associated with executive function
change in the adjusted univariate inflammation measure analyses, and was the only inflammation
variable in the multivariable model. In multivariable analysis, there were no statistically significant
associations between executive function change and baseline inflammatory markers after adjustment for
covariates.
Visual Memory: Based on Table 9, ICAM-1 was significantly associated with executive function change in
the adjusted univariate inflammation measure analyses, and was the only inflammation variable in the
multivariable model. In multivariable analysis, there were no statistically significant associations between
executive function change and baseline inflammatory markers after adjustment for covariates.
NAPS Men.

17
Global Cognition: Based on Table 10, E-selectin, TNF-α, and IL-8 were significantly associated with
global cognition change in the adjusted univariate inflammation measure analyses; these inflammation
measures were included in the multivariable model. After adjusting for age, race, education level, and
baseline global cognition, baseline IL-8 (P-value = 0.0120) was positively statistically significantly
associated with global cognition change in multivariable analysis (Table 27).
Verbal Memory: Based on Table 11, TNF-α was significantly associated with global cognition change in
the adjusted univariate inflammation measure analyses and was the only inflammation variable in the
multivariable model. In multivariable analysis, there were no statistically significant associations between
verbal memory change and baseline inflammatory markers after adjustment for covariates.
Executive Function: Based on Table 12, IL-8 was significantly associated with executive function change
in the adjusted univariate inflammation measure analyses and was the only inflammation variable in the
multivariable model. In multivariable analysis, there were no statistically significant associations between
executive function change and baseline inflammatory markers after adjustment for covariates.
Visual Memory: Based on Table 13, there were no statistically significant associations between visual
memory change and baseline inflammatory markers after adjustment for covariates.
Combined ELITE and NAPS Postmenopausal Women
Global Cognition: Based on Table 14, MCP-1 and TNF-α were significantly associated with global
cognition change in the adjusted univariate inflammation measure analyses; these inflammation
measures were included in the multivariable model. After adjusting for age, race, education level, and
baseline global cognition, baseline TNF-α (P-value = 0.0030) was inversely statistically significantly
associated with global cognition change in multivariable analysis (Table 28).
Verbal Memory: Based on Table 15, there were no statistically significant associations between verbal
memory change and baseline inflammatory markers after adjustment for covariates.

18
Executive Function: Based on Table 16, P-selectin, MCP-1, and TNF-α were significantly associated with
executive function change in the adjusted univariate inflammation measure analyses; these inflammation
measures were included in the multivariable model. After adjusting for age, race, education level, and
baseline executive functions, baseline TNF-α (P-value = 0.011) was inversely statistically significantly
associated with executive functions change in multivariable analysis (Table 29).
Visual Memory: Based on Table 17, E-selectin, P-selectin, VCAM-1, IL-8, MCP-1, and TNF-α were
significantly associated with visual memory change in the adjusted univariate inflammation measure
analyses; these inflammation measures were included in the multivariable model. After adjusting for age,
race, education level, and baseline visual memory, baseline E-selectin (P-value = 0.014) was positively
statistically significantly associated with visual memory change and baseline VCAM-1 (P-value = 0.023)
and baseline TNF-α (P-value = 0.0090) were inversely statistically significantly associated with visual
memory change in multivariable analysis (Table 30).

19
Chapter Five: Discussion
Analysis of associations of baseline inflammation measures with subsequent change in cognitive
performance measured over 2.5-3 years demonstrated the following: (1) In the ELITE trial of
postmenopausal women adjusted for covariates (n=565), baseline IL-1β exhibited positive associations
with 2.5-year change in global cognition, and baseline IL-6 exhibited inverse associations with 2.5-year
change in global cognitive change. Baseline VEGF-A exhibited positive associations with 2.5-year change
in executive function, and baseline IL-6 and baseline TNF-α exhibited inverse associations with 2.5-year
change in executive function. Baseline E-selectin exhibited positive associations with 2.5-year change in
visual memory, and baseline IFNγ exhibited inverse associations with 2.5-year change in visual memory.
(2) In NAPS postmenopausal women analyses adjusted for covariates (n=141), baseline E-selectin
exhibited inverse associations with 3-year change in global cognition. Baseline PIGF exhibited inverse
associations with 3-year change in verbal memory. (3) In NAPS confined to men adjusted for covariates
(n=88), there were no statistically significant associations between 3-year change in cognitive functions
and baseline inflammatory markers. (4) In combined analysis of ELITE and NAPS postmenopausal
women adjusted for covariates (n=704), baseline TNF-α exhibited positive associations with 2.5-3-year
change in global cognition. Baseline TNF-α exhibited positive associations with 2.5-3-year change in
executive function. Baseline E-selectin exhibited positive associations with 2.5-3-year change in visual
memory, and baseline VCAM-1 and baseline TNF-α exhibited inverse associations with 3-year change in
visual memory. These markers can be considered as early indicators for cognitive decline as our
population was cognitively and overall healthy.
Although many studies have evaluated the associations between inflammatory markers and cognitive
decline, most of the studies have focused on elderly populations. A cohort study of 915 healthy middleaged individuals (mean age 55.6, 45–74) evaluated whether low-grade inflammation, measured in midlife,
is associated with a decline in cognitive performance after a 10-year follow-up. In line with our results,
they found that both higher IL-6 and TNF-α at baseline predicted poorer performance in verbal frequency
and word-list learning at 10-year follow-up [24]. It has been observed that inflammation markers such as
serum IL-6 levels rise with aging in a variety of healthy groups [25,26,27]. A cross-sectional study

20
conducted among 216 healthy native German adults (138 males and 78 females, mean age: 39.12 ±
20.19 years) indicated that healthy subjects with higher levels of C-reactive protein (CRP), which is a
marker of peripheral inflammation, exhibited poorer performance in verbal learning memory and general
wakefulness domains of cognition [29]. Therefore, inflammation markers not only exhibited association
with change in cognitive endpoints in postmenopausal women, but also cross-sectional associations in
younger healthy individuals.
In this study, we demonstrated statistically significant associations between inflammation markers and
change in cognitive endpoints including global cognition, verbal memory, executive function, and visual
memory. These results are consistent with other studies that have suggested that chronic inflammation,
indicated by elevated levels of inflammatory markers like C-reactive protein (CRP) or interleukin-6 (IL-6),
were associated with cognitive impairment and neurodegenerative diseases such as Alzheimer's disease
(AD) [30]. However, inflammation markers also have other long-term health effects. Some studies showed
that risk of dementia and cardiovascular pathology, including stroke is associated with inflammation [31,
32, 33]. Furthermore, inflammation is also related to other chronic neurodegenerative diseases, including
ataxia, Huntington’s disease, and motor neuron disease [31]. Elevated inflammation may also to increase
risk of conversion to dementia on longitudinal follow-up [34]. Elevated inflammation is also associated
with some part of brain structural damage and cellular dysfunction, such as hippocampal areas [35].
Therefore, it is reasonable to conclude that the associated inflammatory response is detrimental to
hippocampal neurogenesis.
Our study has several strengths. First, the integration of data from both trials into a combined dataset
(ELITE and NAPS women) increases the statistical power. Second, both trials had a relatively long followup period, which allows for the assessment of changes over time. There are also limitations. The results
of the study have limited generalizability. The results from the ELITE trial cannot be generalized to
women in different reproductive stages and those in the menopausal transition. Also, results are not
applicable to women with primary ovarian insufficiency, women who have undergone premature
menopause due to surgical procedures or cancer treatments, and women with mild cognitive impairment
or dementia [36, 37]. The results from the NAPS trial cannot be generalized to men and women with

21
preexisting cardiovascular disease or diabetes. Furthermore, the sample size for males was relatively
small, which limited our ability to make conclusion on males.

