The association between individual and composite inflammation biomarkers and cognitive function

Abstract

Mild cognitive impairment and Alzheimer's disease contribute to cognitive decline in the aging population, affecting 10–20% of adults ≥60 years and 50 million individuals globally, respectively. Chronic inflammation is implicated in their pathogenesis, but relationships remain unclear. This study examined longitudinal associations between inflammatory biomarkers and cognition in 4228 English Longitudinal Study of Aging participants over two- and ten-year follow-ups. Mixed-effects models evaluated C-reactive protein, ferritin, fibrinogen, and white blood cell count in relation to memory, executive function, processing speed, and overall cognition. The results indicated cumulative inflammation-related cognitive decline in adults aged ≥75 years.

Keywords

Alzheimer's disease cognitive dysfunction inflammation longitudinal studies

Introduction

Mild cognitive impairment (MCI) is a precursor of dementia, with approximately 30–46% progressing to dementia within 2–3 years.¹ Globally, 15–24% of older adults have MCI, and dementia cases have surpassed 50 million, with nearly 10 million new cases annually.^1–3 Alzheimer's disease (AD), accounting for 60–70% of dementia cases, is projected to reach 90–105 million cases by 2050.⁴ Inflammation contributes to neurodegeneration by impairing microglial function and increasing Amyloid-β (Aβ) deposits, accelerating cognitive decline.^5–8 The cognitive decline accelerates more than 15-fold in the years before AD diagnosis, highlighting the need for early prevention.^9,10

High-sensitivity C-reactive protein (hs-CRP), fibrinogen, interleukin-6 (IL-6), and ferritin (Supplemental Table 1), are associated with a 36–45% increased risk of dementia, while elevated white blood cell counts contribute to accelerated brain aging.^11–15 Associations between these markers and cognitive decline are inconsistent, reflecting heterogeneity in study design, populations, and cognitive measurements.^16–23 The combined effects of these biomarkers on specific cognitive domains remain underexplored, warranting integrated biomarker profiling and comprehensive cognitive assessments. We investigated hs-CRP, white blood cells (WBC), fibrinogen, and ferritin in relation to overall and domain-specific cognition (memory, executive function, and processing speed) using cross-sectional and longitudinal analysis.

Methods

Participants

The English Longitudinal Study of Ageing (ELSA) is a national prospective cohort of adults aged ≥50 in England, recruited from the 1998, 1999, and 2001 Health Surveys for England.²⁴ Eligibility required consent to follow-up, birth before 1 March 1952, and residence in a private household. The initial cohort included 11,391 participants (67% response rate). Data was collected through computer-assisted interviews and self-completed questionnaires across waves 4, 5, and 9. Of the 49,896 participants enrolled, 6879 completed cognitive assessments. Among them, 4282 attended nurse visits to Wave 4 for physical assessments and biomarker collection. After excluding ADRD cases, 4228 remained, with 3670 and 2604 completing cognitive testing in Wave 5 and 9, respectively.

Measures of inflammatory markers

Inflammatory marker data were collected during the wave 4 nurse visit. Inflammatory markers measured included C-reactive protein (CRP), ferritin, fibrinogen, and WBC count. The measurement of inflammatory markers followed the standard procedures in the technical report of the Health Survey for England.²⁵

Inflammation score

Inflammatory biomarkers were categorized into quintiles, assigning values from 0 (lowest) to 4 (highest). Inflammation scores were calculated by summing quintile values across inflammatory biomarkers. The first inflammation score (IS1) included CRP, ferritin, and fibrinogen (range: 0–12), while the second (IS2) added WBC count (range: 0–16). An inflammation Z-score was calculated by standardizing each biomarker (subtracting each individual's value from the sample mean, divided by the standard deviation). The global Z-score of inflammation was derived from the sum of the standardized values of all biomarkers.

Cognitive function

Cognitive function was assessed in Waves 4 and 5 (memory, processing speed, executive function), and in Wave 9 (memory, executive function). Memory was assessed using immediate and delayed recall of a 10-word list, with total scores reflecting both tasks.²⁶ Processing speed was evaluated via a letter cancellation task, based on the number of letters identified.²⁷ Executive function was assessed using the Semantic Verbal Fluency test, where participants named as many animals as possible within one minute.²⁷ The global Z-score was calculated to reflect the overall cognitive performance.

The study assessed several demographic variables, including age (≥ 50 years old, continuous/50–75; ≥ 75, categorical), sex (male; female), education (highest qualification: college, some college, secondary school completion, some secondary school, no qualifications), marital status (married; not married), socioeconomic status (Higher; Intermediate; Routine/manual based on occupation); social isolation (yes; no, evaluated through living arrangements, contact frequency, social participation, and UCLA loneliness scale), physical inactivity (yes; no, based on self-reported weekly activity), and excessive television viewing (yes; no, quantified by daily hours).

The analysis further incorporated cardiovascular disease (CVD)-related risk factors impacting cognitive dysfunction, categorized as binary (yes; no, based on physician diagnosis), including ischemic heart disease, stroke, hypertension, high cholesterol, and smoking status. Additionally, modifiable factors identified by the 2024 Lancet Commission on Dementia were examined, also dichotomized (yes; no), comprising self-rated hearing loss, obesity (based on height and weight), depression (assessed by the CES-D 8-item scale), diabetes (self-reported diagnosis and HbA1c value), and poor sleep (measured by weekly trouble sleeping). Alcohol consumption was quantified by frequency of weekly intake (>5 times, 1–4 times, <1 time).²⁸

Statistical analysis

Statistical analysis was performed using SAS 9.4. To address skewness in the distributions, CRP and ferritin concentrations were log-transformed. The Pearson correlation coefficient assessed associations between inflammatory markers and continuous covariates, while two-sample t-tests or one-way analysis of variance (ANOVA) examined relationships between inflammatory markers and categorical covariates.

Elevated CRP, ferritin, fibrinogen, and WBC counts are associated with hippocampal dysfunction, white matter damage, and disruption of frontal-subcortical and cortical-subcortical circuits, contributing to memory impairment, reduced processing speed, and executive dysfunction.^29–32 Ordinary least squares regression was performed to explore the associations between cognitive scores (memory, processing speed, executive function) and aggregated cognitive scores, as well as inflammatory biomarkers (CRP, ferritin, fibrinogen, WBC count), along with IS1 and IS2, in a cross-sectional analysis.

