Alzheimer’s And Parkinson’s Diseases Predict Different COVID-19 Outcomes: A UK Biobank Study Part 2
May 31, 2024
3. Results
3.1. AD and PD Diagnoses Are Associated with an Increase in SARS-CoV-2 Infections in the UKBiobank Cohort
To explore the links between neurodegenerative diseases and COVID-19, we first estimated the risk between COVID-19 and chronic diseases. Chronic diseases often coexist in older adults [36-38].
As the population ages, more and more people are suffering from neurodegenerative diseases. Neurodegenerative diseases refer to a class of diseases caused by the death or degeneration of brain cells or neurons, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, etc. These diseases seriously affect the health and quality of life of patients, the most obvious manifestation of which is the impact on memory.
As the disease progresses, the patient's memory will gradually decline. They may forget the names of their family members, how to use daily necessities, how to walk, etc., which puts a great burden on the patient's family and relatives. However, although neurodegenerative diseases can affect memory, we still have to face these diseases positively and try to reduce their negative impact on life.
Nursing care and drug therapy are both effective ways to alleviate memory impairment caused by neurodegenerative diseases. Nursing care includes providing a comfortable and warm environment and helping patients with daily living activities. Drug therapy can improve patients' neurological symptoms, especially Alzheimer's patients, and can delay the development of memory impairment in the early stages of the disease. In addition, traditional Chinese medicine can also help improve patients' conditions, enhance their body's immunity, and achieve the purpose of alleviating memory impairment.
Not only that, we can also take some positive measures to prevent the occurrence of neurodegenerative diseases. First, we should maintain an optimistic attitude, make more friends, participate in social activities, and exercise. Secondly, maintain a healthy lifestyle, adhere to good eating habits, get enough sleep, and avoid smoking and drinking. Finally, we can stimulate the brain and enhance our memory by embracing new knowledge, learning new skills, and challenging ourselves.
In short, although neurodegenerative diseases have an irreversible impact on memory, we can still take measures to alleviate the condition and prevent the occurrence of the disease. We should pay more attention to the needs and psychology of patients, provide comprehensive care, and actively seek the latest treatments. Most importantly, we should remain optimistic, face the challenges and difficulties in life, and firmly believe that we will be able to overcome the disease and regain a happy and healthy life. It can be seen that we need to improve memory, and Cistanche can significantly improve memory because Cistanche has antioxidant, anti-inflammatory, and anti-aging effects, which can help reduce oxidative and inflammatory reactions in the brain, thereby protecting the health of the nervous system. In addition, Cistanche can also promote the growth and repair of nerve cells, thereby enhancing the connectivity and function of the neural network. These effects can help improve memory, learning ability, and thinking speed, and may also protect against the onset of cognitive dysfunction and neurodegenerative diseases.
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Therefore, we assessed their risk after adjusting for other existing comorbidities (see Figure 1A for the workflow) for an aged and predominantly white cohort in Great Britain (Figure 1B, C). We found that a pre-existing diagnosis of dementia was associated with the largest increase in the likelihood of testing positive for COVID-19 (OR 3.25; 95% CI 2.73–3.87).
This was followed by an increased waist-to-hip ratio (OR 3.07; 95% CI 2.26–4.17), a low education level (OR 1.67; 95% CI 1.38–2.02), a higher number of people per household (OR 1.05; 95% CI 1.03–1.07) and an increased TSDI (OR 1.03; 95% CI 1.02–1.04) (Figure 2A and Supplementary Table S3). Our findings confirm previous studies showing that dementia predicts one of the highest risks of COVID-19 in elderly individuals [16,39].
Furthermore, consistent with previous observations [40], our primary analysis identified white ethnicity (OR 0.72; 95% CI 0.66–0.77), cancer (OR 0.81; 95% CI 0.74–0.89), and decreasing age (OR 0.97; 95% CI 0.97–0.97) as significant predictors of SARSCoV-2 infectivity after adjusting for multiple confounding factors (Figure 2A).