22
References:
1.Stratmann, K., Heinsen, H., Korf, H., Del Turco, D., Ghebremedhin, E., Seidel, K., Bouzrou, M.,
Grinberg, L. T., Bohl, J., Wharton, S. B., den Dunnen, W., & Rüb, U. (2015). Precortical phase of
alzheimer’s disease (ad)-related tau cytoskeletal pathology. Brain Pathology, 26(3), 371–386.
https://doi.org/10.1111/bpa.12289
2. Manly, J. J., Jones, R. N., Langa, K. M., Ryan, L. H., Levine, D. A., McCammon, R., Heeringa, S. G., &
Weir, D. (2022). Estimating the prevalence of dementia and mild cognitive impairment in the US. JAMA
Neurology, 79(12), 1242. https://doi.org/10.1001/jamaneurol.2022.3543
3.McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of
Alzheimer’s disease: Report of the NINCDS-ADRDA Work Group under the auspices of the Department
of Health and Human Services Task Force on Alzheimer’s disease. Neurology 1984;34:939–944.
4.Schneider, P., Hampel, H., & Buerger, K. (2009). Biological Marker candidates of alzheimer’s disease in
blood, plasma, and serum. CNS Neuroscience & Therapeutics, 15(4), 358–374.
https://doi.org/10.1111/j.1755-5949.2009.00104.x
5.Tan ZS, Beiser AS, Vasan RS, et al. Inflammatory markers and the risk of Alzheimer disease: the
Framingham study. Neurology. 2007;68(22):1902-1908. doi: 10.1212/ 01.wnl.0000263217.36439.da
6.Singh-Manoux A, Dugravot A, Brunner E, et al. Interleukin-6 and C-reactive protein as predictors of
cognitive decline in late midlife. Neurology. 2014;83(6):486-493. doi: 10.1212/WNL.0000000000000665
7.Walker KA, Gottesman RF, Wu A, et al. Systemic inflammation during midlife and cognitive change over
20 years: the ARIC Study. Neurology. 2019;92(11): E1256–E1267. doi:
10.1212/WNL.0000000000007094
8.Khan, S.A.; Rehman, S.; Nabi, B.; Iqubal, A.; Nehal, N.; Fahmy, U.A.; Kotta, S.; Baboota, S.; Md, S.; Ali,
J. Boosting the brain delivery of Atazanavir through nanostructured lipid carrier-based approach for
mitigating neuroaids. Pharmaceutics 2020, 12, 1059.

23
9.Akiyama H, Barger S, Barnum S, et al. (2000). Inflammation and Alzheimer's disease. Neurobiology of
Aging, 21(3), 383-421.
10. Hodis HN, Mack WJ, Shoupe D, et al. Methods and baseline cardiovascular data from the Early
versus Late Intervention Trial with Estradiol testing the menopausal hormone timing hypothesis.
Menopause 2014;22:391–401.
11. Henderson VW, St. John JA, Hodis HN, et al. Cognition, mood, and physiological concentrations of
sex hormones in the early and late postmenopause. Proc Natl Acad Sci USA 2013;110:20290–20295.
12. Alma , Ö. G. (2011). Comparison of Robust Regression Methods in Linear Regression. Comparison of
Robust Regression Methods in Linear Regression , 6, 409–421.
13. Hodis HN, Mack WJ, Meiselman HJ, Kalra V, Liebman H, Hwang-Levine J, Dustin L, Kono N, Mert M,
Wenby RB, Huesca E, Li Y, Yan M, St John JA, Whitfield L: Nattokinase atherothrombotic prevention
study: a randomized controlled trial. Clin Hemorheol Microcirc 78:339–353, 2021.
14. Perelman N, Selvaraj SK, Batra S, Luck LR, Erdreich-Epstein A, Coates TD, Kalra VK,
Malik P. Placenta growth factor activates monocytes and correlates with sickle cell disease
severity. Blood. 2003;102:1506-14.
15. Giri RK, Selvaraj SK, Kalra VK. Amyloid peptide-induced cytokine and chemokine
expression in THP-1 monocytes is blocked by small inhibitory RNA duplexes for early growth
response-1 messenger RNA. J Immunol. 2003;170:5281-4.
16. Sundaram N, Tailor A, Mendelsohn L, Wansapura J, Wang X, Higashimoto T, Pauciulo
MW, Gottliebson W, Kalra VK, Nichols WC, Kato GJ, Malik P. High levels of placenta growth
factor in sickle cell disease promote pulmonary hypertension. Blood. 2010;116:109-12.
17. Sultana C, Shen Y, Rattan V, Kalra VK. Lipoxygenase metabolites induced expression of
adhesion molecules and trans-endothelial migration of monocyte-like HL-60 cells is linked to

24
protein kinase C activation. J Cellular Physiol. 1996;167:477-87.
18. Shen Y, Rattan V, Sultana C, Kalra VK. Cigarette smoke condensate-induced adhesion
molecule expression and trans-endothelial migration of monocytes. Am J Physiol. 1996;270:
H1624-33.
19. Giri RK, Rajagopal V, Shahi S, Zlokovic BV, Kalra VK. Mechanism of amyloid peptide
induced CCR5 expression in monocytes and its inhibition by siRNA for Egr-1. Am J Physiol
(Cell Physiol). 2005;289:C264-76.
20. Karim R, Hodis HN,Stanczyk FZ, Lobo RA,Mack WJ.Relationshipbetween serum levels of sex
hormones and progression of subclinical atherosclerosis in postmenopausal women.J Clin Endocrinol
Metab2008;93:131-138.
21. Karim R,StanczykFZ,Hodis HN,Cushman M,Lobo RA, Hwang J,Mack WJ.Associations between
markers of inflammation and physiological and pharmacological levels of circulating sex hormones in
postmenopausal women. Menopause 2010;17:785-790.
22. Friedenreich CM,Neilson HK, Woolcott CG,Wang Q,Stanczyk FZ, McTiernan A,Jones CA,Irwin ML，
Yasui Y, Courneya KS. Inflammatory marker changes in a year-long randomized exercise intervention
trial among postmenopausal women. Cancer Prev Res 2012;5:98-108
23. Woolcott CG,Courneya KS,Boyd NF, Yaffe MJ,McTiernan A,E Brant R, Jones CA,Stanczyk FZ,Terry
T, Cook LS, Wang Q, Friedenreich CM.Association between sex hormo nes, glucose homeostasis,
adipokines, and inflammatory markers and mammographic density among postme nopausal women.
Breast Cancer Res Treat 2013;139:255-265.
24. Teemu Kipinoinen, Sini Toppala, Juha O. Rinne, et al. Neurology 2022;99;e2294-e2302 Published
Online before print October 4, 2022 DOI 10.1212/WNL.0000000000201116

25
25.Wei, J., Xu, H., Davies, J., and Hemmings, G. (1992). Increase of plasma IL-6 concentration with age
in healthy subjects. Life Sci. 51, 1953–1956. doi: 10.1016/0024- 3205(92)90112- 3
26.Hager, K., Machein, U., Krieger, S., Platt, D., Seefried, G., and Bauer, J. (1994). Interleukin-6 and
selected plasma proteins in healthy persons of different ages. Neurobiol. Aging 15, 771–772.
27.Roubenoff, R., Harris, T., Abad, L., Wilson, P., Dallal, G., and Dinarello, C. (1998). Monocyte cytokine
production in an elderly population: Effect of age and inflammation. J. Gerontol. A Biol. Sci. Med. Sci. 53,
M20–M26. doi: 10.1093/gerona/53A.1.M20
28.Ashraf-Ganjouei A, Moradi K, Bagheri S, Aarabi MH. The association between systemic inflammation
and cognitive performance in healthy adults. J Neuroimmunol. 2020 Aug 15;345:577272. doi:
10.1016/j.jneuroim.2020.577272. Epub 2020 May 25. PMID: 32534387.
29.Ashraf-Ganjouei A, Moradi K, Bagheri S, Aarabi MH. The association between systemic inflammation
and cognitive performance in healthy adults. J Neuroimmunol. 2020 Aug 15;345:577272. doi:
10.1016/j.jneuroim.2020.577272. Epub 2020 May 25. PMID: 32534387.
30. Yaffe, K., Kanaya, A., Lindquist, K., Simonsick, E. M., Harris, T., Shorr, R. I., ... & Study of
Osteoporotic Fractures. (2004). The metabolic syndrome, inflammation, and risk of cognitive decline.
JAMA, 292(18), 2237-2242.
31. Blasko I, Stampfer-Kountchev M, Robatscher P, Veerhuis R, Eikelenboom P, Grubeck-Loebenstein B.
How chronic inflammation can affect the brain and support the development of Alzheimer’s disease in old
age: the role of microglia and astrocytes. Aging Cell. 2004;3:169–176.
32, Kuo HK, Yen CJ, Chang CH, Kuo CK, Chen JH, Sorond F. Relation of C-reactive protein to stroke,
cognitive disorders, and depression in the general population: systematic review and metaanalysis. Lancet Neurology. 2005;4:371–80.
33.Paul A, Ko KW, Li L, Yechoor V, McCrory MA, Szalai AJ, Chan L. C-reactive protein accelerates the
progression of atherosclerosis in apolipoprotein E-deficient mice. Circulation. 2004;104:647–655.