Generalized linear mixed-effects models with random intercepts were used to account for individual variability in longitudinal analysis at 2-year (wave 5) and 10-year (wave 9) follow-ups. The processing speed measure was not administered in Wave 9 and was therefore excluded from individual and global cognitive outcomes. Three models were specified: Model 1, adjusted for sociodemographic factors; Model 2, additionally adjusted for CVD risk factors; and Model 3, further adjusted for modifiable factors. The baseline cognitive function was accounted for in the longitudinal analysis. Subgroup analyses were conducted by age (<75 versus ≥75 years) and gender (male versus female) to assess potential effect modification.

Results

Sample characteristics

The cross-sectional analysis included 4228 participants, with 3670 and 2604 participants in the 2-year and 10-year follow-ups, respectively (Table 1). Distributions of age, education, occupation, cognitive scores, inflammatory markers, IS1, IS2, health, and smoking status were consistent across baseline and follow-up. The sample comprised 47% males and 53% females, with an average baseline age of 65. Over 60% had an education below college and worked in intermediate, routine, or manual occupations. Approximately 50% reported poor sleep and excessive television viewing.

Table 1.

Participant characteristics.

Variable	Cross-Sectional (n = 4228)	Longitudinal – Two Year (n = 3670)	Longitudinal – Ten Year (n = 2604)
	n (%) or Mean ± SD	n (%) or Mean ± SD	n (%) or Mean ± SD
Age (y)	65.55 ± 9.07	65.40 ± 9.01	64.93 ± 8.90
Sex
Male	2001 (47.33%)	1761 (47.98%)	1230 (47.24%)
Female	2227 (52.27%)	1909 (52.02%)	1374 (52.76%)
Marital status
Single	1331 (31.48%)	1135 (30.93%)	1331 (31.48%)
Married or civil partnership	2897 (68.52%)	2535 (69.07%)	2897 (68.52%)
Education
No qualifications	1315 (31.10%)	1144 (31.17%)	747 (28.69%)
Some secondary school	909 (21.50%)	792 (21.58%)	582 (22.35%)
Completion of secondary school	398 (9.41%)	348 (9.48%)	266 (10.22%)
Some college	734 (17.36%)	633 (17.25%)	450 (17.28%)
College degree	827 (20.62%)	753 (20.52%)	559 (21.47%)
Occupation
Higher	1541 (36.45%)	1345 (36.65%)	979 (37.60%)
Intermediate	1065 (25.19%)	921 (25.10%)	668 (25.65%)
Routine or manual	1622 (38.36%)	1404 (38.26%)	957 (36.76%)
CVD risk factors
Prevalent ischemic heart disease	383 (9.06%)	322 (8.77%)	211 (8.10%)
History of stroke	127 (3.00%)	112 (3.05%)	82 (3.15%)
Prevalent hypertension	1583 (37.44%)	1359 (37.03%)	931 (35.75%)
Prevalent high cholesterol	1482 (35.05%)	1283 (34.96%)	925 (35.52%)
Obesity
Yes	840 (19.87%)	719 (19.59%)	522 (20.03%)
No	3388 (80.13%)	2951 (80.41%)	2082 (79.97%)
Diabetes
Yes	316 (7.48%)	270 (7.36%)	194 (7.45%)
No	3912 (92.52%)	3400 (92.64%)	2410 (92.55%)
Depression
Yes	573 (13.56%)	502 (13.69%)	28 (13.72%)
No	3655 (86.44%)	3113 (86.31%)	2246 (86.28%)
Poor sleep
Yes	2087 (49.37%)	1844 (50.24%)	1307 (50.18%)
No	2141 (50.63%)	1826 (49.76%)	1119 (49.82%)
Smoking
Current smoker	604 (14.29%)	505 (13.76%)	362 (13.90%)
Former or non-smoker	3624 (85.71%)	3165 (86.24%)	2242 (86.10%)
Hearing loss
Yes	1235 (29.21%)	1116 (30.43%)	1251 (29.64%)
No	2993 (70.79%)	2554 (69.57%)	1353 (70.36%)
Social isolation
Yes	613 (14.75%)	562 (15.63%)	372 (14.29%)
No	3615 (85.25%)	3108 (84.37%)	2232 (85.71%)
Physical inactivity
Yes	1247 (29.53%)	1053 (28.72%)	781 (30.01%)
No	2981 (71.47%)	2617 (71.28%)	1802 (69.99%)
Excessive television reviewing
Yes	1818 (43.01%)	1136 (42.53%)	1092 (41.94%)
No	2410 (56.99%)	1534 (57.47%)	1512 (58.06%)
Cognition at baseline
Memory	10.78 $\pm 3.39$	10.84 $\pm 3.40$	10.97 $\pm 3.35$
Executive function	21.45 $\pm 6.53$	21.56 $\pm 6.52$	21.77 $\pm 6.58$
Processing speed	300.84 $\pm$ 82.96	300.75 $\pm$ 82.24	-
Cognition at follow-up
Memory	-	10.97 $\pm 3.30$	10.63 $\pm 3.63$
Executive function	-	21.99 $\pm 6.49$	22.80 $\pm 7.27$
Processing speed	-	300.15 $\pm$ 79.81	-
Inflammatory markers
CRP (log)	0.65 $\pm 1.13$	0.64 $\pm 1.10$	0.61 $\pm 0.59$
Ferritin (log)	4.49 $\pm 0.85$	4.48 $\pm 0.84$	4.49 $\pm 0.84$
Fibrinogen (g/L)	3.37 $\pm 0.56$	3.37 $\pm 0.58$	70.83.35 $\pm 0.55$
WBC count (x 10⁹ cells/L)	6.44 $\pm 1.92$	6.42 $\pm 1.52$	6.37 $\pm 1.84$

Cross-sectional analysis

In the cross-sectional analysis (Table 1), CRP was correlated with a 19% decline in memory (p < 0.05) after controlling for sociodemographic, CVD-related, and other modified risk factors. Fibrinogen and WBC counts were associated with 13% and 9% reductions in processing speed, respectively (p < 0.05). IS2 was marginally linked to a 6% slower processing speed (p < 0.05). (Table 2)

Table 2.

