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

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

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

Abstract 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

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

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

A NOVEL ALZHEIMER DISEASE LOCUS LOCATED NEAR THE GENE ENCODING TAU PROTEIN

APOE ε4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer’s Project (IGAP) Consortium in APOE ε4+ (10,352 cases and 9,207 controls) and APOE ε4− (7,184 cases and 26,968 controls) subgroups as well as in the total sample testing for interaction between a SNP and APOE ε4 status. Suggestive associations (P<1x10 −4 ) in stage 1 were evaluated in an independent sample (stage 2) containing 4,203 subjects ( APOE ε4+: 1,250 cases and 536 controls; APOE ε4-: 718 cases and 1,699 controls). Among APOE ε4− subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT ) in a meta-analysis of the stage 1 and stage 2 datasets (best SNP, rs2732703, P=5·8x10 −9 ). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100 kilobase region that includes MAPT . Except for previously identified AD loci showing stronger association in APOE ε4+ subjects ( CR1 and CLU ) or APOE ε4− subjects ( MS4A6A/MS4A4A/ MS4A6E ), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6x10 −7 ) is noteworthy because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P≤1.3x10 −8 ), frontal cortex (P≤1.3x10 −9 ), and temporal cortex (P≤1.2x10 −11 ). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2x10 −6 ) and temporal cortex (P=2.6x10 −6 ). Our APOE -stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ε4 compared to persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted

A NOVEL ALZHEIMER DISEASE LOCUS LOCATED NEAR THE GENE ENCODING TAU PROTEIN

APOE ε4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer’s Project (IGAP) Consortium in APOE ε4+ (10,352 cases and 9,207 controls) and APOE ε4− (7,184 cases and 26,968 controls) subgroups as well as in the total sample testing for interaction between a SNP and APOE ε4 status. Suggestive associations (P<1x10−4) in stage 1 were evaluated in an independent sample (stage 2) containing 4,203 subjects (APOE ε4+: 1,250 cases and 536 controls; APOE ε4-: 718 cases and 1,699 controls). Among APOE ε4− subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 datasets (best SNP, rs2732703, P=5·8x10−9). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100 kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ε4+ subjects (CR1 and CLU) or APOE ε4− subjects (MS4A6A/MS4A4A/ MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6x10−7) is noteworthy because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P≤1.3x10−8), frontal cortex (P≤1.3x10−9), and temporal cortex (P≤1.2x10−11). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2x10−6) and temporal cortex (P=2.6x10−6). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ε4 compared to persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted