COVID-19 related outcomes among individuals with neurodegenerative diseases: a cohort analysis in the UK biobank

The coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was declared to be a pandemic by World Health Organization (WHO) in March 2020 [1]. As of September 28th 2021, the disease had led to 232,075,351 confirmed cases and 4,752,988 cases of death. Although most individuals contracted with COVID-19 experience rather mild symptoms [2], elderly people and individuals with chronic diseases are more prone to experience a severe disease course [3‐6].

Neurodegenerative diseases are a group of diseases with progressive loss of neurons in the central nervous system. Alzheimer’s disease (AD) is the most common neurodegenerative disease, characterized by impairment in memory, language, and problems in daily living activities, and is also commonly accompanied with non-cognitive symptoms such as depression [7]. AD affects about 5–7% of the population aged over 65 years worldwide [8]. With the early death of dopaminergic neurons, Parkinson’s disease (PD) mainly affects the motor system, leading to movement disorders typically presented as rest tremor, rigidity, bradykinesia, postural, and gait impairment [9]. Individuals with neurodegenerative diseases are a high-risk population during the COVID-19 pandemic, because of their advanced age and presence of other comorbidities [10‐12]. Self-isolation and social distancing due to COVID-19 may have further influence on individuals living with neurodegenerative diseases [13].

To date, only a handful of studies have assessed the association between neurodegenerative diseases and COVID-19, with inconclusive findings [14‐22]. This inconsistency may be attributable to different study design, varying sample size and the resulting statistical power, and varying degree of control for important confounders (e.g., comorbidity, lifestyle, and socioeconomic status). We summarized findings of the existing studies in Supplementary Table 1.

To this end, taking advantage of the rich information on lifestyle factors and the complete and timely updated follow-up data for somatic disease and COVID-19 infection in the UK Biobank, we aimed to assess the association between previous neurodegenerative diseases, including primary and vascular neurodegenerative diseases, and subsequent risk of COVID-19.

Among the 96,275 participants included in the analysis, 2617 (2.7%) had a pre-pandemic diagnosis of neurodegenerative disease (exposed group) with the other 93,658 (97.3%) included in the unexposed group (Fig. 1). The mean age at COVID-19 outbreak was 67.9 years and 46.4% of the participants were male (Table 1). We observed little difference in race/ethnicity, BMI, smoking, or alcohol use between the exposed and unexposed groups. However, individuals with neurodegenerative disease were older (74.2 years vs 67.7 years) and more likely to be male (53.0% vs 47.0%), and had lower socioeconomic status (annual household income <£18,000: 34.7% vs 19.8%), lower educational attainment (college or university degree: 20.8% vs 30.0%), greater Townsend deprivation score (− 0.74 vs − 1.20), and higher Charlson Comorbidity Index (2.62 vs 1.29), compared with the unexposed individuals.

As of June 14th, 2021, 17,938 individuals were diagnosed with any COVID-19, including 5749 individuals with inpatient COVID-19 and 1181 with COVID-19 related death. We observed an elevated risk of any COVID-19 (27.4% vs 18.4%), inpatient COVID-19 (14.5% vs 5.7%), and COVID-19 related death (7.5% vs 1.1%) among individuals with neurodegenerative disease compared with the unexposed individuals (Table 1). This corresponds to a fully adjusted OR of 2.47 (95%CI 2.25–2.71) for any COVID-19, 2.18 (95%CI 1.94–2.45) for inpatient COVID-19, and 3.67 (95%CI 3.11–4.34) for COVID-19 related death, after adjusting for all available confounders (Fig. 2).

In the analyses for subtypes of neurodegenerative diseases, the elevated risk of any COVID-19 was more pronounced for vascular neurodegenerative diseases, compared with primary neurodegenerative diseases (OR, 4.79 [95%CI 3.84–5.97] vs 2.17 [95%CI 1.95–2.41], p value for difference < 0.001) (Fig. 2). No difference was noted for inpatient COVID-19 or COVID-19 related death. We found an increased risk of all studied COVID-19 outcomes among individuals with PD as well as individuals with AD (Fig. 2).

