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 Mors
Richard 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, Pacific Neuroscience Institute Pacific Brain Health Center Santa Monica California USA; Providence Saint John's Cancer Institute Department of Translational Neurosciences and Neurotherapeutics Santa Monica California USAFollow
David A Merrill, The John Wayne Cancer Institute and Pacific Neuroscience Institute, Providence and St. Johns Health Center, Santa Monica, CA, USAFollow
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

Document Type


Publication Date


Publication Title

Alzheimers Dement (N Y)


california; covid-19; pni; santa monica


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.

Clinical Institute

Neurosciences (Brain & Spine)

Clinical Institute

Mental Health


Behavioral Health


Infectious Diseases