As recent studies highlighted links between the global burden of dementia and COVID-19 death [39], we next assessed whether the diagnosis of dementia increased the risk of COVID-19 mortality in the UK Biobank participants. Similar to the COVID-19 models, we found that a diagnosis of dementia was associated with the largest risk of mortality from COVID-19 (OR 4.32; 95% CI 3.33–5.60), followed by male sex (OR 1.44; 95% CI 1.20–1.73), increased age (OR 1.09; 95% CI 1.08–1.07), and an increased TSDI (OR 1.07; 95% CI 1.05–1.09) (Figure 2B and Supplementary Table S4).
Cancer was negatively associated with an increased risk of mortality in our cohort (OR 0.56; 95% CI 0.44–0.72). Given the prominent role of dementia in COVID-19 diagnoses, we next sought to increase the granularity of our analysis by examining distinct subtypes of dementia. For the analysis of our PD cohort, we observed that only a small subset of patients was diagnosed with dementia (n = 10).
Given the small sample size, we proceeded to exclude PD individuals with clinically diagnosed dementia from our analysis and included only PD patients without dementia (n = 142). Overall, the cumulative incidence of PD and AD diagnosis among COVID-19-positive patients in our cohort was 1.7% and 1.6%, respectively. Our results show that a diagnosis of AD was strongly associated with SARS-CoV-2 infectivity, with AD patients showing the greatest susceptibility to SARS-CoV-2 infectivity compared to individuals without AD (OR 4.15; 95% CI 3.22–5.34).
We also found that an increase in the waist-to-hip ratio (OR 3.08; 95% CI 2.27–4.19) or pre-existing vascular dementia (OR 2.51; 95% CI 1.69–3.71) were also positively associated with COVID-19 (Figure 3A and Supplementary Table S5).
PD diagnosis also emerged as a strong positive predictor of COVID-19 (OR 1.74; 95% CI 1.34–2.27), although the effect was smaller than that for AD diagnosis. Low education level (OR 1.65; 95% CI 1.36–2.0), a higher number of people per household (OR 1.05; 95% CI 1.03–1.07), or an increased TSDI (OR 1.03; 95% CI 1.02–1.04) emerged as significant predictors of a positive COVID-19 diagnosis (Figure 3).
Our analysis shows that patients of white ethnicity (OR 0.72; 95% CI 0.66–0.77) or with a pre-existing diagnosis of cancer (OR 0.81; 95% CI 0.72–0.88) were at lower risk of infection in our cohort while increasing age did not predict an increased risk of infection (OR 0.97; 95% CI 0.97–0.97; Figure 3A).
We further investigated whether there was any difference in the risk of testing positive for COVID-19 in participants with Parkinsonism (n = 157) compared to a subset of patients with PD (n = 142).
We show that including all participants with parkinsonism led to similar results (OR 1.71; 95% CI 1.37–2.14; Supplementary Table S6). We conclude that diagnoses of AD, vascular dementia, and PD increased the risk of testing positive for COVID-19 in UK Biobank participants.
3.2. AD Patients Are at Higher Risk of COVID-19 Death
Although our results show that patients with AD, PD, and vascular dementia are at increased risk of contracting COVID-19, it remains unclear whether the presence of neurodegenerative disorders may exacerbate the risk of mortality in COVID-19 patients.
To address this issue, we examined the characteristics and outcomes of all COVID-19 patients in the cohort using a binary multivariable regression model (Figure 3B and Supplementary Table S7).
In terms of neurodegenerative diseases, a diagnosis of frontotemporal dementia (OR 16.36; 95% CI 5.44–49.15) was associated with the largest risk of COVID-19 death, but this observation suffers from a small sample size (n = 6), so we did not explore frontotemporal dementia further in our analysis. We observed that diagnoses of AD (OR 4.17; 95% CI 2.87–6.05) were associated with COVID-19 death but not diagnoses of PD or vascular dementia.
