Amy Packer: Limited evidence of a shared genetic relationship between C-reactive protein levels and cognitive function in older UK adults of European ancestry

Introduction: Previous studies have shown associations between cognitive function and C-reactive protein (CRP) levels in older adults. Few studies have considered the extent to which a genetic predisposition for higher CRP levels contributes to this association.

Methods: Data was analyzed from 7,817 UK participants aged >50 years as part of the PROTECT study, within which adults without dementia completed a comprehensive neuropsychological battery. We constructed a polygenic risk score (PRS-CRP) that explained 9.61% of the variance in serum CRP levels (p = 2.362 × 10−7) in an independent cohort. Regressions were used to explore the relationship between PRS-CRP and cognitive outcomes.

Results: We found no significant associations between PRS-CRP and any cognitive measures in the sample overall. In older participants (>62 years), we observed a significant positive association between PRS-CRP and self-ordered search score (i.e., spatial working memory).

Conclusion: Whilst our results indicate a weak positive relationship between PRS-CRP and spatial working memory that is specific to older adults, overall, there appears to be no strong effects of PRS-CRP on cognitive function.

1. Introduction

Marked inter-individual differences have been demonstrated in cognitive function and age-related decline (Foster, 2006). Understanding what causes this variability and identifying individuals at-risk of cognitive problems, is of critical importance to our aging population and workforce. Chronic low-grade inflammation, has been identified as one potential contributor to differences in brain age and cognitive function in older adults (Fard and Stough, 2019; Gordleeva et al., 2020).

C-reactive protein (CRP) is an acute-phase protein that has a critical role in the human immune system, and correlates with proinflammatory cytokine levels (Gabay and Kushner, 1999). Both CRP and cytokines found in blood can cross the blood-brain barrier to affect brain function (Quan and Banks, 2007). Animal studies have consistently shown an effect of inflammation on cognitive function. For example, administering the inflammatory agent lipopolysaccharide (LPS) to mice has been shown to cause learning and memory impairment (Salmani et al., 2020). LPS-induced inflammation impairs hippocampal neurogenesis in rats (Ekdahl et al., 2003), providing a putative mechanism connecting inflammation with brain function.

Elevated serum levels of CRP are considered a marker of systemic inflammation, and have been linked to several age-related conditions in humans, including cardiovascular disease, diabetes mellitus, and cognitive impairment (Cesari et al., 2003; De Rekeneire et al., 2006; Michaud et al., 2013). Higher CRP levels are also associated with reduced working memory (Bettcher et al., 2012); poorer executive function and processing speed (Tegeler et al., 2016); greater declines in visuospatial function (Warren et al., 2018); and smaller hippocampal volume across the lifespan (Wang et al., 2022). However, not all findings are consistent; discrepant findings may reflect differences in study design and sample characteristics, such as whether or not the participants being studied have an ongoing disorder (Carlier et al., 2021).

To date, few studies have investigated the relationship between genetic risk for CRP and cognitive function in typical aging. Those that have, are mostly lacking in statistical power or have focused on a limited number of individual CRP SNPs (~3 SNPs; for a review see, Stacey et al., 2017). For instance, one study used an unweighted PRS-CRP calculated using 47 GWAS significant SNPs and found that, after adjusting for sociodemographic and clinical confounders, contrary to hypotheses, higher PRS-CRP (and serum CRP) levels were significantly associated with better performance on a visuospatial memory test but not with reaction times (Milton et al., 2021). Investigation of PRS-CRP associations with a more comprehensive battery of cognitive tests is therefore warranted. Ultimately, if an association were confirmed, a PRS-CRP could be useful in prospectively identifying individuals at risk of both inflammatory conditions and poorer performance in specific cognitive tasks in adulthood. This would allow for the design of interventions such as exercise, anti-inflammatories, or brain training, to compensate for this predisposition (Bamidis et al., 2014; Melnikov et al., 2021).

We aimed to investigate the relationship between genetic risk for CRP levels and cognitive function in a sample of 7,817 individuals without dementia aged >50 years from the PROTECT study. Using the most powerful GWAS to date (i.e., N = 418,642; Han et al., 2020) we identified a PRS-CRP that explained 9.61% of the variance in serum CRP levels in an independent cohort (N = 268, age range = 20–84 years, females = 52.6%). We then assessed associations between PRS-CRP and performance on two cognitive batteries assessing a range of cognitive domains. Given evidence that CRP levels are negatively associated with cognitive function (Bettcher et al., 2012; Tegeler et al., 2016; Warren et al., 2018; Wang et al., 2022), we hypothesized that lower genetically predicted CRP levels would be related to better performance on the cognitive tests. Older individuals have the highest levels of CRP due to “inflammaging” (i.e., the age-related increase in systemic chronic inflammation, Fard and Stough, 2019; Gordleeva et al., 2020), and demonstrate more inter-individual variation in cognitive performance (see, Sánchez-Izquierdo and Fernández-Ballesteros, 2021), therefore we also used a median split to explore possible age-dependent associations specific to the oldest adults in our sample. Our results shed new and unexpected insights into the relationship between CRP levels and cognition in older adults.

2. Methods

2.1. Participants

Participants were recruited to the Platform for Research Online to investigate Genetics and Cognition in Aging study (PROTECT; http://www.protectstudy.org.uk/). PROTECT is a longitudinal UK-based online participant registry that aims to understand the impact of lifestyle, medical and genetic risk factors on cognitive health and dementia risk in older adults (Creese et al., 2021). At the time this project was conducted, the inclusion criteria for enrolling in PROTECT were (1) ≥50 years old; (2) no diagnosis of dementia; and (3) access to a computer and the internet. Volunteers were prospectively recruited from November 2015 through both local and national publicity.

Data collection was ongoing at the time of this study; therefore, a data freeze was implemented in October 2019 with data extracted for analyses up to this date. The sample in the current study was a subset of PROTECT study participants who had completed cognitive testing, provided a saliva sample for genotyping, and were identified as individuals of European ancestry based on genetic principal components (PCs). We selected individuals of European ancestry to match the ancestry of the sample from which the serum CRP GWAS summary statistics were derived for construction of the polygenic risk scores (Han et al., 2020).

Ethical approval was granted through the London Bridge National Research Ethics Committee (reference: 13/LO/1578) and informed consent obtained for all participants. The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimentation and with the Declaration of Helsinki 1975, as revised in 2008.

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