The effects of COVID-19 on cognitive performance in a community-based cohort: A COVID Symptom Study Biobank observational study

Background Cognitive impairment has been reported after many types of infection, including SARS-CoV-2. Whether deficits following SARS-CoV-2 improve over time is unclear. Studies to date have focused on hospitalised individuals with up to a year follow-up. The presence, magnitude, persistence and correlations of effects in community-based cases remain relatively unexplored. Methods Cognitive performance (working memory, attention, reasoning, motor control) was assessed in participants of a voluntary biobank in July, 2021 (Round 1), and April, 2022 (Round 2). Participants, drawn from the COVID Symptom Study smartphone app, comprised individuals with and without SARS-CoV-2 infection and varying symptom duration. Effects of COVID-19 exposures on cognitive accuracy and reaction time scores were estimated using multivariable ordinary least squares linear regression models weighted for inverse probability of participation, adjusting for potential confounders and mediators. The role of ongoing symptoms after COVID-19 infection was examined stratifying for self-perceived recovery. Longitudinal analysis assessed change in cognitive performance between rounds. Findings 3335 individuals completed Round 1, of whom 1768 also completed Round 2. At Round 1, individuals with previous positive SARS-CoV-2 tests had lower cognitive accuracy (N = 1737, β = −0.14 standard deviations, SDs) than negative controls. Deficits were largest for positive individuals with ≥ 12 weeks of symptoms (N = 495, β = −0.22 SDs). Effects were comparable to hospital presentation during illness (N = 281, β = −0.31 SDs), and 10 years age difference (60-70 years vs. 50-60 years, β = −0.21 SDs) in the whole study population. Stratification by self-reported recovery revealed that deficits were only detectable in SARS-CoV-2 positive individuals who did not feel recovered from COVID-19, whereas individuals who reported full recovery showed no deficits. Longitudinal analysis showed no evidence of cognitive change over time, suggesting that cognitive deficits for affected individuals persisted at almost 2 years since initial infection. Interpretation Cognitive deficits following SARS-CoV-2 infection were detectable nearly two years post infection, and largest for individuals with longer symptom durations, ongoing symptoms, and/or more severe infection. However, no such deficits were detected in individuals who reported full recovery from COVID-19. Further work is needed to monitor and develop understanding of recovery mechanisms for those with ongoing symptoms. Funding Chronic Disease Research Foundation, Wellcome Trust, National Institute for Health and Care Research, Medical Research Council, British Heart Foundation, Alzheimer’s Society, European Union, COVID-19 Driver Relief Fund, French National Research Agency. Evidence before this study Abstracts were screened from a PubMed search query (COVID-19) AND (long COVID) AND (cognitive impairment), which returned 409 results between 2020 and January 20, 2023. Multiple systematic reviews and meta-analyses reported consistent observation of cognitive deficits following SARS-CoV-2 infection. Most studies of cognitive impairment have used small samples of less than 200 participants (including any controls), hospitalised cohorts, and measured cognitive impairment through self-report or dichotomised quantitative scales. Only one study was found with a sample size of more than 1,000 individuals, included cases and controls across both community and hospital settings, and used objective cognitive testing that allowed quantitative estimation of the scale of any cognitive impairment. Previous studies have also been limited insofar as focusing on earlier infections in the first year of the COVID-19 pandemic, prior to introduction of vaccination and emerging variants. Studies focusing on longitudinal follow-up for those hospitalised with COVID-19 or with long COVID have found low rates of full recovery from long-term symptoms at up to one year since infection, including cognitive impairment. Added value of this study We report quantitatively on cognitive impairment following SARS-CoV-2 infection, from a large dataset of 4,000 individuals with and without test-confirmed SARS-CoV-2 infection and a range of associated symptom durations, with mostly community-based cases. Importantly, we undertook two rounds of cognitive testing allowing longitudinal tracking