Olfactory dysfunction but not COVID‐19 severity predicts severity of cognitive sequelae following SARS‐CoV‐2 infection in Amerindian older adults

Abstract

Background COVID‐19 has affected more than 380 million people. Infections may result in long term sequelae, including neuropsychiatric symptoms. In older adults COVID‐19 sequelae resemble early Alzheimer’s disease, and may share risk factors and blood biomarkers with it. The Alzheimer’s Association Consortium on Chronic Neuropsychiatric Sequelae of SARS‐CoV‐2 infection (CNS SC2) established harmonized definitions, ascertainment and assessment methodologies to evaluate and longitudinally follow up cohorts of older adults with exposure to COVID‐19. We present one year data in a prospective cohort from Argentina. Method Participants (n = 766) are older adults (≥60 years) recruited from the provincial health registry containing all SARS‐CoV‐2 testing data. We randomly invite older adults stratified by PCR COVID‐19 testing status regardless of symptom severity, between 3 and 6 months after recovery. Assessment includes interview with the Schedules for Clinical Assessment in Neuropsychiatry (SCAN) and Clinical Dementia Rating scale (CDR); neurocognitive assessment; emotional reactivity scale; and neurological assessment including semiquantitative olfactory function test, motor function, coordination and gait. Result We assessed 88.4% infected participants and 11.6 % controls. Education is 10.36 ± 5.6 years and age is 66.9 ± 6.14 years. Level of care during COVID‐19 is described in Figure 1. Normalized cognitive Z‐scores categorize the cohort in 3 groups with decreased performance compared to normal cognition: memory only impairment (Single‐domain,11.7%); impairment in attention+executive function without memory impairment (Two‐domain, 8.3%); and multiple domain impairment (Multiple domain,11.6%). Logistic regression showed that severity of anosmia, but not clinical status, significantly predicts cognitive impairment. No controls had olfactory dysfunction. Cognitive impairment is defined as Z‐scores below (‐ 2) (Table 1). Clinical assessment with SCAN revealed functional memory impairment in two thirds of infected patients (CDR ≥ 1), which was severe in half of them. Phone‐based follow up at 1 year revealed high adherence (4 participants declined). Five were deceased at follow up. Rates of re‐infection (between 10 and 23%) were not affected by the vaccination schedule (Table 2). Conclusion The longitudinal cohort had very high adherence. Persistent cognitive and functional impairment after SARS‐CoV‐2 infection is predicted by persistent anosmia but not by the severity of the initial COVID‐19 disease.

Integrating the Patient’s Voice into the Research Agenda for Treatment of Chemosensory Disorders

“…The fact that the elderly disproportionately develop severe COVID and long COVID raises the concern that olfactory impairment associated with COVID may increase the population's risk for Alzheimer’s disease. At the 2022 Alzheimer’s Association International Conference Gonzales-Aleman et al presented data from 766 Amerindian participants that demonstrated better prediction of cognitive impairment following COVID infection from severity of anosmia than from clinical status ( Gonzales-Aleman et al 2022 ). A study by Wang et al (2022) using electronic health records of both inpatient and outpatient visits between 2/2020 and 5/2021, revealed a significant increase in new-onset AD within 360 days after initial COVID diagnosis.…”

Type I interferon signaling, cognition and neurodegeneration following COVID-19: update on a mechanistic pathogenetic model with implications for Alzheimer’s disease

“…In our model, IFN-I dysregulation occurs in the setting of peripheral infection and is communicated centrally via sites such as the olfactory bulb, the brainstem nuclei and the blood–brain barrier ( Meinhardt et al, 2021 ; Krasemann et al, 2022 ). Sites specifically vulnerable to dysregulated IFN-I such as the olfactory bulb and the hippocampus ( Bayat et al, 2022 ; Stępień et al, 2023 ) may furthermore readily account for both clinical ( Gonzalez-Aleman et al, 2022 ) and neuropathological ( Lou et al, 2021 ) manifestations of the CNS involvement in COVID-19.…”

“…In our model, IFN-I dysregulation occurs in the setting of peripheral infection and is communicated centrally via sites such as the olfactory bulb, the brainstem nuclei and the blood-brain barrier (Meinhardt et al, 2021;Krasemann et al, 2022). Sites specifically vulnerable to dysregulated IFN-I such as the olfactory bulb and the hippocampus (Bayat et al, 2022;Stępień et al, 2023) may furthermore readily account for both clinical (Gonzalez-Aleman et al, 2022) and neuropathological (Lou et al, 2021) manifestations of the CNS involvement in COVID-19. The generation of amyloid-beta and hyperphosphorylated tau, molecules that we currently recognize as inducers of innate immunity (Rexach et al, 2020;Roy et al, 2020;Jin et al, 2021;Roy et al, 2022;Vavougios et al, 2022a;Udeochu et al, 2023), can in turn sustain pathogenic IFN-I in a feed-forward manner acting as danger associated molecular pattern (Asai et al, 2015;Bolós et al, 2016) in a process that has been shown to prime microglia towards phenotypes specifically associated with the earlier stages of neurodegenerative disease (Roy et al, 2020;Jin et al, 2021;Magusali et al, 2021;Udeochu et al, 2023).…”