26
34. Schmidt R, Schmidt H, Curb JD, Masaki K, White LR, Launer LJ. Early inflammation and dementia: A
25-year follow-up of the Honolulu-Asia Aging Study. Annals of Neurology. 2002;52:168–174.
35. Ekdahl CT, Mohapel P, Elmer E, Lindvall O. Caspase inhibitors increase short-term survival of
progenitor-cell progeny in the adult rat dentate gyrus following status epilepticus. European Journal of
Neuroscience. 2001;14:937–945.
36. Rocca WA, Bower JH, Ahlskog JE, Grossardt BR, de Andrade M, Melton LJ III. Increased risk of
cognitive impairment or dementia in women who underwent oophorectomy before menopause. Neurology
2007;69: 1074–1083.
37. Ryan J, Scali J, Carriere I, et al. Impact of a premature menopause on cognitive function in later life.
BJOG 2014; 121:1729–1739.
38. Hodis HN, Mack WJ, Meiselman HJ, Kalra V, Liebman H, Hwang-Levine J, Dustin L, Kono N, Mert M,
Wenby RB, Huesca E, Li Y, Yan M, St John JA, Whitfield L: Nattokinase atherothrombotic prevention
study: a randomized controlled trial. Clin Hemorheol Microcirc 78:339–353, 2021.

27
Table1. Participant characteristics at baseline
ELITE
(n=565)
NAPS Women
(n=141)
NAPS Men
(n=88)
Characteristics
Age in years, mean (IQR) 60.0(55.0- 64.0) 67.1 (61.0- 73.0) 65.2(59.0-71.0)
Race or ethnic background — no. (%)
Non-Hispanic white 396 (70.1) 94 (66.7) 68 (77.3)
Non-Hispanic Black 48 (8.5) 9 (6.4) 4 (4.5)
Asian or Pacific Islander 47 (8.3) 12 (8.5) 8 (9.1)
Hispanic 74 (13.1) 24 (17.0) 8 (9.1)
Native American - 0 0
Other 0 2 (1.4) 0
Education — no. (%)
8th grade or less 1 (0.2) 0 1 (1.1)
Some high school 2 (0.4) 1 (0.7) 0
High school graduate 18 (3.2) 3 (2.1) 0
Trade/business school 14 (2.5) 3 (2.1) 5 (5.7)
Some college 148 (26.2) 40 (28.4) 19 (21.6)
Bachelor's degree 164 (29.0) 36 (25.5) 27 (30.7)
Graduate/professional 218 (38.6) 58 (41.1) 36 (40.9)
Other 0 0 0
Annual Income — no. (%)
Under $10,000 16 (3.0) 3 (2.1) 3 (3.4)
$10,000 to $29,999 63 (12) 18 (12.8) 8 (9.1)
$30,000 to $49,999 80 (15.2) 23 (16.3) 10 (11.3)
$50,000 to $69,999 83 (15.8) 18 (12.8) 11 (12.5)

28
$70,000 to $89,999 65 (12.3) 17 (12.1) 10 (11.4)
$90,000 or higher 220 (41.8) 52 (36.8) 41 (46.5)
Refused or N/A - 10 (7.1) 5 (5.7)
Years since menopause— no. (%)
<6 years 232 (41.0) 15 (11.9) -
>=10 years 333 (58.9) 111 (88.1) -
Height in inches, mean (IQR) 63.7(62.0- 66.0) 63.6 (61.5- 65.0) 69.0(67.0-71.0)
Weight in pounds, mean (IQR) 156.5(134.0- 174.0) 154.0 (133.5- 173.0) 187.3(170.0-204.1)
Body mass index (kg/m-squared),
mean (IQR)
27.1(23.2- 30.2) 26.7 (22.8- 29.7) 27.6(24.9-29.4)
Systolic blood pressure, mmHg, mean
(IQR)
116.3(106.0- 124.0) 121.5 (112.0- 130.0) 123.2(117.5-130.0)
Diastolic blood pressure, mmHg, mean
(IQR)
74.5(70.0- 80.0) 71.3 (68.0- 78.0) 75.2(70.0-80.0)
Inflammation markers
E-selectin, ng/mL, mean (IQR) 25.6 (18.2-30.9) 30.9 (22.7-38.6) 31.2 (22.0-38.0)
P-selectin, ng/mL, mean (IQR) 77.1 (57.1-93.1) 28.8 (20.8-31.0) 30.8 (24.1-37.3)
ICAM-1, ng/mL, mean (IQR) 324.7 (278.0-359.5) 311.3 (255.6-362.7) 297.8 (247.8-355.2)
VCAM-1, ng/mL, mean (IQR) 664.7 (544.0-758.0) 514.1 (406.5-595.5) 498.0 (391.8-565.9)
IL-1β, pg/mL, mean (IQR) 53.9 (0.2-25.6) 0.3 (0.0-0.5) 0.3 (0-0.06)
IL-10, pg/mL, mean (IQR) 30.4 (2.7-8.0) 0.6 (0.1-0.8) 0.6 (0.0-0.9)
MCP-1, pg/mL, mean (IQR) 449.1 (343.0-529.0) 161.8 (108.0-197.7) 168.9 (119.9-205.7)
TNF-α, pg/mL, mean (IQR) 7.8 (6.2-8.9) 1.8 (0.9-2.1) 1.5 (0.8-1.8)
IL-8, pg/mL, mean (IQR) 122.8 (15.3-140.0) 4.2 (1.8-5.3) 4.9 (2.5-6.3)
MIP-1α, pg/mL, mean (IQR) 222.9 (60.6-229.0) - -
IL-1α, pg/mL, mean (IQR) 16.2 (0-7.7) - -
IFNγ, pg/mL, mean (IQR) 1.7 (0.6-1.4) - -

29
IL-6, pg/mL, mean (IQR) 3.4 (1.2-2.6) - -
VEGF-A, pg/mL, mean (IQR) 282.9 (150.0-361.0) - -
PIGF, pg/mL, mean (IQR) - 15.4 (11.4-20.0) 18.4 (13.9-21.9)
VLA-4, RFU, mean (IQR) - 586.1 (441.0-688.0) 563.4 (452.8-656.0)
CD11b, %, mean (IQR) - 69.1 (60.9-80.8) 74.8 (66.7-84.9)
CD14, %, mean (IQR) - 24.7 (13.5-32.9) 16.5 (10.8-27.5)
Baseline cognitive variables
Global cognition, mean (IQR) 0.0 (-1.1-1.3) 0.2 (-0.7-1.4) -0.1 (-0.8-0.9)
Verbal memory, mean (IQR) 0.0 (-0.8-1.0) 0.2 (-0.6-1.3) -0.2 (-1.2-0.7)
Executive function, mean (IQR) 0.0 (-0.8-0.9) 0.1 (-0.7-0.9) -0.1 (-0.8-0.7)
Visual memory, mean (IQR) 0.0 (-0.7-0.8) 0.3 (-0.4-1.1) -0.4 (-1.1-0.3)
Change in cognitive variables
Global cognition, mean (IQR) 0.3 (-0.4-1.1) 0.4 (-0.3-1.0) 0.3 (-0.4-1.0)
Verbal memory, mean (IQR) 0.3 (-0.5-1.0) 0.2 (-0.5-1.0) -0.01(-0.7-0.8)
Executive function mean (IQR) 0 (-0.5-0.4) 0 (-0.4-0.4) 0.2 (-0.3-0.5)
Visual memory, mean (IQR) 0.2 (-0.3-0.8) 0.5 (-0.1-1.0) 0.5 (0.1-0.9)