Cross-sectional association of inflammatory markers and cognitive domains.

Variable	Model 1	Model 2	Model 3
(n = 4228)	β (S.E.)	β (S.E.)	β (S.E.)
C-Reactive Protein
Memory	−0.27 (0.05)**	−0.17 (0.03)**	−0.19 (0.11)*
Executive function	−0.74 (0.32)	−0.49 (0.28)	0.33 (0.21)
Processing speed	−2.37 (1.14)	−2.54 (1.17)	−3.21 (2.01)
Overall cognition	−0.86 (0.24)	−0.43 (0.21)	−0.57 (0.33)
Ferritin
Memory	0.12 (0.03)*	0.19 (0.07)*	0.26 (0.13)
Executive function	0.32 (0.12)*	0.36 (0.24)	0.29 (0.15)
Processing speed	−3.47 (2.16)*	−2.63(1.53)	−1.27 (1.09)
Overall cognition	−0.15 (0.07)	−0.16 (0.09)	0.07 (0.01)
Fibrinogen
Memory	−0.35 (0.29)*	−0.28 (0.16)	−0.12 (0.08)
Executive function	−0.17 (0.07)*	−0.09 (0.02)*	−0.08 (0.01)
Processing speed	−0.52 (0.27)**	−0.17 (0.13)**	−0.13 (0.07)*
Overall cognition	−0.11 (0.02)*	−0.04 (0.02)	0.02 (0.01)
WBC Count
Memory	−0.11 (0.03)*	−0.07 (0.02)*	−0.03 (0.01)
Executive function	−0.13 (0.05)*	−0.12 (0.05)**	0.11 (0.07)
Processing speed	−0.14 (0.03)**	−0.11 (0.04)*	−0.09 (0.02)*
Overall cognition	−0.04 (0.01)*	−0.03 (0.02)	−0.01 (0.01)
Inflammation Score 1
Memory	−0.13 (0.07)*	−0.18 (0.10)	−0.04 (0.02)
Executive function	−0.09 (0.04)*	0.04 (0.03)	0.05 (0.02)
Processing speed	−1.38 (0.45)*	−1.17 (0.23)*	0.07 (0.44)
Overall cognition	−0.06 (0.02)*	0.03 (0.01)	0.02 (0.01)
Inflammation Score 2
Memory	−0.09 (0.01)*	−0.02 (0.01)	−0.01 (0.01)
Executive function	−0.08 (0.03)*	0.02 (0.03)	0.05 (0.03)
Processing speed	−0.09 (0.06)**	−0.05 (0.03)*	−0.06 (0.04)*
Overall cognition	−0.08 (0.04)*	0.06 (0.03)	0.02 (0.01)

β reflects the unstandardized coefficient for the cognitive outcome; S.E. presented are robust standard error estimates

* p < 0.05 ** < 0.01 *** < 0.001, the statistically significant values have been highlighted in bold

Model 1: adjusted for age, sex, marital status, education, occupation, physical inactivity, and TV viewing

Model 2: adjusted for model 1 covariates and prevalent ischemic heart disease, prevalent hypertension, prevalent high cholesterol, history of stroke, current smoking, and alcohol use

Model 3: adjusted for model 2 covariates, self-reported hearing loss, obesity, depression, diabetes, poor sleep, and alcohol drinking

Inflammatory Score 1 included CRP, ferritin, and fibrinogen.

Inflammatory Score 2 included CRP, ferritin, fibrinogen, and WBC.

Longitudinal analysis for 2-year and 10-year follow-up

Tables 3 –7 present the longitudinal findings from 2-year and 10-year follow-ups of the cohort. After adjusting for risk factors, no significant relationships were identified between inflammatory biomarkers or composite inflammation and cognitive domains or overall cognitive function. However, aged participants and males seem to be at a higher risk of cognitive impairment linked to inflammation.

Table 3.

Longitudinal association of inflammatory markers and cognition at two- and ten-years follow-up for the total participants.

Follow-up period	Variable	Model 1	Model 2	Model 3
Follow-up period	(n = 4228)	β (S.E.)	β (S.E.)	β (S.E.)
Two-year	C-Reactive Protein
	Memory	−0.09 (0.06)*	−0.11 (0.05)	−0.10 (0.04)
	Executive function	−0.19 (0.10)*	−0.10 (0.07)	−0.10 (0.08)
	Processing speed	−1.08 (1.03)*	−0.10 (1.10)	−0.07 (0.08)
	Overall cognition	−0.14 (0.06)*	−0.09 (0.04)	−0.07 (0.05)
Ten-year	C-Reactive Protein
	Memory	−0.08 (0.04)**	−0.10 (0.08)	−0.06 (0.02)
	Executive function	−0.15 (0.11)	−0.14 (0.12)	−0.09 (0.11)
	Overall cognition	−0.12 (0.10)	0.03 (0.01)	0.02 (0.01)
Two-year	Ferritin
	Memory	−0.06 (0.08)	−0.05 (0.07)	0.03 (0.02)
	Executive function	−0.12 (0.10)	−0.15 (0.14)	−0.14 (0.14)
	Processing speed	−1.67 (1.38)	−0.21 (0.63)	−0.22 (1.26)
	Overall cognition	−0.11 (0.10)	−0.07 (0.05)	−0.05 (0.03)
Ten-year	Ferritin
	Memory	0.03 (0.04)	0.03 (0.01)	−0.01 (0.00)
	Executive function	−0.08 (0.10)	−0.17 (0.18)	−0.18 (0.17)
	Overall cognition	0.00 (0.02)	0.00 (0.02)	−0.01 (0.02)
Two-year	Fibrinogen
	Memory	−0.14 (0.10)*	−0.03 (0.10)	−0.01 (0.10)
	Executive function	−0.30 (0.19)**	−0.12 (0.09)	−0.11 (0.09)
	Processing speed	−0.21 (0.13)*	−0.17 (0.20)	−0.15 (0.21)
	Overall cognition	−0.04 (0.02)*	−0.03 (0.02)	−0.03 (0.02)
Ten-year	Fibrinogen
	Memory	−0.16 (0.13)*	−0.11 (0.13)	−0.10 (0.14)
	Executive function	−0.17 (0.26)	0.16 (0.26)	0.18 (0.24)
	Overall cognition	−0.03 (0.03)	−0.01 (0.03)	0.02 (0.03)
Two-year	WBC Count
	Memory	−0.05 (0.03)	−0.01 (0.02)	−0.02 (0.02)
	Executive function	−0.07 (0.08)	−0.05 (0.05)	−0.01 (0.03)
	Processing speed	−1.21 (1.03)	−0.84 (0.67)	−0.16 (0.53)
	Overall cognition	−0.01 (0.00)	0.00 (0.00)	0.00 (0.00)
Ten-year	WBC Count
	Memory	−0.07 (0.02)*	−0.04 (0.03)	−0.05 (0.02)
	Executive function	−0.05 (0.06)	−0.03 (0.05)	−0.02 (0.04)
	Overall cognition	−0.03 (0.02)	−0.02 (0.01)	−0.01 (0.00)
Two-year	Inflammation Score 1
	Memory	−0.02 (0.01)	0.00 (0.01)	0.00 (0.00)
	Executive function	−0.12 (0.03)*	−0.09 (0.06)	−0.06 (0.05)
	Processing speed	−0.42 (0.37)*	−0.11 (0.05)	−0.07 (0.08)
	Overall cognition	−0.01 (0.02)	−0.01 (0.00)	0.00 (0.00)
Ten-year	Inflammation Score 1
	Memory	−0.03 (0.03)	−0.02 (0.01)	0.00 (0.01)
	Executive function	−0.09 (0.02)*	−0.06 (0.04)	−0.05 (0.03)
	Overall cognition	−0.01 (0.02)	0.02 (0.04)	0.02 (0.02)
Two-year	Inflammation Score 2
	Memory	−0.01 (0.02)	0.01 (0.02)	0.01 (0.02)
	Executive function	−0.07 (0.03)*	−0.03 (0.03)	−0.02 (0.03)
	Processing speed	−0.08 (0.05)*	−0.05 (0.04)	−0.04 (0.09)
	Overall cognition	−0.05 (0.03)*	0.01 (0.02)	0.02 (0.02)
Ten-year	Inflammation Score 2
	Memory	−0.03 (0.02)	0.01 (0.02)	0.00 (0.02)
	Executive function	−0.05 (0.04)*	−0.01 (0.04)	−0.02 (0.03)
	Overall cognition	−0.04 (0.05)	−0.01 (0.00)	−0.01 (0.00)

