- Email: [email protected]
MECHANISMS OF TREM2 MUTATIONS IN AD
Podium Presentations: Monday, July 25, 2016
New Zealand, Canada and the United States. Three recent studies have shown dementia prevalence is three times higher in both remote (more ‘traditional’) communities and urban (more ‘integrated’) Aboriginal peoples; dementia incidence is also high and onset occurs at an earlier age. Furthermore, while Australian Aboriginal populations are ageing rapidly the life span gap has not reduced in the past 10 years. Methods: We examined potential risk factors for high dementia rates in the total 60 plus population from five NSW urban & rural Aboriginal Communities (n¼336) both proximal (standard bio-medical factors) and early life factors including childhood social trauma (using the CTQ) were measured. Results: As expected, a number of standard bio-medical risk factors were associated with late-life dementia in Aboriginal Australians aged 60 to 92 years; childhood trauma was associated with anxiety, depression and stress disorder into old age; childhood trauma was associated with all-cause dementia & Alzheimer’s dementia. Conclusions: Childhood social trauma is likely important in high dementia rates and the lifespan gap in Aboriginal Australians; this links to work on the role of social determinants (racism, social exclusion, inequality) in life-long health disadvantage. Post-colonisation and ongoing cultural devastation with loss of purpose in childhood and adult life, as well as parenting early education and political recognition, are factors which need to be addressed to tackle poor Indigenous health and premature cognitive decline.
S2-02-03
PAST, PRESENT AND FUTURE OF THE 10/66 DEMENTIA RESEARCH GROUP IN LOW AND MIDDLE INCOME COUNTRIES
Daisy Acosta, the 10/66 Dementia Research Group, Universidad Nacional Pedro Henriquez Ure~ na, Santo Domingo, Dominican Republic. Contact e-mail: [email protected]
Abstract not available.
S2-02-04
ROLE OF CEREBROVASCULAR DISEASE AND VASCULAR PATHOLOGY ON RACIAL AND ETHNIC DIFFERENCES IN RATES OF ALZHEIMER’S DISEASE AND DEMENTIA
Raj N. Kalaria, Newcastle University, Newcastle, United Kingdom. Contact e-mail: [email protected] Background: Cerebrovascular disease (CVD) has long been recog-
nized as an important cause of cognitive impairment worldwide. However, CVD pathology is also common in Alzheimer’s disease (AD). The role of vascular disease in AD has been debated particularly how it may influence the pathogenesis and cognition. Better understanding of cardiovascular risk factors and dementia in different populations may explain frequencies in the burden of AD. Methods: We have conducted prospective cohort studies in elderly subjects (>55 years age) with and without dementia in the United Kingdom, Kenya, Tanzania and Nigeria. In addition, we have assessed post-mortem brains from elderly subjects from Kenya, Tanzania and India. Subjects had clinical, neuropsychometric assessments, were CT/MR scanned and invited for brain donation at death. Brains were examined for standard neurodegenerative and vascular pathology. A systematic review of previously published articles in English until December 2015 was also performed. References were derived from various popular da-
P213
tabases including PubMed of specific interest were searched online. Results: In our various CVD cohort studies, we showed that both neuroimaging measures medial temporal lobe atrophy (MTLA) and white matter hyperintensity (WMH) volume were associated with shorter time to dementia. This suggested a role for both small vessel disease, and Alzheimer pathology in the development of dementia. In the autopsy studies, a staging system (I-VI) related to the natural history of cerebrovascular pathology indicated that >90 of AD subjects with vascular risk factors could be designated at stage V described with a high burden of pathology. These findings were corroborated across different population samples indicating that both neurodegenerative and vascular pathologies are prevalent in tandem with high frequencies of vascular risk factors. Conclusions: Consistent monitoring of modifiable vascular risk factors will benefit in preventing not only CVD related dementia but also reducing the burden of AD in the general population. MONDAY, JULY 25, 2016 EC-02 EMERGING CONCEPTS: THE YIN AND YANG OF TREM2 IN ALZHEIMER’S DISEASE EC-02-01
