Systemic inflammation and modifiable risk factors for cognitive impairment in older persons: Findings from a British birth cohort

Abstract Serum pro‐inflammatory markers may contribute to dementia pathophysiology and cognitive impairment. In a population‐representative birth cohort, serum C‐reactive protein (CRP), interleukin‐6 (IL‐6), and white cell count (WCC) were measured at age 60‐64 years and cognition was assessed using the Addenbrooke's Cognitive Examination (ACE‐III) at age 69 years. Higher baseline CRP and IL‐6 were associated with lower ACE‐III scores, but associations were attenuated on adjustment for educational attainment, sex, and other modifiable life course factors. No associations were found for CRP, IL‐6, and WCC with visual search speed or verbal memory. In conclusion, the relationship between increased baseline systemic inflammation and poorer cognition in later life may be explained by, or share pathways with, education and other modifiable life course factors.


| INTRODUC TI ON
Although neuroinflammation is a feature of Alzheimer's disease, 1 the degree to which pathophysiology may be driven by systemic inflammation is unclear. For example, systemic illnesses with a pro-inflammatory response may contribute to neurodegeneration and worsening dementia severity. [2][3][4][5] However, findings from epidemiological studies have been inconsistent [6][7][8][9][10][11] ; discrepancies may in part reflect complexities in modelling the temporal patterns of modifiable life course factors on both systemic inflammation and cognition. These factors include educational attainment, 12 body mass index (BMI), 13 alcohol intake, 14 smoking, and exercise. 15 Many of these exposures are time-varying and so apparent associations with inflammation and cognition may be subject to reverse causation.
In this study, we set out to quantify the relationships among measures of systemic inflammation, modifiable life course factors known to be associated with cognitive impairment, and subsequent cognitive outcomes. We investigated this in a birth cohort with the advantage of accurate ascertainments of exposures across the whole life course, along with detailed assessment of cognition, to answer the following questions:

| Population sample
The MRC National Survey for Health and Development (NSHD) is the oldest British birth cohort, following a sample of 5362 male and female participants born in 1 week in March 1946. 16 During the 24th data collection in 2014-2015, 2942 participants in the target sample living in England, Scotland, and Wales were contacted: 2453 (83.4%) returned a postal questionnaire and 2149 (73%) participants had a home visit by a research nurse. 17 The target sample did not include participants no longer in the study (n = 2420): 957 (17.8% of the original sample) had already died, 620 (11.6%) had previously withdrawn from the study, 448 (8.3%) had emigrated and had no contact with the study, and 395 (7.4%) had been untraceable for more than 5 years.

| Outcomes: General cognition
At age 69 years, the cognitive assessments comprised the Addenbrooke's Cognitive Examination, third version (ACE-III), and verbal memory and visual search speed tasks, carried out by a research nurse according to the same standardized protocol as at earlier ages. 18 A customized version of the ACE-III was administered by iPad (Apple) using ACE Mobile (http://www.acemobile.org/). Of the 2149 participants visited by the research nurse, complete ACE-III data were available for 1751 participants (81.5% of those who received a home visit). 17 Verbal memory was assessed using a 15-item word-learning task, where each word was presented for 2 seconds.
The score represents the total number of words correctly recalled over three identical trials (maximum 45). Visual search speed was assessed by crossing out the letters P and W, randomly embedded within a grid of other letters, as quickly and accurately as possible in 1 minute. The score represents the total number of letters searched (maximum 600).

| Exposures: Serum inflammatory markers and covariates
At age 60-64 years, participants had attended a clinic or had been visited by a research nurse, during which a blood sample had been taken. Aliquots were frozen and transferred to the MRC Human Nutrition Research Laboratory in Cambridge, UK, where analyses of inflammatory marker C-reactive protein (CRP) and white blood cells were processed according to standardized protocols. 19 Analyses of interleukin-6 (IL-6) were further undertaken by the British Heart Foundation Research Centre in Glasgow, UK.
During the home or clinic visits, waist circumference, height, and weight were measured using standardized protocols, and BMI was calculated (kg/m 2 ). Participants were asked how many times in the last 4 weeks they had taken part in sports or vigorous activities, categorized as inactive (no episodes), less active (1-4 exercise episodes/mo), and more active (≥5 exercise episodes/mo). Smoking history was prospectively self-reported and calculated as pack-years.
Alcohol consumption was defined by frequency: four or more times per week; two to four times per week; two to four times per month; less than monthly; or a lifelong non-drinker of alcohol. Educational qualifications by age 26 were categorized into none or less than ordinary secondary level ("O" levels usually taken at age 16); "O" levels; and advanced secondary level ("A" level) and higher. All data collected at age 60-64 years were used to update corresponding information at earlier ages.

| Statistical analysis
The complete sample with cognitive assessments at 69 years, serum inflammatory markers at 60-64 years, and complete information on covariates data included 1008 participants. CRP, IL-6, and white cell count (WCC) were divided into tertiles, consistent with the previous literature. 6 All cognitive measures and continuous covariates were assessed for Gaussian distributions. Using a complete sample, associations between inflammatory exposures and cognition were estimated using univariate linear regression, then in turn adjusted for each selected covariate. All covariates that resulted in a change in model estimates when adjusted for were included in a final regression model (Table S1).

| RE SULTS
The prevalence of each exposure, including mean and standard deviations of inflammatory markers at age 60-64 years, in relation to the sample followed at age 69 years is shown in Table 1. No significant sex differences were observed between each inflammation marker and individual covariates.

| Inflammation markers
There was an association between CRP and IL-6 with ACE-III scores in univariate analyses (maximum coefficients compared to reference: CRP −1.29 points, IL-6 −1.27 points; P < 0.01). When adjusted for educational attainment, both associations were attenuated.
Associations for all three inflammatory markers were further attenuated when fully adjusted for other modifiable life course factors (  TA B L E 2 (Continued) (P = 0.35; Table 2). No associations were demonstrated between education or modifiable life course factors with later-life visual search speed performance in fully adjusted models (Table S2). Educational attainment, exercise, alcohol intake, and smoking were associated with later life verbal memory performance in fully adjusted models (Table S3). Framingham, 8 and American Health, Aging, Body Composition cohorts, 10 no associations were found in Dutch, 7 Swedish, 11 or other US cohorts. 7,[20][21][22] These discrepancies likely reflect differences in study protocols, cohort ages, secular period, ethnicities, and degree of adjustment by confounders.

| D ISCUSS I ON
Our findings are unique in the following respects: First, participants were in their seventh decade, younger than other cohorts and perhaps at a critical period for when dementia pathophysiology is being initiated. 23 In addition, the ACE-III is a more de- factors like blood-brain barrier permeability are likely to vary between individuals, 25 and even subclinical neurodegeneration may lead to microglial priming and consequent exaggeration of central inflammation. 26 At least in NSHD, it appears the association between systemic inflammation and worse cognitive outcomes may be explained by: (a) pro-inflammatory consequences of poor health behaviors (low physical activity, alcohol use, smoking) and/or (b) shared pathways between poor health behaviors and cognitive impairment. Our findings are consistent with a randomized trial that demonstrated that multi-domain interventions-where exercise was a key componentresulted in cognitive benefits in older people. 27 Furthermore, exercise has been associated with larger hippocampal volumes, increased gadolinium perfusion, and improved complex object recognition. 28 Exercise is likely to be beneficial in reducing the vascular contributions to cognitive impairment from metabolic abnormalities, such as insulin resistance.

CO N FLI C T O F I NTE R E S T
The authors have no conflict of interest to report.