In our model, a pre-existing diagnosis of cancer was negatively associated with COVID-19 death (OR 0.63; 95% CI 0.51–0.79), and no significant association was found with diabetes, C-reactive protein levels or ethnicity and COVID-19 death (Figure 3B).
We also found that a higher TSDI increased the risk of COVID-19 adverse outcomes (OR 1.07; 95% CI 1.05–1.09), while an increased waist-to-hip ratio (OR 5.83; 95% CI 2.18–15.58) or male sex (OR 1.38; 95% CI 1.16–1.65) were positively associated with COVID-19 death, but this relationship did not reach statistical significance. We next focused on the role of AD in COVID-19-related deaths.
We first built a model that contained only participants with a positive AD diagnosis. Using this model, we found that none of the previously mentioned comorbidities were significant. This observation indicates that participants with AD were at higher risk of dying from COVID-19, independent of age, sex, and other comorbidities (Supplementary Table S8).
We used a similar workflow to further show that a diagnosis of PD was not a predictor of COVID-19-related death. In our model containing only participants with a positive PD diagnosis, we show that age, the TSDI, and obesity were significant predictors of COVID-19-related death, indicating that other comorbidities in participants with PD may explain their risk of dying from COVID-19 (Supplementary Table S9).
4. Discussion
Despite considerable uncertainty in estimates of COVID-19 outcomes, age and comorbid medical conditions are consistently associated with adverse health outcomes in hospitalized COVID-19 patients [15].
The incidence of neurological conditions, including dementia and neurodegenerative diseases, increases with age, and it has recently been proposed that individuals with a pre-existing diagnosis of dementia may be at increased risk of developing COVID-19 [16].
In previous viral outbreaks of respiratory pathogens, including severe acute respiratory syndrome, Middle East respiratory syndrome, and H1N1 influenza, several reports also highlighted the presence of neurological comorbidities in affected patients [41,42].
In the present study, we found that the largest risk factor associated with COVID-19 was a pre-existing diagnosis of dementia associated with AD, vascular dementia, or PD.
However, while the diagnosis of AD also predicted an increased risk of COVID-19 mortality, our findings suggest that COVID-19 mortality among PD and vascular dementia patients does not differ from that in the general population.
Thus far, several studies have suggested a relationship between COVID-19 and neurodegenerative disorders. An early report [19] this year showed that a dementia diagnosis was associated with the largest increase in the risk of COVID-19 in the UK Biobank based on a smaller cohort of 507 COVID-19-positive patients from England aged 65 and older.
Dementia has also been found to increase the risk of in-hospital mortality in a large cross-sectional analysis of 20,133 patients already hospitalized for COVID-19 in the UK [13], a finding later replicated by two cohorts, retrospective studies [14,15]. However, these studies mostly focused on hospitalized individuals and did not include data on patients managed in community settings, such as domestic residences.
In addition, in line with government guidelines, testing procedures were limited to individuals with COVID-19 symptoms, meaning that available data fail to include the growing number of people who are asymptomatic or are self-isolating at home due to mild symptoms [13]. Using granular data from the UK Biobank, we developed a more robust analysis pipeline since all participants in our dataset received COVID-19 testing.
Because a large proportion of SARS-CoV-2 infections are asymptomatic, this screening protocol is more sensitive for the analysis of COVID-19 and mortality rates among people diagnosed with neurodegenerative diseases. Our results indicate that AD patients are at increased risk of COVID-19. These findings expand a recent analysis of 1091 COVID-19-positive individuals from the UK Biobank.
In this study, Zhou and colleagues employed a logistic regression analysis of pre-existing conditions that are overrepresented in patients with COVID-19 and showed that AD was the most significant risk factor for COVID-19, although its association with increased COVID-19 mortality was not investigated [43]. Here, we build on these earlier observations to show that AD is a major risk factor associated with COVID-19 mortality after accounting for a large number of comorbidities. Several features of AD may increase the risk of COVID-19 adverse outcomes.