Similar associations were observed across different groups of age, sex, BMI, smoking, alcohol use, annual household income, educational attainment, and Charlson Comorbidity Index (Table 2). A positive association for any COVID-19 was noted during all time periods (OR 1.49 [95%CI 1.13–1.97] before April 26th 2020, OR 4.00 [95%CI 3.11–5.15] during April 27th 2020-July 6th 2020, OR 1.72 [95%CI 1.47–2.01] during July 7th 2020 -December 16th 2020, and OR 2.52 [95%CI 2.15–2.96] from December 17th 2020 onward) (Table 2). No clear trend was observed for time since the first diagnosis of neurodegenerative diseases (Table 3). Finally, among participants with a positive test result for COVID-19, there was also an increased risk of COVID-19 related death among individual with neurodegenerative diseases than others (OR 2.08; 95%CI 1.71–2.53) (Table 4).

In the sensitivity analysis using a matched cohort design, including 2617 exposed individuals and 11,571 birth year- and sex- matched unexposed individuals, we obtained largely comparable results (Supplementary Fig. 1) as in the main analysis. The fully adjusted OR was 2.17 (95%CI 1.96–2.41) for any COVID-19, 2.17 (95%CI 1.89–2.48) for inpatient COVID-19, and 3.90 (95%CI 3.17–4.79) for COVID-19 related death. In the bias analysis, we found a positive association between neurodegenerative disease and all COVID-19 outcomes when assuming different degrees of underestimation of COVID-19 outcomes among individuals without neurodegenerative diseases, although the association was not statistically significant for any COVID-19 when assuming > 65% underestimation among individuals without neurodegenerative diseases (Supplementary Fig. 2).

To the best of our knowledge, this is the first cohort study to comprehensively assess the association between multiple neurodegenerative diseases and the risk of COVID-19 related outcomes. Among the UK Biobank participants who received at least one COVID-19 test, we found individuals with a previous neurodegenerative disease to be at an elevated risk of COVID-19, including any COVID-19 infection, hospitalization for COVID-19, and death due to COVID-19. The association was independent from multiple confounders, such as age and somatic comorbidities, and did not differ greatly between primary neurodegenerative diseases and neurodegenerative diseases with a primary vascular component. The subgroup analysis among individuals with a positive test result for COVID-19 showed that, compared to other people, individuals with neurodegenerative disease had further a higher risk of death, after contracting COVID-19. Taken together, these results suggest that neurodegenerative disease is associated with an increased susceptibility to COVID-19, especially the severe form.

The association between neurodegenerative diseases and COVID-19 has been discussued in nine previous studies, with inconsistent findings [14‐22]. Four cohort studies, conducted in the UK, Russia, and Italy, reported a positive association between dementia and COVID-19 hospitalization and death [14, 19‐21]. Beside a shorter follow-up period and limited number of COVID-19 cases, these studies did not fully control for some important cofounders, such as socioeconomic and lifestyle factors. Similarly, a moderate increase in COVID-19 mortality (30, 95%CI 13–49%) was observed among PD patients in a US cohort study, without however adjusting for comorbidities [22]. Null association was reported in two studies of PD, both with relatively small sample size [16, 17]. Using data from one single hospital in Wuhan, China, patients with AD were found to have a significantly shorter duration of hospital stay for COVID-19 [18]. To this end, the present study, based on a large community-based cohort and with careful consideration of selection bias and a wide range of potential confounders, demonstrated a clear association between various neurodegenerative diseases and a markedly increase risk of COVID-19, especially the severe and fatal form of COVID-19. This highlights the needs of special care or intervention, during the COVID-19 outbreak, for individuals with neurodegenerative diseases.

The underlying mechanisms for the observed association remain unclear. A possible explanation is the generally increased susceptibility to infection, possibly induced by dysregulated immune system inherently involved in the development of neurodegenerative diseases [28‐30], including alterations in the peripheral immune responses [31, 32]. In addition, chronic inflammation is commonly observed in neurodegenerative diseases and may also lead to increased risk of infection [30, 31]. We observed slightly higher OR for AD relative to PD, which might imply special pathways linking AD with COVID-19, in addition to common mechanisms for the entire spectrum of neurodegenerative diseases. Based on experimental studies, SARS-CoV-2 binds to the target cell via transmembrane protein angiotensin-converting enzyme 2 (ACE2), which is expressed in various of organs [33]. Given that elevated ACE2 expression level has been observed in AD patients [34], it is possible that the excess in ACE2 in AD provides more cellular receptors when exposed to SARS-CoV-2, and therefore increases the vulnerability to COVID-19.