30
Table 2. Associations of global cognition change with inflammation variables: ELITE Postmenopausal
Women (N = 565)
Variables Univariate Association Adjusted Association1
Beta 95% CI p-value Beta 95% CI p-value
E-selectin 0.00943 0.000466,
0.0184
0.0397 0.00621 -0.00213,
0.0146
0.14
P-selectin 0.00156 -0.00175,
0.00488
0.36 0.00152 -0.00151,
0.00455
0.33
ICAM-1 0.000274 -0.00116,
0.00170
0.71 0.000186 -0.00112,
0.00149
0.78
VCAM-1 -7.48e-05 -0.000639,
0.000489
0.80 8.62e-05 -0.000435,
0.000607
0.75
IL-1β 0.000420 -0.000243,
0.00108
0.22 0.000721 0.000125,
0.00132
0.0178
IL-10 0.000247 -0.000752,
0.00125
0.62 0.000386 -0.000506,
0.00128
0.40
MCP-1 -0.000282 -0.000910,
0.000346
0.38 4.29e-05 -0.000537,
0.000623
0.89
TNF-α -0.0133 -0.0502,
0.0236
0.48 -0.0306 -0.0641,
0.00288
0.074
IL-8 -0.000194 -0.000657,
0.000269
0.41 -6.15e-05 -0.000476,
0.000353
0.77
MIP-1α -0.000138 -0.000420,
0.000145
0.34 -4.48e-05 -0.000297,
0.000207
0.73

31
IL-1α -0.000567 -0.00255,
0.00142
0.58 7.58e-05 -0.00170,
0.001852
0.93
IFNγ -0.00743 -0.0340,
0.0192
0.59 -0.0127 -0.0365,
0.0110
0.29
IL-6 -0.00462 -0.00852,
-0.000729
0.0203 -0.005298 -0.00878, -
0.00182
0.00297
VEGF-A 1.62e-05 -0.000480,
0.000512
0.95 -0.000009 -0.000463,
0.000445
0.97
1. Adjusted for age, race, education level, and baseline global cognition.

32
Table 3. Associations of verbal memory change with inflammation variables: ELITE Postmenopausal
Women (N = 565)
Variables Univariate Association Adjusted Association1
beta 95% CI p-value Beta 95% CI p-value
E-selectin 0.00879 0.000113,
0.0175
0.0476 0.00329 -0.00268,
0.0148
0.41
P-selectin 0.00144 -0.00177,
0.00465
0.38 0.000201 -0.00191,
0.00444
0.89
ICAM-1 -0.000174 -0.00156,
0.00121
0.81 -0.000407 -0.00162,
0.00111
0.51
VCAM-1 0.000118 -0.000427,
0.000663
0.67 0.000184 -0.000335,
0.000756
0.46
IL-1β 0.000203 -0.000439,
0.000845
0.54 0.000337 -0.000282,
0.000972,
0.24
IL-10 -0.000166 -0.00113,
0.000801
0.74 -0.000215 -0.00116,
0.000708
0.61
MCP-1 -0.000283 -0.000890,
0.000325
0.36 -8.22e-05 -0.000849,
0.000366
0.77
TNF-α 0.00489 -0.0308,
0.0406
0.79 -0.0129 -0.0442,
0.0184
0.42
IL-8 -0.000163 -0.000611,
0.000285
0.48 -0.000104 -0.000524,
0.000345
0.60
MIP-1α -0.000219 -0.000492,
0.0000536
0.12 -0.000144 -0.000441,
8.62e-05
0.23

33
IL-1α -0.000161 -0.00208,
0.00176
0.87 -5.07e-05 -0.00184,
0.00188
0.95
IFNγ -0.000410 -0.0261,
0.0253
0.98 -0.0122 -0.0309,
0.0189
0.28
IL-6 0.00210 -0.00168,
0.00588
0.00106 0.00116 -0.00222,
0.00434
0.53
VEGF-A -0.000378 -0.000857,
0.000100
0.12 -0.000309 -0.000846,
0.000123
0.15
1.Adjusted for age, race, education level, and baseline verbal memory.

34
Table 4. Associations of executive function change with inflammation variables: ELITE Postmenopausal
Women (N = 565)
Variables Univariate Association Adjusted Association1
beta 95% CI p-value Beta 95% CI p-value
E-selectin -0.000328 -0.00602,
0.00536
0.91 -0.00251 -0.00848,
0.00306
0.37
P-selectin -0.000462 -0.00256,
0.00164
0.67 -0.000468 -0.00266,
0.00153
0.64
ICAM-1 -0.000290 -0.00120,
0.000615
0.53 -0.000238 -0.00133,
0.000474
0.59
VCAM-1 -0.000151 -0.000507,
0.000206
0.41 -1.76e-05 -0.000436,
0.000284
0.92
IL-1β 0.00024 -0.000179,
0.000659
0.26 0.000322 -6.55e-05,
0.000760
0.11
IL-10 0.000234 -0.000397,
0.000866
0.47 0.000319 -0.000338,
0.000894
0.28
MCP-1 -6.56e-05 -0.000463,
0.000332
0.75 3.72e-05 -0.000352,
0.000449
0.85
TNF-α -0.00801 -0.0313,
0.0153
0.50 -0.0240 -0.0459,
-0.00197
0.0331
IL-8 -3.95e-05 -0.000332,
0.000253
0.79 5.93e-05 -0.000272,
0.000300
0.67

35
MIP-1α 5.68e-05 -0.000122,
0.000235
0.53 0.000112 -8.06e-05,
0.000267
0.18
IL-1α 9.87e-05 -0.00116,
0.00135
0.88 0.000338 -0.000893,
0.00155
0.57
IFNγ 0.0154 -0.00143,
0.0321
0.074 0.0102 -0.00351,
0.0292
0.20
IL-6 -0.00287 -0.00533,
-0.000403
0.0230 -0.00341 -0.00569,
-0.00114
0.00344
VEGF-A 0.000329 1.65e-05,
0.000641
0.0395 0.000311 -4.035e-06,
0.000621
0.039
1. Adjusted for age, race, education level, and baseline executive function.

36
Table 5. Associations of visual memory change with inflammation variables: ELITE Postmenopausal
Women (N = 565)
Variables Univariate Association Adjusted Association1
beta 95% CI p-value beta 95% CI p-value
E-selectin 0.00650 0.000156,
0.0128
0.045 0.00554 -0.00128,
0.0116
0.062
P-selectin 0.00136 -0.000988,
0.00370
0.26 0.00143 -0.000795,
0.00388
0.19
ICAM-1 0.000394 -0.000619,
0.00141
0.45 0.000296 -0.000542,
0.00147
0.53
VCAM-1 -0.000517 -0.000915,
-0.000120
0.011 -0.000302 -0.000793,
9.72e-06
0.11
IL-1β 0.000255 -0.000214,
0.000724
0.29 0.000350 -0.000130,
0.000793
0.11
IL-10 -0.000382 -0.00109,
0.000325
0.29 -0.000112 -0.000938,
0.000437
0.73
MCP-1 0.000150 -0.000295,
0.000594
0.51 0.000167 -0.000104,
0.000790
0.42
TNF-α 0.00347 -0.0227,
0.0296
0.80 0.00227 -0.0212,
0.0257
0.85
IL-8 -8.11e-05 -0.000409,
0.000246
0.63 -1.69e-05 -0.000372,
0.000267
0.91

37
MIP-1α -2.37e-05 -0.000224,
0.000176
0.82 3.22e-05 -0.000195,
0.000194
0.72
IL-1α -0.000553 -0.00195,
0.000849
0.44 0.000166 -0.00153,
0.00120
0.79
IFNγ -0.0216 -0.0403,
-0.00283
0.024 -0.0182 -0.0407,
-0.00426
0.031
IL-6 0.000504 -0.00226,
0.00327
0.72 7.41e-05 -0.00238,
0.00253
0.96
VEGF-A -4.16e-05 -0.000392,
0.000309
0.82 -5.06e-05 -0.000401,
0.000300
0.78
1. Adjusted for age, race, education level, and baseline visual memory.

