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Amyloid β-protein, Cystatin C and Cathepsin B as Biomarkers of Alzheimer's Disease
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

It is suggested that Alzheimer’s disease (AD) is caused by an imbalance between production, degradation and clearance of the amyloid-β (Aβ) protein. This imbalance leads to aggregation of Aβ and tau proteins and neurodegeneration in the brain. Today there is increasing evidence that the balance between the protease cathepsin B and the protease inhibitor cystatin C affects the tendency for Aβ to aggregate. The primary aim of this thesis was to investigate Aβ, cystatin C and cathepsin B levels in blood and cerebro-spinal fluid (CSF) in relation to the risk of AD.

Studies I & II were based on the re-examinations of participants, at ages 70 and 77, in the Uppsala Longitudinal Study of Adult Men (ULSAM), a community-based prospective study initiated in 1970 (participants then being 50 years of age). In ULSAM, low plasma Aβ1-40 (Study I) and low serum cystatin C levels (Study II) were associated with a higher risk of AD. Studies III & IV were based on a cross-sectional sample of people with AD, mild cognitive impairment and healthy controls, recruited at three Swedish Memory Disorder units: Uppsala University Hospital, Uppsala, Skåne University Hospital, Malmö, and Karolinska University Hospital, Huddinge, Stockholm. In Study III, CSF cystatin C levels were positively correlated with both Aβ1-42 and tau levels. In Study IV, individuals with AD had higher mean plasma cathepsin B levels than healthy controls.

In conclusion, low plasma Aβ1-40 and low serum cystatin C levels may precede clinically manifest AD in elderly men, cystatin C levels are positively correlated with Aβ1-42 and tau levels in CSF, and mean plasma cathepsin B levels are higher in people with AD compared to healthy controls. In addition to Aβ1-42 and tau levels in CSF, Aβ1-40, cystatin C and cathepsin B levels in blood may reflect the risk of AD.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2010. , p. 64
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 626
Keyword [en]
Alzheimer´s disease, amyloid β-protein, cystatin C, cathepsin B, biomarkers, risk factors, epidemiology
National Category
Geriatrics
Research subject
Medicine
Identifiers
URN: urn:nbn:se:uu:diva-132175ISBN: 978-91-554-7956-5 (print)OAI: oai:DiVA.org:uu-132175DiVA, id: diva2:360959
Public defence
2011-01-20, Enghoffsalen, Ing. 50, bv, Akademiska sjukhuset, Uppsala, 13:00 (English)
Opponent
Supervisors
Available from: 2010-12-20 Created: 2010-10-15 Last updated: 2017-01-25Bibliographically approved
List of papers
1. Plasma β Amyloid and the Risk of Alzheimer Disease and Dementia in Elderly Men: A Prospective, Population-Based Cohort Study
Open this publication in new window or tab >>Plasma β Amyloid and the Risk of Alzheimer Disease and Dementia in Elderly Men: A Prospective, Population-Based Cohort Study
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2008 (English)In: Archives of Neurology, ISSN 0003-9942, E-ISSN 1538-3687, Vol. 65, no 2, p. 256-63Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Beta amyloid (Abeta) protein accumulates in the brains of individuals with Alzheimer disease (AD) and is detectable in cerebrospinal fluid and plasma. OBJECTIVE: To examine plasma levels of Abeta peptides Abeta(40) and Abeta(42) as predictors of incident AD and other types of dementia. DESIGN: Prospective, population-based cohort study. SETTING: The Uppsala Longitudinal Study of Adult Men. PARTICIPANTS: Plasma Abeta(40) and Abeta(42) levels were analyzed as predictors of incident AD in 1045 men at age 70 years and 680 men at age 77 years using Cox proportional hazards analyses. Alzheimer disease and other types of dementia were diagnosed by standardized screening, clinical evaluation, and medical record review. MAIN OUTCOME MEASURES: Hazard ratios of AD (primary outcome) and vascular dementia or other dementia (secondary outcomes) according to baseline levels of plasma Abeta(40) and Abeta(42). RESULTS: From the age of 77 years at baseline, 46 individuals developed AD at follow-up (median, 5.3 years). A low plasma Abeta(40) level at age 77 years was associated with higher incidence of AD. The multivariate-adjusted hazard ratio was 4.87 (95% confidence interval, 1.63-14.6) for the lowest Abeta(40) tertile compared with the highest tertile. On follow-up from age 70 years at baseline (median, 11.2 years), 82 individuals developed AD. Plasma Abeta(40) and Abeta(42) levels measured at age 70 years were not significantly associated with incident AD. CONCLUSIONS: Low plasma Abeta(40) levels predicted incident AD in elderly men independently of potential confounders. Plasma Abeta(42) levels were not significantly associated with AD incidence. The clinical value of Abeta measurement in plasma remains to be established in future studies.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-15781 (URN)10.1001/archneurol.2007.57 (DOI)000253058800015 ()18268197 (PubMedID)
Available from: 2008-03-05 Created: 2008-03-05 Last updated: 2017-12-08Bibliographically approved
2. Serum cystatin C and the risk of Alzheimer disease in elderly men
Open this publication in new window or tab >>Serum cystatin C and the risk of Alzheimer disease in elderly men
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2008 (English)In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 71, no 14, p. 1072-1079Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Multiple lines of research suggest that increased cystatin C activity in the brain protects against the development of Alzheimer disease (AD). METHODS: Serum cystatin C levels were analyzed at two examinations of the Uppsala Longitudinal Study of Adult Men, a longitudinal, community-based study of elderly men (age 70 years, n = 1,153 and age 77 years, n = 761, a subset of the age 70 examination). Cox regressions were used to examine associations between serum cystatin C and incident AD. AD cases were identified by cognitive screening and comprehensive medical chart review in all subjects. RESULTS: On follow-up (median 11.3 years), 82 subjects developed AD. At age 70 years, lower cystatin C was associated with higher risk of AD independently of age, APOE4 genotype, glomerular filtration rate, diabetes, hypertension, stroke, cholesterol, body mass index, smoking, education level, and plasma amyloid-beta protein 40 and 42 levels (hazard ratio [HR] for lowest [<1.12 micromol/L] vs highest [>1.30 micromol/L] tertile = 2.67, 95% CI 1.22-5.83, p < 0.02). The results were similar at age 77 years (43 participants developed AD during follow-up). Furthermore, a 0.1-mumol/L decrease of cystatin C between ages 70 and 77 years was associated with a 29% higher risk of incident AD (HR 1.29, 95% CI 1.03-1.63, p < 0.03). CONCLUSIONS: Low levels of serum cystatin C precede clinically manifest Alzheimer disease (AD) in elderly men free of dementia at baseline and may be a marker of future risk of AD. These findings strengthen the evidence for a role for cystatin C in the development of clinical AD.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-103489 (URN)10.1212/01.wnl.0000326894.40353.93 (DOI)000259649100007 ()18824671 (PubMedID)
Available from: 2009-05-19 Created: 2009-05-19 Last updated: 2017-12-13Bibliographically approved
3. Cystatin C Levels are Positively Correlated with both Aβ42 and Tau Levels in Cerebrospinal Fluid in Persons with Alzheimer's Disease, Mild Cognitive Impairment, and Healthy Controls
Open this publication in new window or tab >>Cystatin C Levels are Positively Correlated with both Aβ42 and Tau Levels in Cerebrospinal Fluid in Persons with Alzheimer's Disease, Mild Cognitive Impairment, and Healthy Controls
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2010 (English)In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 21, no 2, p. 471-478Article in journal (Refereed) Published
Abstract [en]