MECHANISMS OF TREM2 MUTATIONS IN AD
Gernot Kleinberger, Ludwig-Maximilians-University Munich, Munich, Germany. Contact e-mail: [email protected]. de Background: Genetic variants in the triggering receptor expressed on myeloid cells 2 (TREM2) increase the risk for several neurodegenerative diseases including Alzheimer’s disease (AD) in a similar order of magnitude than the more common APOE4 allele. TREM2 is a type-I transmembrane glycoprotein that is selectively expressed in microglia in the brain. Proteolytic processing of TREM2 results in the release of a soluble form (sTREM2), which is increased in the cerebrospinal fluid (CSF) of early symptomatic stages of AD and hence may be a biomarker for microglial activity in AD. Homozygous mutations in TREM2 lead to Nasu-Hakola-Disease or a frontotemporal-like dementia, two rare forms of presenile dementia, clearly supporting a loss-of-function mechanism in the disease pathogenesis. Most of the TREM2 variants that have been identified so far are causing amino-acid changes in the immunoglobulin-like domain, the major functional domain of TREM2. However, a few variants have also been reported in the stalk region as well as in the cytosolic domain. Methods: We used methods previously described in Kleinberger et al. (Sci. Transl. Med. 2014). Results: Here we will present an outline of the current knowledge on the molecular biology of TREM2 variants and their consequences for the pathogenesis of Alzheimer’s disease. Conclusions: Genetic and functional evidence favors a loss of function hypothesis of TREM2 variants in Alzheimer’s disease and other neurodegenerative diseases.
EC-02-02
TREM2 CLEARANCE OFAMYLOID: PERIPHERAL VS. CNS-DERIVED CELLS
Bruce T. Lamb, Indiana University, Stark Neurosciences Research Institute, Indianapolis, IN, USA. Contact e-mail: [email protected] Background: The R47H variant in TREM2 is a substantial risk for
late-onset AD. We assessed the age-related and cell-type specific role of TREM2 in regulating AD pathology. Methods: TREM2
New Zealand, Canada and the United States. Three recent studies have shown dementia prevalence is three times higher in both remote (more ‘traditional’) communities and urban (more ‘integrated’) Aboriginal peoples; dementia incidence is also high and onset occurs at an earlier age. Furthermore, while Australian Aboriginal populations are ageing rapidly the life span gap has not reduced in the past 10 years. Methods: We examined potential risk factors for high dementia rates in the total 60 plus population from five NSW urban & rural Aboriginal Communities (n¼336) both proximal (standard bio-medical factors) and early life factors including childhood social trauma (using the CTQ) were measured. Results: As expected, a number of standard bio-medical risk factors were associated with late-life dementia in Aboriginal Australians aged 60 to 92 years; childhood trauma was associated with anxiety, depression and stress disorder into old age; childhood trauma was associated with all-cause dementia & Alzheimer’s dementia. Conclusions: Childhood social trauma is likely important in high dementia rates and the lifespan gap in Aboriginal Australians; this links to work on the role of social determinants (racism, social exclusion, inequality) in life-long health disadvantage. Post-colonisation and ongoing cultural devastation with loss of purpose in childhood and adult life, as well as parenting early education and political recognition, are factors which need to be addressed to tackle poor Indigenous health and premature cognitive decline.
S2-02-03
PAST, PRESENT AND FUTURE OF THE 10/66 DEMENTIA RESEARCH GROUP IN LOW AND MIDDLE INCOME COUNTRIES
Daisy Acosta, the 10/66 Dementia Research Group, Universidad Nacional Pedro Henriquez Ure~ na, Santo Domingo, Dominican Republic. Contact e-mail: [email protected]
Abstract not available.