38
Table 6. Associations of global cognition change with inflammation variables: NAPS Postmenopausal
Women (N = 141)
Variables Univariate Association Adjusted Association1
beta 95% CI p-value beta 95% CI p-value
E-selectin -0.0113 -0.0256,
0.00301
0.12 0.00554 -0.0265,
-0.000270
0.0623
P-selectin -0.000604 -0.0144,
0.0132
0.93 0.00143 -0.0102,
0.0156
0.18
ICAM-1 0.000575 -0.00154,
0.00269
0.60 0.000296 -0.00163,
0.00231
0.53
VCAM-1 0.000695 -0.000398,
0.00179
0.22 -0.000302 -0.000637,
0.00140
0.11
IL1β -0.0942 -0.569,
0.380
0.70 0.000350 -0.593,
0.321
0.10
IL-10 0.000953 -0.208,
0.210
0.99 -0.000112 -0.248,
0.145
0.72
MCP-1 0.000785 -0.00146,
0.00303
0.49 0.000178 -0.00187,
0.00223
0.86
TNF-α -0.0152 -0.123,
0.0923
0.78 -0.0196 -0.110,
0.0887
0.56
IL-8 0.0279 -0.0323,
-0.0880
0.37 -0.00909 -0.0642,
0.0461
0.75

39
PIGF -0.0315 -0.0531,
-0.00927
0.025 -0.0302 -0.0561, -
0.00432
0.022
VLA-4 -0.000280 -0.00120,
0.000640
0.55 2.15e-05 -0.000655,
0.00112
0.94
CD11b 0.00178 -0.00935,
0.01291
0.76 -0.00165 -0.0126,
0.00931
0.77
CD14 0.00125 -0.0108,
0.0133
0.84 0.00697 -0.00484,
0.0188
0.25
1. Adjusted for age, race, education level, and baseline global cognition.

40
Table 7. Associations of verbal memory change with inflammation variables: NAPS Postmenopausal
Women (N = 141)
Variables Univariate Association Adjusted Association1
beta 95% CI p-value beta 95% CI p-value
E-selectin -0.00231 -0.0167,
0.0121
0.75 -0.00664 -0.0206,
0.00729
0.35
P-selectin 0.00343 -0.0104,
0.0172
0.63 0.00520 -0.00830,
0.0187
0.45
ICAM-1 0.00195 -0.000139,
0.00404
0.070 0.00155 -0.000499,
0.00359
0.14
VCAM-1 0.000566 -0.000526,
0.00166
0.31 0.000423 -0.000641,
0.00149
0.44
IL1β -0.193 -0.673,
0.288
0.44 -0.199 -0.708,
0.309
0.44
IL-10 -0.0188 -0.227,
0.189
0.86 -0.110 -0.316,
0.0953
0.29
MCP-1 -0.000233 -0.00247,
0.00201
0.84 -0.000944 -0.00309,
0.00120
0.86
TNF-α 0.0185 -0.0886,
0.126
0.74 -0.00141 -0.106,
0.103
0.98
IL-8 0.0238 -0.0362,
0.0839
0.44 -0.0219 -0.0806,
0.0368
0.47
PIGF -0.0315 -0.0531, 0.025 -0.0302 -0.0561, 0.022

41
-0.00927 -0.00432
VLA-4 -0.000421 -0.00134,
0.000495
0.37 8.35e-05 -0.000853,
0.00102
0.86
CD11b 0.00178 -0.00935,
0.01291
0.76 -0.00165 -0.0126,
0.00931
0.77
CD14 0.00125 -0.0108,
0.0133
0.84 0.00697 -0.00484,
0.0188
0.25
1. Adjusted for age, race, education level, and baseline verbal memory.

42
Table 8. Associations of executive function change with inflammation variables: NAPS Postmenopausal
Women (N = 141)
Variables Univariate Association Adjusted Association1
beta 95% CI p-value beta 95% CI p-value
E-selectin 0.00288 -0.00576,
0.0115
0.51 0.000584 -0.00738,
0.00855
0.89
P-selectin -0.00639 -0.0146,
0.00184
0.13 -0.00652 -0.0142,
0.00116
0.096
ICAM-1 -0.000118 -0.00139,
0.00115
0.86 -0.000260 -0.00144,
0.000918
0.66
VCAM-1 0.000101 -0.000558,
0.000760
0.76 3.98e-05 -0.000570,
0.000649
0.90
IL1β 0.0781 -0.182,
0.338
0.56 0.0448 -0.220,
0.310
0.74
IL-10 0.0512 -0.0737,
0.176
0.42 0.0328 -0.0839,
0.150
0.58
MCP-1 -0.000130 -0.00148,
0.00122
0.85 -4.14e-06 -0.00123,
0.00122
0.99
TNF-α 0.0213 -0.0431,
0.0857
0.52 0.00774 -0.0518,
0.0673
0.80
IL-8 0.0143 -0.0218,
0.0504
0.44 -0.000420 -0.0331,
0.0322
0.98

43
PIGF -0.00299 -0.0197,
0.0137
0.73 0.00132 -0.0139,
0.0166
0.87
VLA-4 -9.25e-05 -0.000645,
0.000460
0.74 6.42e-05 -0.000463,
0.000592
0.81
CD11b 0.00405 -0.00272,
0.0108
0.24 0.00182 -0.00450,
0.00814
0.57
CD14 -0.00283 -0.00914,
0.00245
0.45 0.000403 -0.00635,
0.00716
0.91
1. Adjusted for age, race, education level, and baseline executive function.

44
Table 9. Associations of visual memory change with inflammation variables: NAPS Postmenopausal
Women (N = 141)
Variables Univariate Association Adjusted Association1
beta 95% CI p-value beta 95% CI p-value
E-selectin -0.00229 -0.0127,
0.00813
0.67 -0.0049 -0.0139,
0.00398
0.28
P-selectin 0.00406 -0.00591,
0.0140
0.43 0.00236 -0.00528,
0.0117
0.59
ICAM-1 -0.00126 -0.00279,
0.000281
0.11 -0.00123 -0.00250,
0.000101
0.064
VCAM-1 0.000174 -0.000624,
0.000971
0.67 -0.000165 -0.000851,
0.000537
0.64
IL1β 0.105 -0.227,
0.438
0.54 -0.0714 -0.375,
0.242
0.66
IL-10 -0.0249 -0.176,
0.126
0.75 -0.0404 -0.156,
0.100
0.54
MCP-1 0.00120 -0.000411,
0.00281
0.15 0.000905 -0.000477,
0.00229
0.20
TNF-α -0.0323 -0.110,
0.0451
0.42 -0.0156 -0.0859,
0.0467
0.64
IL-8 0.0249 -0.0189,
0.0688
0.27 0.000896 -0.0369,
0.0387
0.96

45
PIGF 0.0112 -0.00877,
0.0312
0.27 0.00975 -0.00548,
0.0282
0.25
VLA-4 -0.000243 -0.000906,
0.000421
0.47 9.47e-05 -0.000558,
0.000601
0.75
CD11b 0.00135 -0.00690,
0.00960
0.75 -0.00099 -0.00788,
0.00613
0.78
CD14 -0.00136 -0.0101,
0.00737
0.76 0.000647 -0.00686,
0.00806
0.87
1. Adjusted for age, race, education level, and baseline visual memory.

46
Table 10. Associations of global cognition change with inflammation variables: NAPS Men (N = 88)
Variables Univariate Association Adjusted Association1
beta 95% CI p-value beta 95% CI p-value
E-selectin -0.00105 -0.0196,
0.0175
0.91 0.00149 -0.0189,
0.0181
0.087
P-selectin 0.00206 -0.0201,
0.0243
0.86 0.00729 -0.0131,
0.0323
0.52
ICAM-1 0.00202 -0.000825,
0.00486
0.17 0.000567 -0.00159,
0.00404
0.69
VCAM-1 -0.000806 -0.00240,
0.000784
0.32 -0.000237 -0.00237,
0.000852
0.78
IL1β 0.357 -0.152,
0.865
0.19 0.527 -1.036,
2.474
0.54
IL-10 0.0473 -0.229,
0.324
0.74 0.0416 -0.251,
0.289
0.76
MCP-1 0.00101 -0.00215,
0.00417
0.53 0.00207 -0.00105,
0.00518
0.20
TNF-α 0.235 0.0138,
0.456
0.0403 0.216 0.00255,
0.443
0.0549
IL-8 0.0742 0.0170,
0.131
0.0128 0.0748 0.0188,
0.131
0.0105
PIGF -0.0177 -0.0519,
0.0165
0.31 -0.0249 -0.0539,
0.0145
0.15

47
VLA-4 -2.02e-05 -0.00137,
0.00133
0.98 -0.000158 -0.00158,
0.00123
0.83
CD11b 0.00519 -0.0124,
0.0228
0.57 0.000331 -0.0147,
0.0206
0.97
CD14 -0.00203 -0.0203,
0.0162
0.83 -0.00211 -0.0234,
0.0154
0.83
1. Adjusted for age, race, education level, and baseline global cognition.

