Introduction: Coronavirus disease 2019 (COVID-19) has caused >3.5 million deaths worldwide and affected >160 million people. At least twice as many have been infected but remained asymptomatic or minimally symptomatic. COVID-19 includes central nervous system manifestations mediated by inflammation and cerebrovascular, anoxic, and/or viral neurotoxicity mechanisms. More than one third of patients with COVID-19 develop neurologic problems during the acute phase of the illness, including loss of sense of smell or taste, seizures, and stroke. Damage or functional changes to the brain may result in chronic sequelae. The risk of incident cognitive and neuropsychiatric complications appears independent from the severity of the original pulmonary illness. It behooves the scientific and medical community to attempt to understand the molecular and/or systemic factors linking COVID-19 to neurologic illness, both short and long term. Methods: This article describes what is known so far in terms of links among COVID-19, the brain, neurological symptoms, and Alzheimer's disease (AD) and related dementias. We focus on risk factors and possible molecular, inflammatory, and viral mechanisms underlying neurological injury. We also provide a comprehensive description of the Alzheimer's Association Consortium on Chronic Neuropsychiatric Sequelae 4 of 24 DE ERAUSQUIN ET AL.of SARS-CoV-2 infection (CNS SC2) harmonized methodology to address these questions using a worldwide network of researchers and institutions.Results: Successful harmonization of designs and methods was achieved through a consensus process initially fragmented by specific interest groups (epidemiology, clinical assessments, cognitive evaluation, biomarkers, and neuroimaging). Conclusions from subcommittees were presented to the whole group and discussed extensively.Presently data collection is ongoing at 19 sites in 12 countries representing Asia, Africa, the Americas, and Europe.Discussion: The Alzheimer's Association Global Consortium harmonized methodology is proposed as a model to study long-term neurocognitive sequelae of SARS-CoV-2 infection.

Background COVID‐19 has affected more than 150 million people. The causal coronavirus, SARS‐CoV‐2 has infected twice as many individuals who have remained asymptomatic. COVID‐19 includes central nervous system (CNS) manifestations and may result in chronic neuropsychiatric sequelae. Risk factors for COVID‐19 sequelae overlap with those for Alzheimer’s disease (AD), particularly older age and ApoE4 status. 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 variable exposure to COVID‐19. We present preliminary data from CNS SC2 in a prospective cohort of 234 older adult Amerindians from Argentina. Method Participants are ≥ 60 years recruited from the health registry of the Province of Jujuy containing all SARS‐CoV‐2 testing data (regardless of clinical status and of the result of the testing). We randomly invite older adults stratified by testing status regardless of symptom severity, a minimum of 3 months after clinical recovery (maximum 6 months); refusal to participate is <45%. Assessment includes interview with the Schedules for Clinical Assessment in Neuropsychiatry (SCAN) and Clinical Dementia Rating scale; neurocognitive assessment; emotional reactivity scale; and neurological assessment including semiquantitative olfactory function test, motor function, coordination and gait. We present here the results of olfactory testing and cognitive assessments. Result We assessed 233 infected participants and 64 controls. Average duration of formal learning is 9.35 ± 2.6 years and mean age is 66.7 ± 5.13 years. Normative data for the local population were available for Word list, Corsi Blocks, Oral Trails and Five Digit Tests and were used to normalize Z‐scores and categorize the sample in 3 groups: normal cognition (NC,44.6%); memory only impairment (MOI,21%); and multiple domain impairment (MDI,34.4%). Individuals with MDI presented severe alterations in short‐term memory; semantic memory; naming; executive function and attention compared to NC or MO groups (Table 1). Severity of cognitive impairment was significantly correlated with severity of olfactory dysfunction (χ2 = 13.82; p= 0.003) but not severity of acute COVID‐19. Conclusion Older adults frequently suffer persistent cognitive impairment after recovery from SARS‐CoV‐2 infection; cognitive impairment is correlated with persistent anosmia.

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.