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COVID-19 has been associated with a threefold increased risk of Alzheimer’s disease (AD) and a doubling of Parkinson’s disease (PD) risk, a new study suggests. However, the research also showed there was no excess risk of these neurologic disorders following COVID than other respiratory infections such as influenza or community-acquired bacterial pneumonia.
Considering these results, study investigator Pardis Zarifkar, MD, Department of Neurology, Rigshospitalet, Copenhagen University Hospital, Denmark, urged doctors to “keep an eye on” COVID patients and use “a critical mindset” if these patients present with neurologic issues.
“They should consider whether the patient’s condition is something new or if there were already signs and symptoms before they had COVID-19,” she told Medscape Medical News.
The findings were presented at the Congress of the European Academy of Neurology (EAN) 2022 and published online June 23 in Frontiers in Neurology.
“Surprising” Increased Risk
Previous research shows more than 80% of patients hospitalized with COVID-19 have neurologic symptoms including anosmia, dysgeusia, headache, dizziness, memory and concentration difficulties, fatigue, and irritability.
However, it’s unclear whether COVID- 19 affects the risk for specific neurologic diseases and if so, whether this association differs from other respiratory infections.
From electronic health records covering about half the Danish population, researchers identified adults who were tested for COVID-19 or diagnosed with community-acquired bacterial pneumonia from February 2020 to November 2021. They also flagged individuals with influenza in the corresponding prepandemic period (February 2018 to November 2019).
Zarifkar noted influenza A or B and community-acquired bacterial pneumonia are two of the most common respiratory tract infections.
Investigators tracked neurologic diseases up to 12 months after a positive test. They looked at two neurodegenerative diseases, AD and PD, as well as cerebrovascular disorders including ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage.
The study included 43,262 individuals with a positive COVID test without a history of influenza A/B in the past year and 876,356 without a positive COVID test. It also included 1474 individuals with community acquired pneumonia without a history of COVID and 8102 with influenza A or B.
“We wanted to investigate whether COVID-19 is really that much worse than all these other common respiratory infections that we have had for ages and see every single year,” said Zarifkar.
After 12 months, the relative risk (RR) for AD was 3.4 (95% CI, 2.3 – 5.1) in the COVID positive group vs the COVID negative group. The risks were greater among inpatients vs outpatients.
These results were rather unexpected, said Zarifkar. “I would have expected a small increase, but the extent of the increase was quite surprising.”
However, there was no difference when comparing the COVID-19 group to the influenza or bacterial pneumonia groups, which Zarifkar said was “very reassuring.”
The findings were similar for PD, where there was a 2.2-fold increased risk of a PD diagnosis within the first 12 months in COVID positive individuals compared with COVID negative people (RR 2.2; 95% CI, 1.5 – 3.4). Again, there was no excess risk compared with influenza or bacterial pneumonia.
Zarifkar believes a “constellation” of factors may explain higher risks of these diagnoses in COVID patients. Part of it could be a result of neuroinflammation, which can lead to a toxic accumulation of beta amyloid in AD and alpha-synuclein in PD, said Zarifkar.
“It can accelerate a neurodegenerative disease already in the making,” she said. But perhaps the biggest driver of differences between the groups is the “scientific focus” on COVID patients, she said.
“In Denmark, almost everyone who has had COVID-19, especially severe COVID-19, is offered some sort of cognitive testing, and if you hand out MoCAs [Montreal Cognitive Assessments] which is the cognitive test we use, to almost everyone you’re meeting, you’re going to catch these disorders earlier than you might have otherwise.”
As for cerebrovascular disorders, the study showed an increased risk of ischemic stroke in COVID-positive vs COVID-negative subjects at 12 months (RR, 2.87; 95% CI, 2.2 – 3.2).
The relatively strong inflammatory response associated with COVID-19, which may create a hypercoagulable state, may help explain the increased ischemic stroke risk in COVID patients, said Zarifkar.
The study did not show an increased risk for subarachnoid hemorrhage in COVID-positive compared with COVID-negative subjects but did reveal an increased risk of intracerebral hemorrhage after 12 months (RR, 4.8; 95% CI, 1.8 – 12.9).
This could be explained by COVID positive subjects having a higher risk for ischemic stroke and receiving thrombolysis that may increase risk for bleeding in the brain. However, an analysis accounting for medication use found differences in thrombolysis rates didn’t change the result, said Zarifkar.
It’s also possible that extracorporeal membrane oxygenation and mechanical ventilation — interventions more frequently used in COVID-19 patients — may increase the risk for bleeding in brain, she added.
Researchers did not find an increased risk for multiple sclerosis, myasthenia gravis, Guillain-Barré syndrome, or narcolepsy in COVID patients. However, Zarifkar noted that it can take years to detect an association with autoimmune disorders.
The investigators did not stratify risk by disease severity, although this would be an important step, she said.
“The threshold of being admitted to the hospital with COVID-19 has been much lower than for influenza or bacterial pneumonia where you’re typically quite ill before you’re admitted, so this might actually dilute the findings and underestimate our findings.”
A national, registry-based study that includes the entire Danish population and additional information on vaccination status, virus variants, socioeconomic status, and comorbidities is needed, said Zarifkar.
The study was supported by Lundbeck Foundation and Novo Nordisk. Zarifkar reports no relevant financial relationships.
Congress of the European Academy of Neurology (EAN) 2022. Abstract A-22-03666. Presented June 25, 2022.
Front Neurol. Published June 23, 2022. Full text