The major strength of our study is the use of a large community-based cohort, where data on exposure and outcome were collected prospectively and independently. The large sample size made it possible to perform detailed analysis for different subtypes of neurodegenerative disease, as well as for individuals with different characteristics. In addition, the rich information on sociodemographic and medical conditions enabled us to adjust for a wide range of confounders. Also, the application of a matched-cohort design in the sensitivity analysis demonstrated the robustness of our findings to age, as an important confounder. Finally, as multiple data sources were used for the identification of COVID-19 status, we were able to study COVID-19 with different levels of severity, any COVID-19 infection, COVID-19 requiring inpatient care, and COVID-19 related death.

There were several limitations in this study. First, under ascertainment of COVID-19 cases, especially cases with mild or no symptoms, is a concern of all population-based studies for COVID-19. Individuals with chronic diseases (e.g., neurodegenerative diseases) might have different access to health care and therefore different access to COVID-19 test. For example, patients undergo non-COVID-19 related health care might receive additional COVID-19 test. Thus number of potential under ascertainment cases of mild and no symptoms COVID-19 cases in exposed group and unexposed group is likely differential and would lead to selection bias in a study aiming to examine the association between neurodegenerative diseases and COVID-19. As a result, in the main analysis, we restricted the analyses to individuals who had received at least one COVID-19 test, instead of studying the entire UK Biobank population. While the tested population is strongly influenced by the testing policy, especially in the beginning of the pandemic due to the limited testing capacity, they were restricted in the inpatients with typical syndrome of respiratory system. To address this, we further performed a bias analysis, assuming 5 to 100% underestimate of COVID-19 outcomes among individuals without neurodegenerative diseases, whereas no underestimate among individuals with neurodegenerative diseases, and found reassuringly positive associations in even the relatively extreme scenarios. Second, we had no information on place of residence (e.g., care home) for the study participants, which might raise a concern that the noted positive association might have been influenced by the spreading of COVID-19 in care homes, assuming that more individuals with neurodegenerative diseases were residing in care homes than others. However, the outbreak in UK care homes mainly occurred in spring 2020 (i.e., March to early May) [27]. Together, based on data from Whole Care Home Testing Programme, including test results from all 9081 care homes for 65+ in England, the positive rate of COVID-19 tests was as low as 3.9% (6747 out of 172,066) between 11th May and 7th June 2020 [35]. We believe therefore that the spreading of COVID-19 in care homes did not pertain to the entire period of our study. In subgroup analyses by calendar periods, we set the time points according to the changing of test policy (April 27th 2020, July 7th 2020) and the dominant variants in the UK (December 17th 2020) [36]. We observed constantly increased risk of COVID-19 outcomes among individuals with neurodegenerative diseases before April 26th 2020, during April 27th 2020-July 6th 2020, during July 7th 2020 -December 16th 2020, and from December 17th 2020 onward. If the spreading of COVID-19 in care homes indeed contributed heavily to our results, we should have expected a specifically high OR during July 7th 2020 -December 16th 2020, as regular COVID-19 tests have been offered in all care homes in the UK since July 7th 2020 [25]. We believe therefore that the spreading of COVID-19 in care homes was unlikely to explain completely our findings. This concern was further alleviated by the fact that we observed increased risk of COVID-19 related death in relation to neurodegenerative disease in the subgroup analysis of individuals tested positive for COVID-19. Third, somatic comorbidities were measured by diagnoses extracted from inpatient hospital data, as a result we might have missed milder comorbidities (e.g., diabetes) that did not require hospitalization. The adjustment of Charlson Comorbidity Index may not completely relieve the concern on confounding due to differential somatic conditions between individuals with neurodegenerative diseases and the unexposed group. Fourth, with only 5.5% response rate among the target population, the UK Biobank participants are not representative of the general population in the UK. Caution is therefore required when generalizing these findings to the whole UK or other populations [37]. Finally, as we defined neurodegenerative diseases according to inpatient hospital data, our findings might not be directly applicable to individuals with neurodegenerative diseases that are never attended by inpatient care.

Among the UK Biobank participants who underwent a test for SARS-CoV-2, a pre-existing diagnosis of neurodegenerative diseases was associated with a subsequently elevated risk of COVID-19, especially the severe form. Although validations from future studies are needed, these findings underscore the need for better surveillance and medical care for individuals with neurodegenerative diseases during the COVID-19 outbreak, both before and after contracting the infection.