β reflects the unstandardized coefficient for the cognitive outcome

S.E. presented are robust standard error estimates

* p < 0.05

Model 1: adjusted for age, sex, marital status, education, occupation, physical inactivity, and TV viewing

Model 2: adjusted for model 2 covariates and prevalent ischemic heart disease, prevalent hypertension, prevalent high cholesterol, history of stroke, and current smoking

Model 3: adjusted for model 3 covariates, self-reported hearing loss, obesity, depression, diabetes, poor sleep, and alcohol drinking

Inflammatory Score 1 included CRP, ferritin, and fibrinogen.

Inflammatory Score 2 included CRP, ferritin, fibrinogen, and WBC.

Table 4.

Longitudinal association of inflammatory markers and cognition at two- and ten-year follow-up for participants older than 75 years old.

Follow-up period	Variable	Model 1	Model 2	Model 3
Follow-up period	(n = 4228)	β (S.E.)	β (S.E.)	β (S.E.)
Two-year	C-Reactive Protein
	Memory	−0.15 (0.07)**	−0.13 (0.09)*	−0.12 (0.10)
	Executive function	−0.21 (0.13)*	−0.15 (0.13)	−0.12 (0.08)
	Processing speed	−0.09 (0.03)**	−0.05 (0.02)**	−0.03 (0.01)*
	Overall cognition	−0.14 (0.06)*	−0.07 (0.09)	−0.06 (0.05)
Ten-year	C-Reactive Protein
	Memory	−0.20 (0.08)**	−0.17 (0.05)**	−0.18 (0.10)**
	Executive function	−0.16 (0.04)*	−0.15 (0.15)	−0.14 (0.16)
	Overall cognition	−0.12 (0.10)*	−0.03 (0.02)*	−0.03 (0.01)*
Two-year	Ferritin
	Memory	−0.07 (0.07)	−0.08 (0.09)	0.05 (0.04)
	Executive function	−0.11 (0.09)	−0.16 (0.14)	−0.16 (0.15)
	Processing speed	−1.53 (1.62)	−0.18 (1.15)	−0.17 (1.20)
	Overall cognition	−0.10 (0.07)	−0.05 (0.05)	−0.06 (0.04)
Ten-year	Ferritin
	Memory	0.01 (0.00)	−0.02 (0.01)	−0.03 (0.01)
	Executive function	−0.05 (0.08)	−0.14 (0.16)	−0.15 (0.16)
	Overall cognition	−0.02 (0.01)	−0.01 (0.02)	−0.01 (0.03)
Two-year	Fibrinogen
	Memory	−0.18 (0.09)*	−0.10 (0.07)	−0.05 (0.03)
	Executive function	−0.42 (0.26)**	−0.29 (0.19)*	−0.20 (0.11)
	Processing speed	−0.24 (0.12)*	−0.14 (0.04)*	−0.12 (0.09)*
	Overall cognition	−0.03 (0.01)*	−0.02 (0.02)*	−0.03 (0.03)
Ten-year	Fibrinogen
	Memory	−0.13 (0.14)	−0.09 (0.10)	−0.10 (0.11)
	Executive function	−0.14 (0.10)*	−0.10 (0.07)*	−0.07 (0.04)*
	Overall cognition	−0.07 (0.02)*	−0.03 (0.01)*	−0.02 (0.00)*
Two-year	WBC Count
	Memory	−0.10 (0.08)	−0.04 (0.02)	−0.06 (0.05)
	Executive function	−0.04 (0.07)	−0.02 (0.03)	0.02 (0.01)
	Processing speed	−1.24 (0.63)	−1.03 (0.77)	−0.07 (0.05)
	Overall cognition	0.00 (0.01)	−0.01 (0.02)	−0.03 (0.02)
Ten-year	WBC Count
	Memory	−0.04 (0.02)*	−0.01 (0.03)	−0.04 (0.04)
	Executive function	−0.11 (0.07)	−0.09 (0.08)	−0.07 (0.05)
	Overall cognition	−0.01 (0.01)	−0.00 (0.00)	−0.00 (0.00)
Two-year	Inflammation Score 1
	Memory	−0.04 (0.01)*	−0.02 (0.02)	−0.01 (0.02)
	Executive function	−0.12 (0.03)*	−0.08 (0.06)	−0.05 (0.04)
	Processing speed	−1.53 (0.14)*	−1.23 (0.66)	−1.06 (0.53)
	Overall cognition	−0.03 (0.02)*	−0.01 (0.00)	0.00 (0.00)
Ten-year	Inflammation Score 1
	Memory	−0.06 (0.03)*	−0.04 (0.02)	−0.05 (0.03)
	Executive function	−0.10 (0.05)*	−0.09 (0.07)	−0.09 (0.10)
	Overall cognition	−0.02 (0.01)	−0.01 (0.04)	0.00 (0.00)
Two-year	Inflammation Score 2
	Memory	−0.02 (0.01)*	0.01 (0.02)	0.00 (0.00)
	Executive function	−0.10 (0.05)*	−0.05 (0.04)	−0.04 (0.05)
	Processing speed	−0.19 (0.08)*	−0.10 (0.07)*	−0.11 (0.04)*
	Overall cognition	−0.07 (0.02)*	−0.02 (0.02)	0.00 (0.01)
Ten-year	Inflammation Score 2
	Memory	−0.04 (0.01)*	−0.02 (0.01)*	−0.02 (0.00)*
	Executive function	−0.011 (0.04)*	−0.06 (0.04)	−0.02 (0.03)
	Overall cognition	−0.08 (0.03)*	−0.04 (0.01)*	−0.03 (0.00)*

