Following COVID-19 hospitalization, patients’ serum neurodegenerative biomarkers were elevated to levels observed in individuals with Alzheimer disease (AD) dementia, and were associated with encephalopathy and worse outcomes, according to study findings published in Alzheimer’s & Dementia.

Hospitalized patients with COVID-19 are likely to experience neurologic complications, specifically encephalopathy, and about 50% are likely to experience long-term cognitive abnormalities. The mechanisms behind cognitive dysfunction in those with acute and post-acute COVID-19 are unclear. The objective of the current study was to assess blood biomarkers of neurodegeneration in patients hospitalized for COVID-19 without a history of dementia and understand how they correlate with neurologic complications and hospital outcomes.

The researchers conducted a retrospective analysis among patients with COVID-19 who were prospectively enrolled in the Study of Neurologic and Psychiatric Events in Acute COVID-19 (SNaP Acute COVID) study.

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SNaP Acute COVID is a prospective study of consecutive patients with COVID-19 who were hospitalized at 4 New York City–area hospitals within the same hospital system between March 10, 2020, and May 20, 2020. All patients were evaluated by a team of neurologists for the development of new neurologic disorders during hospitalization for SARS-CoV-2 infection. A total of 4491 patients were included in SNaP Acute COVID, 606 of whom exhibited new neurologic events and 3885 of whom did not display any neurologic events.

Study inclusion criteria were hospital admission, reverse-transcriptase polymerase chain reaction–positive SARS-CoV-2 infection from nasopharyngeal sampling, and consent to store blood biospecimens in the New York University Center (NYU) for Biospecimen Research and Development biorepository for utilization in experimental analyses. Control non-COVID-19 participants with blood samples that were banked before January 1, 2020 were chosen from the NYU Alzheimer’s Disease Research Center Clinical Core cohort. The following 3 control populations were included: (1) cognitively normal individuals; (2) individuals with mild cognitive impairment (MCI); and (3) individuals with dementia due to AD.

The primary study outcomes were comparisons of serum levels of total tau (t-tau), phosphorylated tau-181 (p-tau181), neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCHL1), amyloid beta (Aβ)40, Aβ42, the ratio of Aβ40 to Aβ4, and the ratio of p-tau181 to Aβ42 between patients hospitalized for COVID-19, according to the following criteria: (1) patients who developed toxic metabolic encephalopathy (TME) vs those who did not; (2) patients who died in the hospital or were discharged to hospice vs those who survived to hospital discharge; and (3) patients who were discharged home vs other discharge instructions.

Secondary outcomes were the comparison of serum biomarker levels among patients with COVID-19 to plasma biomarker levels of NfL, GFAP, and UCHL1 in control individuals without COVID who had normal cognition, MCI, or AD.

A total of 251 patients with COVID-19 were included in the final analysis. The median age among the patients with COVID-19 was 71 years (range, 60 to 83 years); 63% were male. In contrast, among the non-COVID-19 cognitively normal control individuals, the mean age was 71 years (range, 65 to 76 years), and 35% were male. Among the non-COVID-19 MCI control individuals, the mean age was 77 years (range, 70 to 86 years) and 20% were male, and among patients with AD but without COVID-19, the mean age was 82 years (range, 72 to 88 years) and 40% were male. 

In patients with COVID-19, mechanical ventilation was required in 31%, in-hospital deaths were reported among 25%, and discharge to home occurred in 53%. New neurologic events during hospitalization were reported in 48% (120 of 251) of patients, with the most common diagnoses reported being TME in 63% of patients and hypoxic/ischemic brain injury in 46%.

Elevations in neurodegenerative biomarkers among patients with COVID-19 were associated with older age and severity of COVID-19 illness. NfL, T-tau, and p-tau181 levels were most strongly linked to COVID-19 severity. Significant associations were also observed between p-tau181, NfL, GFAP, and elevated D-dimer levels. Compared with patients with COVID-19 with no new neurologic events, those in whom new neurologic events were reported during hospitalization exhibited statistically significant elevations in t-tau (P =.009), p-tau181 (P =.042), NfL (P =.006), and UCHL1 (P =.002) levels. Of note, neurodegenerative biomarker concentrations for t-tau,
p-tau181, GFAP, and NfL were even higher among patients with COVID-19 with TME vs those without TME.

The study had several limitations, including the possibility of some patients with COVID-19 having preclinical or undiagnosed cognitive impairment, measuring biomarkers at only one point without trajectory of these biomarkers, not having inflammatory marker data in control group individuals, limited availability of specimens for p-tau181, Aβ40, or Aβ42 analysis, the inability to compare p-tau181, Aβ40, or Aβ42 to control group individuals, and the lack of availability of cerebrospinal fluid specimens for biomarker analysis.

“Additional studies tracking trajectories of these biomarkers over time and their association with long-term cognitive outcomes among COVID-19 survivors are warranted,” the researchers concluded.

Disclosure: Some of the study authors have declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.


Frontera JA, Boutajangout A, Masurkar AV, et al. Comparison of serum neurodegenerative biomarkers among hospitalized COVID-19 patients versus non-COVID subjects with normal cognition, mild cognitive impairment, or Alzheimer’s dementia. Alzheimers Dement. Published online January 13, 2022. doi:10.1002/alz.12556