Cystatin C is suggested to be involved in neurodegeneration and the development of Alzheimer's disease (AD) by binding to soluble amyloid-beta (Abeta) peptides. Studies of cystatin C levels in cerebrospinal fluid (CSF) in relation to risk of AD are conflicting and relations between cystatin C, Abeta42, and tau levels in CSF in AD, mild cognitive impairment (MCI), and healthy controls are unknown. The objective of this study was to investigate cystatin C, Abeta42, and tau levels in CSF in AD, MCI, and controls. As a secondary aim, the relationships between cystatin C, Abeta42, and tau levels across disease groups were investigated. Cystatin C, Abeta42, total tau, and phosphorylated tau levels in CSF were analyzed by turbidimetry (cystatin C) and xMAP Luminex technology (Abeta and tau) in persons with AD (n=101), MCI (n=84), and healthy control subjects (n=28). Mean cystatin C levels were similar in cases of AD (5.6 mumol/L +/- 1.7), MCI (5.4 mumol/L +/- 1.48), and controls (5.6 mumol/L +/- 1.6). However, CSF cystatin C levels were strongly and positively correlated with total tau and phosphorylated tau levels (r=0.61-0.81, p< 0.0001) and Abeta42 (r=0.35-0.65, p< 0.001) independent of age, gender, and APOE genotype. Mean CSF cystatin C levels did not differ between patients with AD and MCI and healthy controls. Interestingly, cystatin C levels were positively correlated with both tau and Abeta42 levels in CSF independent of age, gender, and APOE genotype.

Keyword
Alzheimer's disease, biomarkers, case control study, cystatin C, epidemiology, risk factor
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-130132 (URN)10.3233/JAD-2010-091594 (DOI)000281887600013 ()20555147 (PubMedID)
Available from: 2010-10-15 Created: 2010-09-01 Last updated: 2017-12-12Bibliographically approved
4. Higher Cathepsin B Levels in Plasma in Alzheimer's Disease Compared to Healthy Controls
Open this publication in new window or tab >>Higher Cathepsin B Levels in Plasma in Alzheimer's Disease Compared to Healthy Controls
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2010 (English)In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 22, no 4, p. 1223-1230Article in journal (Refereed) Published
Abstract [en]

Cathepsin B is suggested to be involved in amyloid-β (Aβ) processing and Alzheimer's disease (AD). Studies of cathepsin B levels in plasma and cerebrospinal fluid (CSF) have not been previously performed. We examined cathepsin B levels in plasma and CSF samples in persons with AD, mild cognitive impairment (MCI), and healthy controls in order to test the hypothesis that cathepsin B levels can discriminate persons with AD or MCI from healthy controls. Cathepsin B, Cystatin C, Aβ1-40 and Aβ1-42, total tau, phosphorylated tau, and albumin levels in plasma and CSF were analyzed by ELISA (Cathepsin B) turbidimetry (cystatin C), xMAP Luminex technology (Aβ1-40 and Aβ1-42 and tau), and Cobas C501 analyzer (albumin) in persons with AD (n=101), MCI (n=84), and healthy control subjects (n=28). Plasma cathepsin B levels were higher in persons with AD compared to healthy controls, both in unadjusted models and in multivariable models adjusting for age, gender, APOE genotype, cystatin C, and albumin levels: Odds ratio (OR) for AD per 1 SD of plasma cathepsin B; 2.04, 95% confidence interval (CI); 1.01-4.14, p= 0.05. There was no difference between diagnostic groups in cathepsin B levels in CSF: OR for AD per 1 SD of CSF cathepsin B; 0.93, 95% CI; 0.37-2.30, p= 0.87. Plasma cathepsin B levels were higher in persons with AD compared to healthy controls whereas there was no difference between diagnostic groups in cathepsin B levels in CSF. Further investigation of cathepsin B as a predictor of AD is warranted.

Keyword
Alzheimer's disease, biomarkers, case control study, cathepsin B, cystatin C, epidemiology, risk factor
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-132167 (URN)10.3233/JAD-2010-101023 (DOI)000286185300016 ()20930303 (PubMedID)
Available from: 2010-10-15 Created: 2010-10-15 Last updated: 2017-12-12Bibliographically approved

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