of cognitive performance. Our longitudinal methods allowed us to report on deficits up to two years since infection, and following infections with SARS-CoV-2 variants that have emerged over 2021 and 2022, not previously studied in the context of COVID-19 and cognition. Implications of all the available evidence This study adds to existing evidence of cognitive deficits following SARS-CoV-2 infection, but finds important exceptions. At initial testing in mid-2021, cognitive deficits are not found for individuals who self-report as feeling recovered from COVID-19, even for those with longest symptom duration. In follow-up testing in mid-2022, we find that deficits appear persistent for those with earlier infections and ongoing symptoms, consistent with previous smaller studies. More research is required to monitor those experiencing persistent cognitive impairment and understand the mechanisms underlying recovery. ### Competing Interest Statement NJC is supported by NIHR via their institution; CHS is supported by Alzheimer's Society via their institution and is Scientific Advisor to BrainKey; WRT is a part time employee H2 Cognitive Designs, who market the online testing platform used in this study; PJH is the Chief Executive and Co-founder of H2 Cognitive Designs LTD, who market the online testing platform used in this study; M. Modat reports funding support from UK Department of Health and Social Care, UKRI, EPSRC and Wellcome Trust via their institution; SO is supported by French National Research Agency, Wellcome Trust, EPSRC and UK Department of Health and Social Care; A. Hampshire is an owner/director of Future Cognition Ltd and co-owner and co-director of H2 Cognitive Designs, which provide cognitive assessment services and software for third parties; CJS is supported by UKRI, Wellcome Trust and Chronic Disease Research Foundation via their institution, and declares a consultancy contract with ZOE Ltd. All other authors make no disclosures. ### Funding Statement The CSS Biobank is supported by the Chronic Disease Research Foundation. Authors affiliated with King's College London are also supported by the Wellcome Engineering and Physical Sciences Research Council Centre for Medical Engineering at King's College London (KCL, WT [203148/Z/16/Z]) and the UK Department of Health via the National Institute for Health and Care Research (NIHR) comprehensive Biomedical Research Centre award to Guy's & St Thomas' NHS Foundation Trust (GSTT) in partnership with KCL and King's College Hospital NHS Foundation Trust. Investigators also received support from Medical Research Council, British Heart Foundation, Alzheimer's Society, European Union, NIHR (including CONVALESCENCE study [COV-LT-0009]), COVID-19 Driver Relief Fund, Wellcome Trust [215010/Z/18/Z], and the NIHR-funded BioResource and Clinical Research Facility. NJC was supported by NIHR [COV-LT-0009]. RSP is a fellow on the Multimorbidity Doctoral Training Programme for Health Professionals, which is supported by the Wellcome Trust [223499/Z/21/Z]. AH and VG are supported by the NIHR Imperial Biomedical Research Centre. WT is supported by the EPSRC Centre for Doctoral Training in Neurotechnology. MHM & KJD are supported by the King's Together Rapid COVID-19 Call award. MHM is supported by the Wellcome Trust [106223/Z/14/Z]. KJD thanks Fondation Dormeur, Vaduz for funding equipment. SO was supported by the French government, through the 3IA Cote d'Azur Investments in the Future project managed by the National Research Agency (ANR) with the reference number [ANR-19-P3IA-0002]. ZOE Ltd provided in-kind support for all aspects of building, running and supporting the COVID Symptom Study app and service to all users worldwide. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Yorkshire & Humber NHS Research Ethics Committee gave ethical approval for this work (Ref: 20/YH/0298) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Access to data in the CSS Biobank is available to bona fide health researchers on application to the CSS Biobank Management Group. Further details are available online at including application forms and contact information. Analysis code used in this study will be made available openly on Github at . Anonymised COVID Symptom Study data are available to researchers to be shared with researchers according to their protocols in the public interest through Health Data Research UK (HDRUK) and Secure Anonymised Information Linkage consortium, housed in the UK Secure Research Platform (Swansea, UK) at .