Neuropathological and genetic determinants of dementia : a prospective and population-based study on very elderly finns

Mira Mäkelä

Research output: ThesisDoctoral ThesisCollection of Articles

Abstract

The number of individuals suffering from dementia increases as the population ages. Alzheimer’s disease (AD) is the most common type of dementia, neuropathologically characterized by neuritic plaques (NP) and neurofibrillary tangles (NFT). Cerebral amyloid angiopathy (CAA, deposition of amyloid β (Aβ) in the cerebral vessels) is often found in AD, but its role in dementia has been unclear. Recent genome-wide association studies have revealed approximately 30 AD risk loci. The aim of this thesis was to assess the neuropathological and genetic risk factors of dementia in a population-based cohort of very elderly (Vantaa 85+). Of the 601 subjects aged >85 years and living in Vantaa in 1991, 300 (mean age‐at‐death 92±3.7 years) were examined neuropathologically and 278 genetically. The diagnosis of clinical dementia was based on the DSM III-R criteria. In addition to AD –related neuropathology, Lewy body (LB)-related pathology and several vascular pathologies were analysed. Genetic analyses were based on genome wide approaches. 65% of the study subjects were demented. Except for one subject, at least one type of neuropathology was found in every individual. Presence of at least two of these pathologies almost doubled the risk of dementia. Severe NFT -pathology was the most common finding, and associated most strongly with dementia. LB-related pathology and small cortical infarcts in the anterior brain regions were also independent contributors of dementia. In addition, severe CAA in the frontal lobe was nearly significantly associated with dementia. CAA was found in nearly 70% of the subjects, but it was mostly mild, found approximately in 1% of the brain vessels. The parietal and frontal lobes were affected most often. In this study, the presence of capillary Aβ (capAβ) was for the first time investigated in a population-based setting and was found in 28.6% of the subjects. Interestingly, every subject with severe capAβ deposition in multiple brain areas was demented. Analyses of 24 of previously known genetic risk loci for AD revealed associations with various types of AD neuropathologies (NP, NFT, CAA, capAβ). Genetic risk factors for capAβ were identified for the first time. This study confirmed in a population-based setting previously described findings on neuropathological and genetic factors of dementia. The very high frequency of CAA and the association of capAβ with dementia were shown. Genetic associations of capAβ were reported for the first time. Key words: dementia, Alzheimer´s disease, cerebral amyloid angiopathy, capillary amyloid angiopathy, population-based study
Original languageEnglish
Supervisors/Advisors
  • Tanskanen, Maarit, Supervisor
  • Myllykangas, Liisa, Supervisor
  • Paetau, Anders, Supervisor
Place of PublicationHelsinki
Publisher
Print ISBNs978-951-51-4472-0
Electronic ISBNs978-951-51-4473-7
Publication statusPublished - 2018
MoE publication typeG5 Doctoral dissertation (article)

Fields of Science

  • Dementia
  • +diagnosis
  • +epidemiology
  • +etiology
  • +genetics
  • Alzheimer Disease
  • Frontotemporal Dementia
  • Amyloid
  • Cerebral Amyloid Angiopathy
  • Neurofibrillary Tangles
  • Aging
  • Clusterin
  • HLA-DR Antigens
  • Phosphatidylinositols
  • Aged, 80 and over
  • Brain
  • Atrophy
  • Cerebral Infarction
  • Mental Disorders
  • 3112 Neurosciences
  • 3124 Neurology and psychiatry
  • 3111 Biomedicine

Cite this

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title = "Neuropathological and genetic determinants of dementia : a prospective and population-based study on very elderly finns",
abstract = "The number of individuals suffering from dementia increases as the population ages. Alzheimer’s disease (AD) is the most common type of dementia, neuropathologically characterized by neuritic plaques (NP) and neurofibrillary tangles (NFT). Cerebral amyloid angiopathy (CAA, deposition of amyloid β (Aβ) in the cerebral vessels) is often found in AD, but its role in dementia has been unclear. Recent genome-wide association studies have revealed approximately 30 AD risk loci. The aim of this thesis was to assess the neuropathological and genetic risk factors of dementia in a population-based cohort of very elderly (Vantaa 85+). Of the 601 subjects aged >85 years and living in Vantaa in 1991, 300 (mean age‐at‐death 92±3.7 years) were examined neuropathologically and 278 genetically. The diagnosis of clinical dementia was based on the DSM III-R criteria. In addition to AD –related neuropathology, Lewy body (LB)-related pathology and several vascular pathologies were analysed. Genetic analyses were based on genome wide approaches. 65{\%} of the study subjects were demented. Except for one subject, at least one type of neuropathology was found in every individual. Presence of at least two of these pathologies almost doubled the risk of dementia. Severe NFT -pathology was the most common finding, and associated most strongly with dementia. LB-related pathology and small cortical infarcts in the anterior brain regions were also independent contributors of dementia. In addition, severe CAA in the frontal lobe was nearly significantly associated with dementia. CAA was found in nearly 70{\%} of the subjects, but it was mostly mild, found approximately in 1{\%} of the brain vessels. The parietal and frontal lobes were affected most often. In this study, the presence of capillary Aβ (capAβ) was for the first time investigated in a population-based setting and was found in 28.6{\%} of the subjects. Interestingly, every subject with severe capAβ deposition in multiple brain areas was demented. Analyses of 24 of previously known genetic risk loci for AD revealed associations with various types of AD neuropathologies (NP, NFT, CAA, capAβ). Genetic risk factors for capAβ were identified for the first time. This study confirmed in a population-based setting previously described findings on neuropathological and genetic factors of dementia. The very high frequency of CAA and the association of capAβ with dementia were shown. Genetic associations of capAβ were reported for the first time. Key words: dementia, Alzheimer´s disease, cerebral amyloid angiopathy, capillary amyloid angiopathy, population-based study",
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author = "Mira M{\"a}kel{\"a}",
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year = "2018",
language = "English",
isbn = "978-951-51-4472-0",
publisher = "[M. M{\"a}kel{\"a}]",
address = "Finland",

}

Neuropathological and genetic determinants of dementia : a prospective and population-based study on very elderly finns. / Mäkelä, Mira.

Helsinki : [M. Mäkelä], 2018. 122 p.

Research output: ThesisDoctoral ThesisCollection of Articles

TY - THES

T1 - Neuropathological and genetic determinants of dementia : a prospective and population-based study on very elderly finns

AU - Mäkelä, Mira

N1 - M1 - 122 s. + liitteet

PY - 2018

Y1 - 2018

N2 - The number of individuals suffering from dementia increases as the population ages. Alzheimer’s disease (AD) is the most common type of dementia, neuropathologically characterized by neuritic plaques (NP) and neurofibrillary tangles (NFT). Cerebral amyloid angiopathy (CAA, deposition of amyloid β (Aβ) in the cerebral vessels) is often found in AD, but its role in dementia has been unclear. Recent genome-wide association studies have revealed approximately 30 AD risk loci. The aim of this thesis was to assess the neuropathological and genetic risk factors of dementia in a population-based cohort of very elderly (Vantaa 85+). Of the 601 subjects aged >85 years and living in Vantaa in 1991, 300 (mean age‐at‐death 92±3.7 years) were examined neuropathologically and 278 genetically. The diagnosis of clinical dementia was based on the DSM III-R criteria. In addition to AD –related neuropathology, Lewy body (LB)-related pathology and several vascular pathologies were analysed. Genetic analyses were based on genome wide approaches. 65% of the study subjects were demented. Except for one subject, at least one type of neuropathology was found in every individual. Presence of at least two of these pathologies almost doubled the risk of dementia. Severe NFT -pathology was the most common finding, and associated most strongly with dementia. LB-related pathology and small cortical infarcts in the anterior brain regions were also independent contributors of dementia. In addition, severe CAA in the frontal lobe was nearly significantly associated with dementia. CAA was found in nearly 70% of the subjects, but it was mostly mild, found approximately in 1% of the brain vessels. The parietal and frontal lobes were affected most often. In this study, the presence of capillary Aβ (capAβ) was for the first time investigated in a population-based setting and was found in 28.6% of the subjects. Interestingly, every subject with severe capAβ deposition in multiple brain areas was demented. Analyses of 24 of previously known genetic risk loci for AD revealed associations with various types of AD neuropathologies (NP, NFT, CAA, capAβ). Genetic risk factors for capAβ were identified for the first time. This study confirmed in a population-based setting previously described findings on neuropathological and genetic factors of dementia. The very high frequency of CAA and the association of capAβ with dementia were shown. Genetic associations of capAβ were reported for the first time. Key words: dementia, Alzheimer´s disease, cerebral amyloid angiopathy, capillary amyloid angiopathy, population-based study

AB - The number of individuals suffering from dementia increases as the population ages. Alzheimer’s disease (AD) is the most common type of dementia, neuropathologically characterized by neuritic plaques (NP) and neurofibrillary tangles (NFT). Cerebral amyloid angiopathy (CAA, deposition of amyloid β (Aβ) in the cerebral vessels) is often found in AD, but its role in dementia has been unclear. Recent genome-wide association studies have revealed approximately 30 AD risk loci. The aim of this thesis was to assess the neuropathological and genetic risk factors of dementia in a population-based cohort of very elderly (Vantaa 85+). Of the 601 subjects aged >85 years and living in Vantaa in 1991, 300 (mean age‐at‐death 92±3.7 years) were examined neuropathologically and 278 genetically. The diagnosis of clinical dementia was based on the DSM III-R criteria. In addition to AD –related neuropathology, Lewy body (LB)-related pathology and several vascular pathologies were analysed. Genetic analyses were based on genome wide approaches. 65% of the study subjects were demented. Except for one subject, at least one type of neuropathology was found in every individual. Presence of at least two of these pathologies almost doubled the risk of dementia. Severe NFT -pathology was the most common finding, and associated most strongly with dementia. LB-related pathology and small cortical infarcts in the anterior brain regions were also independent contributors of dementia. In addition, severe CAA in the frontal lobe was nearly significantly associated with dementia. CAA was found in nearly 70% of the subjects, but it was mostly mild, found approximately in 1% of the brain vessels. The parietal and frontal lobes were affected most often. In this study, the presence of capillary Aβ (capAβ) was for the first time investigated in a population-based setting and was found in 28.6% of the subjects. Interestingly, every subject with severe capAβ deposition in multiple brain areas was demented. Analyses of 24 of previously known genetic risk loci for AD revealed associations with various types of AD neuropathologies (NP, NFT, CAA, capAβ). Genetic risk factors for capAβ were identified for the first time. This study confirmed in a population-based setting previously described findings on neuropathological and genetic factors of dementia. The very high frequency of CAA and the association of capAβ with dementia were shown. Genetic associations of capAβ were reported for the first time. Key words: dementia, Alzheimer´s disease, cerebral amyloid angiopathy, capillary amyloid angiopathy, population-based study

KW - Dementia

KW - +diagnosis

KW - +epidemiology

KW - +etiology

KW - +genetics

KW - Alzheimer Disease

KW - Frontotemporal Dementia

KW - Amyloid

KW - Cerebral Amyloid Angiopathy

KW - Neurofibrillary Tangles

KW - Aging

KW - Clusterin

KW - HLA-DR Antigens

KW - Phosphatidylinositols

KW - Aged, 80 and over

KW - Brain

KW - Atrophy

KW - Cerebral Infarction

KW - Mental Disorders

KW - 3112 Neurosciences

KW - 3124 Neurology and psychiatry

KW - 3111 Biomedicine

M3 - Doctoral Thesis

SN - 978-951-51-4472-0

PB - [M. Mäkelä]

CY - Helsinki

ER -