β reflects the unstandardized coefficient for the cognitive outcome

S.E. presented are robust standard error estimates

* p < 0.05, the statistically significant values have been highlighted in bold

Model 1: adjusted for age, sex, marital status, education, occupation, physical inactivity, and TV viewing

Model 2: adjusted for model 2 covariates and prevalent ischemic heart disease, prevalent hypertension, prevalent high cholesterol, history of stroke, and current smoking

Model 3: adjusted for model 3 covariates, self-reported hearing loss, obesity, depression, diabetes, poor sleep, and alcohol drinking

Inflammatory Score 1 included CRP, ferritin, and fibrinogen.

Inflammatory Score 2 included CRP, ferritin, fibrinogen, and WBC.

Table 5.

Longitudinal association of inflammatory markers and cognition at two- and ten-year follow-up for participants younger than 75 years old.

Follow-up period	Variable	Model 1	Model 2	Model 3
Follow-up period	(n = 4228)	β (S.E.)	β (S.E.)	β (S.E.)
Two-year	C-Reactive Protein
	Memory	−0.04 (0.02)*	−0.07 (0.06)	−0.05 (0.04)
	Executive function	−0.17 (0.11)*	−0.06 (0.07)	−0.06 (0.04)
	Processing speed	−1.12 (1.25)	−0.10 (0.11)	−0.08 (0.09)
	Overall cognition	−0.12 (0.04)*	−0.07 (0.09)	−0.06 (0.05)
Ten-year	C-Reactive Protein
	Memory	−0.03 (0.02)*	−0.04 (0.03)	0.01 (0.00)
	Executive function	−0.13 (0.04)*	−0.11 (0.10)	−0.07 (0.09)
	Overall cognition	−0.14 (0.12)	0.06 (0.10)	0.05 (0.07)
Two-year	Ferritin
	Memory	−0.04 (0.04)	−0.02 (0.01)	0.01 (0.01)
	Executive function	−0.11 (0.10)	−0.14 (0.16)	−0.08 (0.08)
	Processing speed	−2.32 (1.90)	−0.38 (0.27)	−0.25 (0.13)
	Overall cognition	−0.12 (0.11)	−0.09 (0.07)	−0.03 (0.05)
Ten-year	Ferritin
	Memory	0.06 (0.04)	0.08 (0.03)	0.01 (0.00)
	Executive function	−0.12 (0.09)	−0.19 (0.11)	−0.21 (0.18)
	Overall cognition	0.03 (0.02)	−0.05 (0.04)	−0.04 (0.06)
Two-year	Fibrinogen
	Memory	−0.09 (0.08)	−0.02 (0.05)	0.01 (0.00)
	Executive function	−0.19 (0.07)*	−0.15 (0.11)	−0.10 (0.12)
	Processing speed	−3.82 (1.97)*	−2.10 (2.05)	−1.17 (1.13)
	Overall cognition	−0.10 (0.03)*	−0.07 (0.05)	−0.06 (0.04)
Ten-year	Fibrinogen
	Memory	−0.15 (0.11)	−0.02 (0.15)	0.02 (0.17)
	Executive function	−0.19 (0.35)	0.24 (0.41)	0.28 (0.37)
	Overall cognition	−0.02 (0.01)	0.01 (0.02)	0.06 (0.07)
Two-year	WBC Count
	Memory	−0.05 (0.04)	0.02 (0.03)	0.00 (0.01)
	Executive function	−0.07 (0.06)	−0.05 (0.04)	−0.03 (0.02)
	Processing speed	−1.24 (0.63)	−1.03 (0.77)	−0.07 (0.05)
	Overall cognition	0.00 (0.01)	−0.01 (0.02)	−0.03 (0.02)
Ten-year	WBC Count
	Memory	−0.10 (0.09)	−0.08 (0.05)	−0.08 (0.06)
	Executive function	−0.04 (0.02)	−0.03 (0.05)	−0.01 (0.02)
	Overall cognition	−0.03 (0.02)	−0.02 (0.01)	−0.02 (0.00)
Two-year	Inflammation Score 1
	Memory	0.03 (0.03)	0.02 (0.01)	0.02 (0.02)
	Executive function	−0.09 (0.02)*	−0.08 (0.06)	−0.05 (0.04)
	Processing speed	−1.28 (0.37)*	−0.54 (0.28)	−0.48 (0.42)
	Overall cognition	−0.03 (0.02)*	−0.01 (0.00)	0.00 (0.00)
Ten-year	Inflammation Score 1
	Memory	0.04 (0.02)	0.03 (0.03)	0.03 (0.01)
	Executive function	−0.11 (0.08)	−0.09 (0.10)	−0.08 (0.05)
	Overall cognition	0.05 (0.03)	0.04 (0.02)	0.02 (0.01)
Two-year	Inflammation Score 2
	Memory	−0.01 (0.02)	−0.03 (0.04)	−0.03 (0.00)
	Executive function	−0.05 (0.02)*	−0.02 (0.03)	−0.01 (0.04)
	Processing speed	−0.57 (0.14)*	−0.21 (0.10)	−0.13 (0.14)
	Overall cognition	0.03 (0.04)	0.02 (0.02)	0.01 (0.01)
Ten-year	Inflammation Score 2
	Memory	−0.01 (0.03)	0.0 (0.01)	0.02 (0.03)
	Executive function	−0.01 (0.04)*	−0.06 (0.04)	−0.02 (0.03)
	Overall cognition	0.02 (0.04)	0.01 (0.03)	0.00 (0.00)

β reflects the unstandardized coefficient for the cognitive outcome

S.E. presented are robust standard error estimates

* p < 0.05

Model 1: adjusted for age, sex, marital status, education, occupation, physical inactivity, and TV viewing

Model 2: adjusted for model 2 covariates and prevalent ischemic heart disease, prevalent hypertension, prevalent high cholesterol, history of stroke, and current smoking

Model 3: adjusted for model 3 covariates, self-reported hearing loss, obesity, depression, diabetes, poor sleep, and alcohol drinking

Inflammatory Score 1 included CRP, ferritin, and fibrinogen.

Inflammatory Score 2 included CRP, ferritin, fibrinogen, and WBC.

Table 6.

Longitudinal association of inflammatory markers and cognition at two- and ten-year follow-up for the female participants.

Follow-up period	Variable	Model 1	Model 2	Model 3
Follow-up period	(n = 4228)	β (S.E.)	β (S.E.)	β (S.E.)
Two-year	C-Reactive Protein
	Memory	−0.10 (0.03)*	−0.07 (0.04)	−0.06 (0.02)
	Executive function	−0.21 (0.11)*	−0.14 (0.10)	−0.12 (0.09)
	Processing speed	−0.13 (0.06)*	−0.11 (0.06)	−0.08 (0.09)
	Overall cognition	−0.17 (0.08)*	−0.13 (0.05)	−0.10 (0.03)
Ten-year	C-Reactive Protein
	Memory	−0.12 (0.03)**	−0.11 (0.07)	−0.09 (0.03)
	Executive function	−0.18 (0.07)*	−0.13 (0.06)	−0.09 (0.04)
	Overall cognition	−0.15 (0.05)*	0.01 (0.01)	0.00 (0.00)
Two-year	Ferritin
	Memory	−0.05 (0.06)	−0.03 (0.04)	0.01 (0.02)
	Executive function	−0.11 (0.09)	−0.13 (0.11)	−0.13 (0.08)
	Processing speed	−1.63 (1.24)	−0.81 (0.58)	−0.47 (0.32)
	Overall cognition	−0.10 (0.09)	−0.07 (0.05)	−0.05 (0.03)
Ten-year	Ferritin
	Memory	0.02 (0.03)	0.01 (0.00)	0.00 (0.00)
	Executive function	−0.07 (0.08)	−0.15 (0.15)	−0.17 (0.11)
	Overall cognition	0.01 (0.02)	−0.01 (0.01)	0.00 (0.00)
Two-year	Fibrinogen
	Memory	−0.15 (0.11)*	−0.07 (0.09)	−0.03 (0.08)
	Executive function	−0.14 (0.16)	−0.12 (0.39)	−0.13 (0.27)
	Processing speed	−4.28 (3.16)	−2.58 (1.14)	−1.72 (0.71)
	Overall cognition	−0.04 (0.02)*	−0.03 (0.02)	−0.03 (0.02)
Ten-year	Fibrinogen
	Memory	−0.11 (0.07)*	−0.13 (0.09)	−0.10 (0.07)
	Executive function	−0.16 (0.13)	0.12 (0.10)	0.13 (0.08)
	Overall cognition	−0.02 (0.04)	−0.01 (0.03)	0.03 (0.04)
Two-year	WBC Count
	Memory	−0.07 (0.06)	−0.01 (0.03)	−0.01 (0.03)
	Executive function	−0.06 (0.06)	−0.03 (0.06)	0.00 (0.06)
	Processing speed	−1.31 (0.74)	−0.86 (0.73)	−0.15 (0.76)
	Overall cognition	−0.01 (0.01)	−0.01 (0.01)	0.00 (0.01)
Ten-year	WBC Count
	Memory	−0.08 (0.04)*	−0.06 (0.04)	−0.07 (0.04)
	Executive function	−0.07 (0.08)	−0.05 (0.08)	−0.03 (0.08)
	Overall cognition	−0.02 (0.01)	−0.01 (0.01)	−0.01 (0.01)
Two-year	Inflammation Score 1
	Memory	−0.01 (0.02)	0.01 (0.02)	0.01 (0.02)
	Executive function	−0.10 (0.04)*	−0.06 (0.04)	−0.04 (0.04)
	Processing speed	−1.37 (0.46)*	−0.88 (0.46)	−0.66 (0.47)
	Overall cognition	−0.01 (0.00)*	−0.01 (0.00)	0.00 (0.00)
Ten-year	Inflammation Score 1
	Memory	−0.02 (0.02)	−0.01 (0.00)	0.01 (0.02)
	Executive function	−0.10 (0.05)*	−0.07 (0.06)	−0.05 (0.05)
	Overall cognition	−0.01 (0.01)	0.03 (0.04)	0.03 (0.03)
Two-year	Inflammation Score 2
	Memory	0.00 (0.01)	0.01 (0.02)	0.01 (0.01)
	Executive function	−0.06 (0.05)	−0.04 (0.03)	−0.02 (0.03)
	Processing speed	−0.76 (0.12)*	−0.26 (0.35)	−0.24 (0.27)
	Overall cognition	−0.07 (0.04)*	0.03 (0.01)	0.02 (0.01)
Ten-year	Inflammation Score 2
	Memory	−0.02 (0.03)	0.02 (0.01)	0.01 (0.00)
	Executive function	−0.06 (0.02)*	−0.03 (0.04)	−0.02 (0.02)
	Overall cognition	−0.05 (0.06)	−0.02 (0.01)	−0.01 (0.00)

β reflects the unstandardized coefficient for the cognitive outcome

S.E. presented are robust standard error estimates

* p < 0.05

Model 1: adjusted for age, sex, marital status, education, occupation, physical inactivity, and TV viewing

Model 2: adjusted for model 2 covariates and prevalent ischemic heart disease, prevalent hypertension, prevalent high cholesterol, history of stroke, and current smoking

Model 3: adjusted for model 3 covariates, self-reported hearing loss, obesity, depression, diabetes, poor sleep, and alcohol drinking

Inflammatory Score 1 included CRP, ferritin, and fibrinogen.

Inflammatory Score 2 included CRP, ferritin, fibrinogen, and WBC.

Table 7.

Longitudinal association of inflammatory markers and cognition at two- and ten-year follow-up for the male participants.

Follow-up period	Variable	Model 1	Model 2	Model 3
Follow-up period	(n = 4228)	β (S.E.)	β (S.E.)	β (S.E.)
Two-year	C-Reactive Protein
	Memory	−0.09 (0.02)*	−0.12 (0.13)	−0.11 (0.06)
	Executive function	−0.15 (0.08)*	−0.09 (0.03)	−0.08 (0.05)
	Processing speed	−0.12 (0.13)	−0.10 (0.08)	−0.09 (0.07)
	Overall cognition	−0.10 (0.05)*	−0.07 (0.03)	−0.05 (0.02)
Ten-year	C-Reactive Protein
	Memory	−0.07 (0.04)	−0.04 (0.09)	−0.04 (0.05)
	Executive function	−0.12 (0.10)	−0.14 (0.19)	−0.08 (0.16)
	Overall cognition	−0.08 (0.12)	0.04 (0.03)	0.03 (0.02)
Two-year	Ferritin
	Memory	−0.07 (0.08)	−0.06 (0.03)	0.04 (0.05)
	Executive function	−0.14 (0.12)	−0.18 (0.15)	−0.16 (0.13)
	Processing speed	−1.71 (1.42)	−0.08 (0.23)	−0.13 (1.14)
	Overall cognition	−0.14 (0.11)	−0.07 (0.05)	−0.06 (0.08)
Ten-year	Ferritin
	Memory	0.05 (0.03)	0.04 (0.02)	0.01 (0.01)
	Executive function	−0.10 (0.09)	−0.18 (0.16)	−0.19 (0.15)
	Overall cognition	−0.01 (0.03)	0.01 (0.02)	0.01 (0.03)
Two-year	Fibrinogen
	Memory	−0.10 (0.04)**	−0.03 (0.01)*	−0.02 (0.00)
	Executive function	−0.36 (0.17)**	−0.11 (0.05)	−0.07 (0.03)
	Processing speed	−6.41 (1.91)*	−1.13 (1.28)	−1.10 (1.12)
	Overall cognition	−0.03 (0.01)*	−0.02 (0.00)	−0.01 (0.00)
Ten-year	Fibrinogen
	Memory	−0.17 (0.12)*	−0.06 (0.04)*	−0.02 (0.00)*
	Executive function	−0.19 (0.31)	0.17 (0.29)	0.18 (0.25)
	Overall cognition	−0.10 (0.07)*	−0.04 (0.02)	0.01 (0.00)
Two-year	WBC Count
	Memory	−0.09 (0.07)	−0.03 (0.04)	−0.01 (0.00)
	Executive function	−0.05 (0.04)	−0.02 (0.03)	0.01 (0.02)
	Processing speed	−1.41 (0.62)	−0.88 (0.79)	−0.13 (0.82)
	Overall cognition	−0.01 (0.02)	−0.01 (0.01)	0.00 (0.01)
Ten-year	WBC Count
	Memory	−0.09 (0.03)*	−0.07 (0.05)	−0.07 (0.04)
	Executive function	−0.08 (0.07)	−0.06 (0.05)	−0.04 (0.06)
	Overall cognition	−0.01 (0.01)	−0.01 (0.00)	0.00 (0.01)
Two-year	Inflammation Score 1
	Memory	−0.01 (0.01)	0.02 (0.01)	0.01 (0.01)
	Executive function	−0.09 (0.04)*	−0.04 (0.03)	−0.02 (0.01)
	Processing speed	−1.32 (0.53)*	−0.83 (0.35)	−0.52 (0.47)
	Overall cognition	−0.01 (0.00)*	−0.01 (0.00)	0.00 (0.00)
Ten-year	Inflammation Score 1
	Memory	−0.01 (0.02)	0.00 (0.01)	0.02 (0.01)
	Executive function	−0.11 (0.08)	−0.08 (0.07)	−0.06 (0.03)
	Overall cognition	0.00 (0.01)	0.03 (0.02)	0.04 (0.03)
Two-year	Inflammation Score 2
	Memory	−0.02 (0.01)	0.02 (0.01)	0.01 (0.01)
	Executive function	−0.08 (0.04)*	−0.05 (0.03)	−0.03 (0.02)
	Processing speed	−0.85 (0.42)*	−0.42 (0.37)	−0.40 (0.35)
	Overall cognition	−0.04 (0.05)	0.00 (0.01)	0.02 (0.02)
Ten-year	Inflammation Score 2
	Memory	−0.03 (0.01)*	0.00 (0.02)	0.00 (0.00)
	Executive function	−0.04 (0.05)	−0.01 (0.01)	−0.02 (0.03)
	Overall cognition	−0.04 (0.05)	−0.01 (0.00)	−0.01 (0.00)

β reflects the unstandardized coefficient for the cognitive outcome

S.E. presented are robust standard error estimates

* p < 0.05, the statistically significant values have been highlighted in bold

Model 1: adjusted for age, sex, marital status, education, occupation, physical inactivity, and TV viewing

Model 2: adjusted for model 2 covariates and prevalent ischemic heart disease, prevalent hypertension, prevalent high cholesterol, history of stroke, and current smoking

Model 3: adjusted for model 3 covariates, self-reported hearing loss, obesity, depression, diabetes, poor sleep, and alcohol drinking

Inflammatory Score 1 included CRP, ferritin, and fibrinogen.

Inflammatory Score 2 included CRP, ferritin, fibrinogen, and WBC.