First, the neuropathology of AD could facilitate COVID-19 complications. Increasing evidence from animal studies suggests that amyloid fibrils induce microglial activation and increased activation of the type-1 interferon (IFN) pathway, a crucial component of COVID-19 [44]. Current theories propose that the IFN response in AD may synergize with COVID-19 upon SARS-CoV-2 infection, creating the 'perfect storm' of excessive immune responses and thus exacerbating pathology [45].
Supporting the hypothesis of a neurobiological link between AD and COVID-19 mortality, a recent pathological examination of post-mortem tissue from AD patients demonstrated that the protein expression levels of angiotensin-converting enzyme 2 (ACE2), the entry receptor for SARS-CoV-2, were upregulated in the brains of AD patients [46].
This finding raises the hypothesis that higher ACE2 expression may underscore higher viral load in the brains of AD patients, corroborating a potential link between AD neuropathology and COVID-19 mortality [47].
Finally, the social behavior of patients with dementia and AD must be considered. Cognitive decline may compromise the ability of individuals with AD to follow the recommendations of public health authorities, increasing the likelihood of contagion and the need for carers [48].
Behavioral and psychological symptoms (BPSD) of dementia and AD, such as motor agitation, intrusiveness, or wandering, may further undermine efforts to maintain isolation.
We also found that PD is associated with a heightened risk of SARS-CoV-2 infectivity but not mortality. This is consistent with two recent studies from Italy showing increased COVID-19 mortality rates among PD patients. One group gathered clinical information on 120 community-dwelling PD patients and reported a mortality rate of 20%, a value significantly higher than that of the general population [49].
The second study found that PD patients of older age (>78 years) displayed increased susceptibility to COVID-19 death compared to younger patients [20]. However, both studies used clinically suspected (nonlaboratory confirmed) COVID-19 cases, which complicates their interpretation.
As noted by the authors, the increased susceptibility to COVID-19 may have resulted in some patients being incorrectly identified as COVID-19-positive, thus leading to a misclassification of COVID-19-related deaths. Moreover, the accuracy of prevalence data might further be hampered by the existence of asymptomatic cases and the lack of population screening campaigns in Italy.
Our results support those of a recent case-controlled study that showed that PD was not associated with any apparent risk of morbidity and mortality compared to the general population [22]. Although the biological basis for the higher mortality rate in AD compared to PD patients remains to be elucidated, a recent commentary suggested that PD neuropathology itself might exercise a neuroprotective effect against COVID-19 [50].
For instance, SARSCoV-2 binds to the ACE2 receptor, which is highly expressed in dopaminergic neurons of the striatum [51]. However, PD-related neuropathology induces significant degeneration of these neurons, raising the hypothesis of reduced neuroinvasion in these patients, as proposed elsewhere [50].
Second, increased neuronal expression of α-synuclein following acute West Nile virus infection suggests that this protein could function as a native antiviral factor within neurons [52]. Finally,severalf PD drugs have been hypothesized to play a therapeutic role in COVID-19. Among these, accumulating evidence shows that amantadine may inhibit viral replication and protect against severe outcomes in PD patients [53].
The proposed mechanism of action involves a disruption of the lysosomal machinery needed for viral replication [54], and there is preliminary evidence of a protective effect against COVID-19 in a small cohort of PD patients, all taking L-DOPA and having tested positive for COVID-19 [55]. In the present study, none of the PD patients receiving amantadine treatment developed severe complications from COVID-19, and only one patient tested positive for SARS-CoV-2 (Supplementary Tables S10 and S11).
Although limited by a small sample size, our preliminary analysis is in line with the hypothesis that amantadine may exert a protective effect against both COVID-19 and mortality. Further clinical studies should be conducted to corroborate the therapeutic utility of amantadine for the treatment of COVID-19.
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