Chronic neuropsychiatric sequelae of SARS-CoV-2: Protocol and methods from the Alzheimer's Association Global Consortium

Gabriel A. de Erausquin, Heather Snyder, Traolach S. Brugha, Sudha Seshadri, Maria Carrillo, Rajesh Sagar, Yueqin Huang, Charles Newton, Carmela Tartaglia, Charlotte Teunissen, Krister Håkanson, Rufus Akinyemi, Kameshwar Prasad, Giovanni D'Avossa, Gabriela Gonzalez-Aleman, Akram Hosseini, George D. Vavougios, Perminder Sachdev, John Bankart, Niels Peter Ole MorsRichard Lipton, Mindy Katz, Peter T. Fox, Mohammad Zia Katshu, M. Sriram Iyengar, Galit Weinstein, Hamid R. Sohrabi, Rachel Jenkins, Dan J. Stein, Jacques Hugon, Venetsanos Mavreas, John Blangero, Carlos Cruchaga, Murali Krishna, Ovais Wadoo, Rodrigo Becerra, Igor Zwir, William T. Longstreth, Golo Kroenenberg, Paul Edison, Elizabeta Mukaetova-Ladinska, Ekkehart Staufenberg, Mariana Figueredo-Aguiar, Agustín Yécora, Fabiana Vaca, Hernan P. Zamponi, Vincenzina Lo Re, Abdul Majid, Jonas Sundarakumar, Hector M. Gonzalez, Mirjam I. Geerlings, Ingmar Skoog, Alberto Salmoiraghi, Filippo Martinelli Boneschi, Vibuthi N. Patel, Juan M. Santos, Guillermo Rivera Arroyo, Antonio Caballero Moreno, Pascal Felix, Carla Gallo, Hidenori Arai, Masahito Yamada, Takeshi Iwatsubo, Malveeka Sharma, Nandini Chakraborty, Catterina Ferreccio, Dickens Akena, Carol Brayne, Gladys Maestre, Sarah Williams Blangero, Luis I. Brusco, Prabha Siddarth, Timothy M. Hughes, Alfredo Ramírez Zuñiga, Joseph Kambeitz, Agustin Ruiz Laza, Norrina Allen, Stella Panos, David Merrill, Agustín Ibáñez, Debby Tsuang, Nino Valishvili, Srishti Shrestha, Sophia Wang, Vasantha Padma, Kaarin J. Anstey, Vijayalakshmi Ravindrdanath, Kaj Blennow, Paul Mullins, Emilia Łojek, Anand Pria, Thomas H. Mosley, Penny Gowland, Timothy D. Girard, Richard Bowtell, Farhaan S. Vahidy

Research output: Contribution to journalArticlepeer-review


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 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. Key Points: The following review describes what is known so far in terms of molecular and epidemiological links among COVID-19, the brain, neurological symptoms, and AD and related dementias (ADRD) The primary objective of this large-scale collaboration is to clarify the pathogenesis of ADRD and to advance our understanding of the impact of a neurotropic virus on the long-term risk of cognitive decline and other CNS sequelae. No available evidence supports the notion that cognitive impairment after SARS-CoV-2 infection is a form of dementia (ADRD or otherwise). The longitudinal methodologies espoused by the consortium are intended to provide data to answer this question as clearly as possible controlling for possible confounders. Our specific hypothesis is that SARS-CoV-2 triggers ADRD-like pathology following the extended olfactory cortical network (EOCN) in older individuals with specific genetic susceptibility. The proposed harmonization strategies and flexible study designs offer the possibility to include large samples of under-represented racial and ethnic groups, creating a rich set of harmonized cohorts for future studies of the pathophysiology, determinants, long-term consequences, and trends in cognitive aging, ADRD, and vascular disease. We provide a framework for current and future studies to be carried out within the Consortium. and offers a “green paper” to the research community with a very broad, global base of support, on tools suitable for low- and middle-income countries aimed to compare and combine future longitudinal data on the topic. The Consortium proposes a combination of design and statistical methods as a means of approaching causal inference of the COVID-19 neuropsychiatric sequelae. We expect that deep phenotyping of neuropsychiatric sequelae may provide a series of candidate syndromes with phenomenological and biological characterization that can be further explored. By generating high-quality harmonized data across sites we aim to capture both descriptive and, where possible, causal associations.

Original languageEnglish
Article numbere12348
Pages (from-to)e12348
JournalAlzheimer's and Dementia: Translational Research and Clinical Interventions
Issue number1
StatePublished - 2022

Bibliographical note

Funding Information:
The authors wish to thank the ongoing technical advice and expert consultations of Dr. Dévora Kestel, Director, Department of Mental Health and Substance Abuse and Dr. Tarun Dua, Director, Program for Neurological Diseases and Neuroscience, Management of Mental and Brain Disorders in the Department of Mental Health and Substance Abuse at the World Health Organization.

Funding Information:
To facilitate data sharing with ongoing studies, wherever feasible sites will collect information to fill the National Alzheimer's Coordinating Center Uniform Data Set (NACC UDS). The NACC established the UDS for longitudinal data by means of a standardized clinical evaluation. NACC is responsible for developing and maintaining a database of participant information collected from all of the Alzheimer's Disease Centers (ADCs) funded by the National Institute on Aging (NIA). UDS defines an expanded, standardized clinical data set to provide ADC researchers a standard set of assessment procedures, collected longitudinally, to better characterize ADC participants with mild AD and MCI compared to non‐demented controls. The UDS has data collection forms for initial and follow‐up visits based on NACC definitions, a relational database, and a data submission system enhanced to provide efficient and secure access data submission and retrieval systems ( ). The NACC UDS is validated for international AD cohorts and is available in English, Spanish, and Chinese (Mandarin). Psychosocial measures, including quality of life, stressful life events, and poverty and financial hardship will also be collected where possible. Admittedly, this information is partially duplicative with other components of the proposed assessment. Local decisions over use will be driven by the availability of locally validated and culturally adapted assessment tools, as well as participant burden. 127–130 127–130 128

Publisher Copyright:
© 2022 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's Association.


  • cognitive impairment
  • dementia
  • neuropsychiatric sequelae
  • predictors
  • SARS-CoV-2

ASJC Scopus subject areas

  • Clinical Neurology
  • Psychiatry and Mental health


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