In adults aged 75 years and older, CRP was significantly associated with a 3% reduction in processing speed (p < 0.05) over 2 years and an 18% decline in memory (p < 0.01) after 10 years. Additionally, CRP was linked to a 3% decrease in overall cognitive outcomes (p < 0.05) after 10 years. Fibrinogen exhibited a more substantial effect, resulting in a 12% reduction in processing speed over 2 years (p < 0.05), alongside a 7% decline in executive function and a 2% decrease in overall cognitive performance after 10 years. Notably, processing speed was the only cognitive domain that experienced a 2-year reduction of 11% due to IS2 (p < 0.05). Conversely, the 10-year follow-up indicated declines of 2% (p < 0.05) in memory and 3% (p < 0.05) in overall cognition associated with IS2. Furthermore, males faced a 2% decline in memory (p < 0.05) after 10 years, primarily attributed to fibrinogen.

Discussion

This cohort study investigated relationships between inflammatory markers and cognitive outcomes cross-sectionally and longitudinally. CRP, fibrinogen, and composite inflammation were consistently linked to multiple cognitive domains among adults aged 75 and older, with stronger 10-year than 2-year effects, reflecting cumulative inflammation-related cognitive decline. Processing speed, assessed only at 2 years, showed a significant decrease, suggesting its vulnerability to inflammation. Associations between inflammation and cognition were attenuated after adjusting for cardiovascular risk factors, highlighting the pivotal role of CVD in cognitive impairment.

Consistent with our findings, elevated CRP has been associated with a smaller left medial temporal lobe (MTL) volume in older adults, potentially contributing to memory loss.³³ While processing speed is primarily linked to white matter integrity, reduced MTL volume may indirectly impair it in the context of widespread neurodegeneration.³⁴ In contrast, the CARDIA study reported an association between higher levels of CRP and poorer midlife executive function, though this may be influenced by attrition bias over 18 years.³⁵ Fibrinogen contributes to chronic inflammation, endothelial dysfunction, and blood-brain barrier disruption, accelerating neurodegeneration.³⁶ Supporting our results, prior studies have linked higher midlife Fibrinogen levels to a later decline in executive function, processing speed, and overall cognition.^20,37 However, evidence on its association with memory is mixed, due to differences in age and comorbidities.^38,39 Our results suggest a stronger impact of fibrinogen on cognition in males, but overall evidence is inconclusive, highlighting the need for large-scale, sex-stratified research.

A negative association between WBC count and processing speed was observed but did not persist in the long-term follow-up across the whole sample or by age and gender subgroups. Although no studies have directly examined the impact of WBC on cognitive outcomes, emerging research suggests elevated WBC counts may marginally mediate PM2.5-related neurotoxicity.⁴⁰ Ferritin showed no association with cognitive domains in either cross-sectional or longitudinal analyses. While low ferritin reflects iron-deficiency anemia, and is prevalent in older adults with cognitive impairment, prior evidence is contradictory, with a positive relationship observed in Spain and a negative association found in NHANES.^41–43 These discrepancies may reflect variations in study design, cognitive assessments, population, and comorbidities.

Cognitive decline was modest in the short term but became significant over 10 years, with CRP, fibrinogen, and composite inflammation associated with cognitive impairment. However, Aβ, race, metabolic syndrome, and CVD may play a more critical role. A 20-year analysis found Aβ, rather than systemic inflammation, was more strongly linked to cognitive impairment.^44,45 Decline in visual memory and visual-constructive abilities was observed only among African Americans, while metabolic syndrome predicted impairment only with elevated inflammation, suggesting a modifying role of inflammation.^21,46 Aligning with prior evidence, associations weakened after CVD adjustment, highlighting the dominant role of CVD in cognitive decline.^16,17

This study leveraged a large sample with comprehensive sociodemographic and health data, but it has a few limitations. As an observational study, causality cannot be inferred. Generalizability is limited by a predominantly White cohort, given stronger inflammation-cognition associations in African Americans.^19,37^47–49 The absence of attention, visuospatial skills, additional biomarkers (e.g., IL-6), and APOE4 status constrains cognitive assessment.^50,51 The omission of factors like traumatic brain injury and air pollution may inflate results.^52,53 Attrition bias may also affect longitudinal validity. Future studies incorporating expanded cognitive and biomarker assessments could strengthen these findings.

Conclusion

CRP, fibrinogen, and overall inflammation were associated with cognitive decline among older adults. A more holistic approach, incorporating genetic, psychiatric, and environmental factors, along with alternative biomarkers, and diverse, high-risk populations, can help understand the intricate relationship between inflammation and cognition.

Supplemental Material

sj-docx-1-alz-10.1177_13872877251394331 - Supplemental material for The association between individual and composite inflammation biomarkers and cognitive function

Supplemental material, sj-docx-1-alz-10.1177_13872877251394331 for The association between individual and composite inflammation biomarkers and cognitive function by Fanli Yi, Reddy Ananya, Kasra Moazzami, Jingkai Wei and Ambar Kulshreshtha in Journal of Alzheimer's Disease

Footnotes

Acknowledgements

The English Longitudinal Study of Ageing was developed by a team of researchers based at University College London, NatCen Social Research, the Institute for Fiscal Studies, the University of Manchester, and the University of East Anglia. NatCen Social Research collected the data. This work was supported by the National Institute on Aging in the US and a consortium of UK government departments coordinated by the National Institute for Health Research and the Economic and Social Research Council. The content of the manuscript appeared as Emory Theses and Dissertations online.

ORCID iD

Ambar Kulshreshtha

Ethical considerations

The English Longitudinal Study of Ageing (ELSA) received ethical approval.

Consent to participate

All participants provided informed consent for data collection and follow-up.

Author contribution(s)

Fanli Yi: Writing – review, secondary analysis & editing.

Reddy Ananya: Formal analysis; Methodology.

Kasra Moazzami: Writing – review & editing.

Jingkai Wei: Writing – review & editing.

Ambar Kulshreshtha: Investigation; Resources; Supervision; Writing – review & editing.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Institute of Health Sciences', (grant number K23AG066931-01A1).

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data availability statement

The data support restrictions. This study's findings are available on request from the corresponding author. However, the data are not publicly available due to privacy or ethical restrictions.

Supplemental material

Supplemental material for this article is available online.

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