S2-02-04
ROLE OF CEREBROVASCULAR DISEASE AND VASCULAR PATHOLOGY ON RACIAL AND ETHNIC DIFFERENCES IN RATES OF ALZHEIMER’S DISEASE AND DEMENTIA
Raj N. Kalaria, Newcastle University, Newcastle, United Kingdom. Contact e-mail: [email protected] Background: Cerebrovascular disease (CVD) has long been recog-
nized as an important cause of cognitive impairment worldwide. However, CVD pathology is also common in Alzheimer’s disease (AD). The role of vascular disease in AD has been debated particularly how it may influence the pathogenesis and cognition. Better understanding of cardiovascular risk factors and dementia in different populations may explain frequencies in the burden of AD. Methods: We have conducted prospective cohort studies in elderly subjects (>55 years age) with and without dementia in the United Kingdom, Kenya, Tanzania and Nigeria. In addition, we have assessed post-mortem brains from elderly subjects from Kenya, Tanzania and India. Subjects had clinical, neuropsychometric assessments, were CT/MR scanned and invited for brain donation at death. Brains were examined for standard neurodegenerative and vascular pathology. A systematic review of previously published articles in English until December 2015 was also performed. References were derived from various popular da-
P213
tabases including PubMed of specific interest were searched online. Results: In our various CVD cohort studies, we showed that both neuroimaging measures medial temporal lobe atrophy (MTLA) and white matter hyperintensity (WMH) volume were associated with shorter time to dementia. This suggested a role for both small vessel disease, and Alzheimer pathology in the development of dementia. In the autopsy studies, a staging system (I-VI) related to the natural history of cerebrovascular pathology indicated that >90 of AD subjects with vascular risk factors could be designated at stage V described with a high burden of pathology. These findings were corroborated across different population samples indicating that both neurodegenerative and vascular pathologies are prevalent in tandem with high frequencies of vascular risk factors. Conclusions: Consistent monitoring of modifiable vascular risk factors will benefit in preventing not only CVD related dementia but also reducing the burden of AD in the general population. MONDAY, JULY 25, 2016 EC-02 EMERGING CONCEPTS: THE YIN AND YANG OF TREM2 IN ALZHEIMER’S DISEASE EC-02-01
MECHANISMS OF TREM2 MUTATIONS IN AD
Gernot Kleinberger, Ludwig-Maximilians-University Munich, Munich, Germany. Contact e-mail: [email protected]. de Background: Genetic variants in the triggering receptor expressed on myeloid cells 2 (TREM2) increase the risk for several neurodegenerative diseases including Alzheimer’s disease (AD) in a similar order of magnitude than the more common APOE4 allele. TREM2 is a type-I transmembrane glycoprotein that is selectively expressed in microglia in the brain. Proteolytic processing of TREM2 results in the release of a soluble form (sTREM2), which is increased in the cerebrospinal fluid (CSF) of early symptomatic stages of AD and hence may be a biomarker for microglial activity in AD. Homozygous mutations in TREM2 lead to Nasu-Hakola-Disease or a frontotemporal-like dementia, two rare forms of presenile dementia, clearly supporting a loss-of-function mechanism in the disease pathogenesis. Most of the TREM2 variants that have been identified so far are causing amino-acid changes in the immunoglobulin-like domain, the major functional domain of TREM2. However, a few variants have also been reported in the stalk region as well as in the cytosolic domain. Methods: We used methods previously described in Kleinberger et al. (Sci. Transl. Med. 2014). Results: Here we will present an outline of the current knowledge on the molecular biology of TREM2 variants and their consequences for the pathogenesis of Alzheimer’s disease. Conclusions: Genetic and functional evidence favors a loss of function hypothesis of TREM2 variants in Alzheimer’s disease and other neurodegenerative diseases.
EC-02-02
TREM2 CLEARANCE OFAMYLOID: PERIPHERAL VS. CNS-DERIVED CELLS
Bruce T. Lamb, Indiana University, Stark Neurosciences Research Institute, Indianapolis, IN, USA. Contact e-mail: [email protected] Background: The R47H variant in TREM2 is a substantial risk for
late-onset AD. We assessed the age-related and cell-type specific role of TREM2 in regulating AD pathology. Methods: TREM2