48
Table 11. Associations of verbal memory change with inflammation variables: NAPS Men (N = 88)
Variables Univariate Association Adjusted Association1
beta 95% CI p-value beta 95% CI p-value
E-selectin -0.00450 -0.0162,
0.0252
0.67 0.00794 -0.0113,
0.0272
0.42
P-selectin 0.0137 -0.0110,
0.0384
0.28 0.0146 -0.00873,
0.0379
0.22
ICAM-1 0.00316 1.15e-05,
0.00631
0.0524 0.00114 -0.00157,
0.00440
0.35
VCAM-1 -0.00119 -0.00296,
0.000587
0.19 -0.000504 -0.00223,
0.00123
0.57
IL1β 0.377 -0.105,
0.859
0.15 0.280 -0.291,
0.851
0.34
IL-10 -0.0350 -0.345,
0.275
0.83 -0.00244 -0.281,
0.276
0.99
MCP-1 -0.00166 -0.00519,
0.00188
0.36 -0.000406 -0.00378,
0.00297
0.81
TNF-α 0.279 0.0321,
0.526
0.0294 0.211 -0.0233,
0.446
0.078
IL-8 0.0407 -0.0253,
0.107
0.23 0.0497 -0.0118,
0.111
0.12
PIGF -0.0267 -0.0656,
0.0121
0.18 -0.0281 -0.0648,
0.00859
0.13

49
VLA-4 0.000119 -0.00139,
0.00163
0.88 0.000352 -0.00113,
0.00184
0.64
CD11b -0.00153 -0.0212,
0.0182
0.88 -0.0129 -0.0311,
0.00526
0.16
CD14 0.00519 -0.0152,
0.0256
0.62 0.0135 -0.00673,
0.0338
0.19
1. Adjusted for age, race, education level, and baseline verbal memory.

50
Table 12. Associations of executive function change with inflammation variables: NAPS Men (N = 88)
Variables Univariate Association Adjusted Association1
beta 95% CI p-value beta 95% CI p-value
E-selectin -0.00237 -0.0125,
0.00772
0.65 0.000393 -0.0102,
0.0110
0.94
P-selectin -0.00171 -0.0138,
0.0104
0.78 -0.000255 -0.0132,
0.0127
0.97
ICAM-1 -0.000118 -0.00259,
0.000512
0.86 -0.00130 -0.00291,
0.000306
0.11
VCAM-1 -0.000144 -0.00102,
0.000728
0.75 0.000126 -0.000823,
0.00107
0.80
IL-1β -0.0907 -0.413,
0.232
0.59 -0.387 -1.189,
0.415
0.34
IL-10 0.0689 -0.0815,
0.219
0.37 0.0602 -0.0921,
0.2128
0.44
MCP-1 0.00130 -0.000407,
0.00301
0.14 0.00138 -0.000355,
0.00311
0.12
TNF-α 0.0184 -0.105,
0.142
0.77 0.0564 -0.0748,
0.187
0.40
IL-8 0.0264 -0.00549,
0.0583
0.108 0.0300 -0.00206,
0.0621
0.0703
PIGF -0.00623 -0.0254,
0.0130
0.53 -0.00958 -0.0301,
0.0110
0.36

51
VLA-4 0.000216 -0.000520,
0.000951
0.57 0.000319 -0.000493,
0.00113
0.44
CD11b 0.00333 -0.00628，
0.0129
0.50 0.00167 -0.00843,
0.0118
0.75
CD14 -0.00230 -0.0122,
0.00763
0.65 -0.00187 -0.0130,
0.00926
0.74
1. Adjusted for age, race, education level, and baseline executive function.

52
Table 13. Associations of visual memory change with inflammation variables: NAPS Men (N = 88)
Variables Univariate Association Adjusted Association1
beta 95% CI p-value beta 95% CI p-value
E-selectin 0.00527 -0.00549,
0.0160
0.34 0.00429 -0.00716,
0.0157
0.46
P-selectin 0.00739 -0.00547,
0.0203
0.26 0.00906 -0.00489,
0.0230
0.20
ICAM-1 -0.000587 -0.00227,
0.00109
0.49 -0.000703 -0.00247,
0.00107
0.44
VCAM-1 -2.79e-05 -0.000962,
0.000906
0.95 5.83e-05 -0.000978,
0.00109
0.91
IL-1β -0.0630 -0.449,
0.323
0.75 -0.296 -0.848,
0.256
0.29
IL-10 -0.0574 -0.219,
0.104
0.49 -0.0543 -0.220,
0.111
0.52
MCP-1 0.00151 -0.000308,
0.00334
0.11 0.00154 -0.000331,
0.00340
0.11
TNF-α 0.0140 -0.120,
0.147
0.84 0.00156 -0.142,
0.146
0.98
IL-8 0.0364 -0.00602,
1 0.0788
0.0963 0.0334 -0.0106,
0.0774
0.14
PIGF 0.00946 -0.0106,
0.0295
0.36 0.00819 -0.0136,
0.0300
0.46

53
VLA-4 -0.000488 -0.00128,
0.000301
0.23 -0.000475 -0.00137,
0.000423
0.30
CD11b 0.00344 -0.00698,
0.0139
0.52 0.00355 -0.00743,
0.0145
0.53
CD14 -0.00631 -0.0170,
0.00436
0.25 -0.00719 -0.0193,
0.00490
0.24
1. Adjusted for age, race, education level, and baseline visual memory.

54
Table 14. Associations of global cognition change with inflammation variables: Combined ELITE and
NAPS Postmenopausal Women (N = 704)
Variables Univariate Association Adjusted Association1
beta 95% CI p-value beta 95% CI p-value
E-selectin 0.00418 -0.00334,
0.0117
0.28 0.00273 -0.00424,
0.00969
0.44
P-selectin 0.000696 -0.00188,
0.00327
0.60 -0.00149 -0.00386,
0.000890
0.22
ICAM-1 0.000312 -0.000880,
0.00150
0.61 -9.63e-05 -0.00118,
0.000984
0.86
VCAM-1 4.68e-05 -0.000426,
0.000519
0.85 -0.000114 -0.000548,
0.000319
0.61
IL-10 0.000221 -0.000757,
0.00120
0.66 0.000170 -0.00708,
0.000105
0.70
IL-8 -0.000199 -0.000641,
0.000244
0.38 -0.000233 -0.000632,
0.000167
0.25
MCP-1 -0.000178 -0.000641,
0.000286
0.45 -0.000466 -0.000891,
-4.08e-05
0.0317
TNF-α -0.0102 -0.0349,
0.0145
0.42 -0.0424 -0.0651,
-0.0198
0.00024
1. Adjusted for age, race, education level, and baseline global cognition.

55
Table 15. Associations of verbal memory change with inflammation variables: Combined ELITE and
NAPS Postmenopausal Women (N = 704)
Variables Univariate Association Adjusted Association1
beta 95% CI p-value beta 95% CI p-value
E-selectin 0.00467 -0.00265,
0.0120
0.21 0.00173 -0.00491,
0.00836
0.61
P-selectin 0.00202 -0.000165,
0.00513
0.114 -0.000372 -0.00264,
0.00189
0.75
ICAM-1 0.000463 -0.000698,
0.00162
0.44 3.65e-05 -0.000990,
0.000106
0.95
VCAM-1 0.000291 -0.000169,
0.000751
0.22 0.000112 -0.000300,
0.000524
0.59
IL-10 -7.13e-05 -0.00118,
0.000915
0.88 -0.000258 -0.00109,
0.000577
0.55
IL-8 -7.66e-05 -0.000508,
0.000355
0.73 -0.000149 -0.000529,
0.000231
0.44
MCP-1 3.22e-05 -0.000692,
0.000278
0.89 -0.000225 -0.000630,
0.000180
0.28
TNF-α 0.0147 -0.0094,
0.0388
0.23 -0.0128 -0.0345,
0.00893
0.25
1. Adjusted for age, race, education level, and baseline verbal memory

56
Table 16. Associations of executive function change with inflammation variables: Combined ELITE and
NAPS Postmenopausal Women (N = 704)
Variables Univariate Association Adjusted Association1
beta 95% CI p-value beta 95% CI p-value
E-selectin 0.000512 -0.00421,
0.00523
0.83 0.000371 -0.00414,
0.00488
0.87
P-selectin -0.000546 -0.00216,
0.000107
0.51 -0.00203 -0.00356,
-0.000493
0.00958
ICAM-1 -0.000243 -0.000991,
0.000505
0.52 -0.000328 -0.00103,
0.000370
0.36
VCAM-1 -0.000100 -0.000397,
0.000196
0.51 -0.00187 -0.000467,
9.34e-05
0.19
IL-10 0.000226 -0.000387,
0.000840
0.47 -0.00017 -0.000398,
0.000738
0.56
IL-8 -0.000404 -0.000318,
0.000237
0.78 -5.79e-05 -0.000316,
0.000201
0.66
MCP-1 -5.17e-05 -0.000343,
0.000239
0.73 -0.000302 -0.000578,
-2.54e-05
0.0323
TNF-α -0.00317 -0.0187,
0.0123
0.69 -0.0280 -0.0428,
-0.0131
0.00023
1. Adjusted for age, race, education level, and baseline executive function.

57
Table 17. Associations of visual memory change with inflammation variables: Combined ELITE and
NAPS Postmenopausal Women (N = 704)
Variables Univariate Association Adjusted Association1
beta 95% CI p-value beta 95% CI p-value
E-selectin 0.00574 0.000376,
0.0111
0.0363 0.00562 0.000656,
0.0106
0.00265
P-selectin -0.000758 -0.00260,
0.00109
0.42 -0.00228 -0.00397,
-0.000578
0.00861
ICAM-1 -0.000186 -0.00104,
0.000671
0.67 -0.000380 -0.00115,
0.000394
0.34
VCAM-1 -0.000517 -0.000854,
-0.000180
0.00273 -0.000597 -0.000905,
-0.000289
0.00015
IL-10 -0.000528 -0.00122,
0.000170
0.14 -0.000419 -0.00105,
0.000207
0.19
IL-8 -0.000200 -0.000516,
0.000116
0.22 -0.000247 -0.000532,
3.78e-05
0.089
MCP-1 -0.000205 -0.000536,
0.000127
0.23 -0.000526 -0.000832,
-0.000221
0.00073
TNF-α -0.0200 -0.0377,
-0.00239
0.0264 -0.0386 -0.0237,
-0.0225
2.70e-06
1. Adjusted for age, race, education level, and baseline visual memory.

58
Table 18. Robust associations of global cognition change with inflammation variables: ELITE
Postmenopausal Women (N = 565)
Variables Univariate Association Adjusted Association1
Beta 95% CI p-value Beta 95% CI p-value
E-selectin 0.00943 0.000466,
0.0184
0.0397 0.0063 1.46 0.14
P-selectin 0.00156 -0.00175,
0.00488
0.36 0.0020 1.28 0.20
ICAM-1 0.000274 -0.00116,
0.00170
0.71 0.0003 0.52 0.60
VCAM-1 -7.48e-05 -0.000639,
0.000489
0.80 0.0001 0.48 0.63
IL-1β 0.000420 -0.000243,
0.00108
0.22 0.0005 1.56 0.12
IL-10 0.000247 -0.000752,
0.00125
0.623 0.0003 0.65 0.51
MCP-1 -0.000282 -0.000910,
0.000346
0.38 0.0002 0.69 0.50
TNF-α -0.0133 -0.0502,
0.0236
0.48 -0.032 -1.88 0.063
IL-8 -0.000194 -0.000657,
0.000269
0.41 0.0001 -0.20 0.85
MIP-1α -0.000138 -0.000420,
0.000145
0.34 0.0001 -0.22 0.82

59
IL-1α -0.000567 -0.00255,
0.00142
0.58 0.0003 0.30 0.76
IFNγ -0.00743 -0.0340,
0.0192
0.59 -0.013 -1.08 0.27
IL-6 -0.00462 -0.00852,
-0.000729
0.0203 -0.0053 -3.00 0.00229
VEGF-A 1.62e-05 -0.000480,
0.000512
0.95 0.0001 0.11 0.91
1. Adjusted for age, race, education level, and baseline global cognition.

60
Table 19. Robust associations of verbal memory change with inflammation variables: ELITE
Postmenopausal Women (N = 565)
Variables Univariate Association Adjusted Association1
beta 95% CI p-value Beta t-value p-value
E-selectin 0.00879 0.000113,
0.0175
0.0476 0.0031 0.75 0.45
P-selectin 0.00144 -0.00177,
0.00465
0.379 0.0001 -0.017 0.99
ICAM-1 -0.000174 -0.00156,
0.00121
0.806 -0.0003 0.52 0.67
VCAM-1 0.000118 -0.000427,
0.000663
0.671 0.0002 0.83 0.41
IL-1β 0.000203 -0.000439,
0.000845
0.535 0.0003 0.93 0.35
IL-10 -0.000166 -0.00113,
0.000801
0.737 -0.0002 0.65 0.63
MCP-1 -0.000283 -0.000890,
0.000325
0.362 0.0001 0.11 0.92
TNF-α 0.00489 -0.0308,
0.0406
0.788 -0.011 -0.68 0.50
IL-8 -0.000163 -0.000611,
0.000285
0.476 0.0001 -0.20 0.85
MIP-1α -0.000219 -0.000492,
0.0000536
0.116 -0.0002 -1.44 0.15

61
IL-1α -0.000161 -0.00208,
0.00176
0.87 0.0001 0.100 0.92
IFNγ -0.000410 -0.0261,
0.0253
0.975 -0.012 -1.03 0.31
IL-6 0.00210 -0.00168,
0.00588
0.00106 0.001 0.59 0.55
VEGF-A -0.000378 -0.000857,
0.000100
0.122 -0.0003 -1.34 0.91
1. Adjusted for age, race, education level, and baseline verbal memory.

62
Table 20. Robust associations of executive function change with inflammation variables: ELITE
Postmenopausal Women (N = 565)
Variables Univariate Association Adjusted Association1
beta 95% CI p-value beta t-value p-value
E-selectin -0.000328 -0.00602,
0.00536
0.91 -0.0021 -0.75 0.45
P-selectin -0.000462 -0.00256,
0.00164
0.67 -0.0004 -0.41 0.68
ICAM-1 -0.000290 -0.00120,
0.000615
0.53 -0.0002 -0.55 0.58
VCAM-1 -0.000151 -0.000507,
0.000206
0.41 0.0001 0.0025 1.0
IL-1β 0.00024 -0.000179,
0.000659
0.26 0.0002 1.18 0.24
IL-10 0.000234 -0.000397,
0.000866
0.47 0.0002 0.63 0.52
MCP-1 -6.56e-05 -0.000463,
0.000332
0.75 0.0001 0.36 0.72
TNF-α -0.00801 -0.0313,
0.0153
0.50 -0.0231 -2.10 0.0347
IL-8 -3.95e-05 -0.000332,
0.000253
0.79 0.0001 -0.19 0.85

63
MIP-1α 5.68e-05 -0.000122,
0.000235
0.53 0.0001 1.15 0.25
IL-1α 9.87e-05 -0.00116,
0.00135
0.88 0.0001 0.18 0.86
IFNγ 0.0154 -0.00143,
0.0321
0.074 0.0091 1.16 0.24
IL-6 -0.00287 -0.00533,
-0.000403
0.023 -0.0034 -2.96 0.00252
VEGF-A 0.000329 1.65e-05,
0.000641
0.0395 0.0003 1.72 0.085
1. Adjusted for age, race, education level, and baseline executive function.

64
Table 21. Robust associations of visual memory change with inflammation variables: ELITE
Postmenopausal Women (N = 565)
Variables Univariate Association Adjusted Association1
beta 95% CI p-value beta 95% CI p-value
E-selectin 0.00650 0.000156,
0.0128
0.0451 0.0042 1.40 0.16
P-selectin 0.00136 -0.000988,
0.00370
0.26 0.0017 1.56 0.12
ICAM-1 0.000394 -0.000619,
0.00141
0.45 0.0002 0.34 0.73
VCAM-1 -0.000517 -0.000915,
-0.000120
0.011 -0.0003 -1.62 0.11
IL-1β 0.000255 -0.000214,
0.000724
0.29 0.0004 1.74 0.082
IL-10 -0.000382 -0.00109,
0.000325
0.29 -0.0002 -0.48 0.63
MCP-1 0.000150 -0.000295,
0.000594
0.51 0.0001 0.64 0.52
TNF-α 0.00347 -0.0227,
0.0296
0.80 0.00227 -0.30 0.76
IL-8 -8.11e-05 -0.000409,
0.000246
0.63 0.0001 -0.20 0.85

65
MIP-1α -2.37e-05 -0.000224,
0.000176
0.82 0.0001 0.36 0.72
IL-1α -0.000553 -0.00195,
0.000849
0.44 0.0001 0.0005 1.0
IFNγ -0.0216 -0.0403,
-0.00283
0.0244 -0.20 -2.40 0.0146
IL-6 0.000504 -0.00226,
0.00327
0.72 0.0001 0.11 0.91
VEGF-A -4.16e-05 -0.000392,
0.000309
0.82 -0.0001 -0.77 0.44
1. Adjusted for age, race, education level, and baseline visual memory.

66
Table 22. Multivariable associations of global cognition change with inflammation variables: ELITE
Postmenopausal Women (N = 565)
Beta 95% CI P-value
IL-1β 0.000665 6.88e-05, 0.00126 0.0192
IL-6 -0.00514 -8.61e-03, -0.00167 0.00284

67
Table 23. Multivariable associations of executive function change with inflammation variables: ELITE
Postmenopausal Women (N = 565)
Beta 95% CI P-value
IL-6 -0.00340 -5.66e-03, -0.00114 0.00335
TNF-α -0.0271 -4.89e-02, -0.00523 0.0155
VEGF-A 0.000330 3.61e-05, 0.000624 0.0282

68
Table 24. Multivariable associations of visual memory change with inflammation variables: ELITE
Postmenopausal Women (N = 565)
Beta 95% CI P-value
E-selectin 0.00627 0.000432, 0.0121 0.0357
IFNγ -0.0201 -0.0366, -0.00346 0.0182

69
Table 25. Multivariable associations of global cognition change with inflammation variables: NAPS
postmenopausal women (N = 141)
Beta 95% CI P-value
E-selectin -0.0134 -0.0265, -0.000270 0.0476

70
Table 26. Multivariable associations of verbal memory change with inflammation variables: NAPS
postmenopausal women (N = 141)
Beta 95% CI P-value
PIGF -0.03022 -0.0561, -0.00432 0.0239

71
Table 27. Multivariable associations of global cognition change with inflammation variables: NAPS Men
(N = 88)
Beta 95% CI P-value
IL-8 0.071596 0.0172, 0.125 0.0120

72
Table 28. Multivariable associations of global cognition change with inflammation variables: Combined
ELITE and NAPS Postmenopausal Women (N = 704)
Beta 95% CI P-value
TNF-α -4.0e-02 -0.0666, -0.0137 0.00298

73
Table 29. Multivariable associations of executive function change with inflammation variables: Combined
ELITE and NAPS Postmenopausal Women (N = 704)
Beta 95% CI P-value
TNF-α -2.4e-02 -0.0417, -0.00547 0.0110

74
Table 30. Multivariable associations of visual memory change with inflammation variables: Combined
ELITE and NAPS Postmenopausal Women (N = 704)
Beta 95% CI P-value
E-selectin 0.00613 0.00120, 1.10e-02 0.0143
VCAM-1 -0.000384 -0.000722, -6.56e-05 0.0226
TNF-α -0.0267 -0.0468, -6.78e-03 0.00901

75
Figure 1: Lowess plot of associations of global cognition change with inflammation variables: ELITE
Postmenopausal Women (N = 565)

76
Figure 2. Lowess plot of associations of verbal memory change with inflammation variables: ELITE
Postmenopausal Women (N = 565)

77
Figure 3. Lowess plot of associations of executive function change with inflammation variables: ELITE
Postmenopausal Women (N = 565)

78
Figure 4. Lowess plot of associations of visual memory change with inflammation variables: ELITE
Postmenopausal Women (N = 565)

79
Figure 5. Lowess plot of associations of global cognition change with inflammation variables: NAPS
Postmenopausal Women (N = 141)

80
Figure 6. Lowess plot of associations of verbal memory change with inflammation variables: NAPS
Postmenopausal Women (N = 141)

81
Figure 7. Lowess plot of associations of executive function change with inflammation variables: NAPS
Postmenopausal Women (N = 141)

82
Figure 8. Lowess plot of associations of visual memory change with inflammation variables: NAPS
Postmenopausal Women (N = 141)

83
Figure 9. Lowess plot of associations of global cognition change with inflammation variables: NAPS Men
(N = 88)

84
Figure 10. Lowess plot of associations of verbal memory change with inflammation variables: NAPS Men
(N = 88)

85
Figure 11. Lowess plot of associations of executive function change with inflammation variables: NAPS
Men (N = 88)

86
Figure 12. Lowess plot of associations of visual memory change with inflammation variables: NAPS Men
(N = 88)

87
Figure 13. Lowess plot of associations of global cognition change with inflammation variables: Combined
ELITE and NAPS Postmenopausal Women (N = 704)

88
Figure 14. Lowess plot of associations of verbal memory change with inflammation variables: Combined
ELITE and NAPS Postmenopausal Women (N = 704)

89
Figure 15. Lowess plot of associations of executive function change with inflammation variables:
Combined ELITE and NAPS Postmenopausal Women (N = 704)

90
Figure 16. Lowess plot of associations of visual memory change with inflammation variables: Combined
ELITE and NAPS Postmenopausal Women (N = 704)

91

Abstract (if available)

Abstract This is a post-hoc analysis using the data collected in two completed clinical trials. The Early vs Late Intervention Trial with Estradiol (ELITE) was a single-center, randomized, double-blinded, placebo-controlled trial that tested whether time since menopause modifies the effect of estradiol therapy on specified health outcomes, including progression of subclinical atherosclerosis and cognition. The Nattokinase Atherothrombotic Prevention Study (NAPS) was a single-center, randomized, double-blinded, placebo-controlled trial that tested whether daily nattokinase supplementation reduces progression of subclinical atherosclerosis. A combined dataset was based on harmonized common variables, including E-selectin, P-selectin, ICAM-1, VCAM-1, IL-1β, IL-10, MCP-1, and TNF-α, from ELITE and NAPS trials. Inflammation variables were composite measures derived from a neuropsychological test battery. The primary outcome for this analysis was 2.5-year change in cognitive endpoints in the ELITE trial and 3-year change in cognitive endpoints in NAPS trial. Associations between inflammation markers measured at baseline (prior to randomization) and change in cognitive performance were analyzed with linear regression models. Associations between inflammation markers and 2.5-3-year change in cognitive endpoints were analyzed with multivariable linear regression models adjusted for age, race, education level, and baseline cognition.

Our results suggest that TNF-α and IL-6 were inflammation markers that showed in general inverse associations with changes in various aspects of cognitive performance over a 2.5-3-year period in healthy cognitively intact older adults.

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Asset Metadata

Creator Zhang, Yuhan (author)

Core Title Associations between inflammatory markers and change in cognitive endpoints

School Keck School of Medicine

Degree Master of Science

Degree Program Biostatistics

Degree Conferral Date 2024-05

Publication Date 06/12/2024

Defense Date 05/06/2024

Publisher Los Angeles, California (original), University of Southern California (original), University of Southern California. Libraries (digital)

Tag clinical trial,cognitive change,Inflammation,OAI-PMH Harvest

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Language English

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Advisor Mack, Wendy (committee chair), Hodis, Howard (committee member), Karim, Roksana (committee member)

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