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| 2. |
- Daborg, Jonny, et al.
(författare)
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Cerebrospinal fluid levels of complement proteins C3, C4 and CR1 in Alzheimer's disease.
- 2012
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Ingår i: Journal of neural transmission (Vienna, Austria : 1996). - : Springer Science and Business Media LLC. - 1435-1463 .- 0300-9564. ; 119:7, s. 789-97
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD) is strongly associated with loss of synapses. The complement system has been shown to be involved in synaptic elimination. Several studies point to an association between AD and the complement system. The purpose of this study was to examine the association of cerebrospinal fluid (CSF) levels of complement components 3 and 4 (C3 and C4, respectively), and complement receptor 1 (CR1) with AD in 43 patients with AD plus dementia, 42 patients with mild cognitive impairment (MCI) who progressed to AD during follow-up (MCI-AD), 42 patients with stable MCI and 44 controls. Complement levels were also applied in a multivariate model to determine if they provided any added value to the core AD biomarkers Aβ42, T-tau and P-tau. We found elevated CSF levels of C3 and C4 in AD compared with MCI without progression to AD, and elevated CSF levels of CR1 in MCI-AD and AD when these groups were merged. These results provide support for aberrant complement regulation as a part in the AD process, but the changes are not diagnostically useful.
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| 4. |
- Lautner, Ronald, et al.
(författare)
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Apolipoprotein e genotype and the diagnostic accuracy of cerebrospinal fluid biomarkers for Alzheimer disease.
- 2014
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Ingår i: JAMA psychiatry. - : American Medical Association (AMA). - 2168-6238 .- 2168-622X. ; 71:10, s. 1183-91
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Tidskriftsartikel (refereegranskat)abstract
- Several studies suggest that the apolipoprotein E (APOE) ε4 allele modulates cerebrospinal fluid (CSF) levels of β-amyloid 42 (Aβ42). Whether this effect is secondary to the association of the APOE ε4 allele with cortical Aβ deposition or whether APOE ε4 directly influences CSF levels of Aβ42 independently of Aβ pathology remains unknown.
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| 5. |
- Lautner, Ronald
(författare)
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Biomarkers for Alzheimer's disease and the APOE polymorphism
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Alzheimer’s disease (AD) is the most common form of dementia and cerebrospinal fluid (CSF) biomarkers reflecting the core pathology of AD are now widely used for diagnosis making, in particular β-amyloid[1-42] (Aβ42) reflecting amyloid plaque pathology, phosphorylated tau (P-tau) reflecting neurofibrillary tangle pathology and total tau (T-tau) reflecting general neurodegeneration. In addition, blood-based biomarkers for AD are in the pipeline with recent studies showing promising diagnostic potential. The most important genetic risk factor for sporadic AD is the ε4 allele of the apolipoprotein E (APOE) polymorphism, increasing risk for AD diagnosis in a dose-dependent manner as well as lowering the age of onset. We conducted a comprehensive meta-analysis of the AD biomarker literature from 1984 to 2014, which could confirm the robust diagnostic performance of the above-mentioned established CSF biomarker triad for AD, and also revealed possible new biomarker candidates in both CSF and blood that could contribute to the diagnostic work-up of the disease as well as serve as tools for monitoring new disease-modifying treatments. In a large multicentre study, we confirmed the strong association between the APOE ε4 genotype and AD and showed that the ε4 allele also affects concentrations of CSF Aβ42 in a dose-dependent manner. However, the APOE polymorphism does not blur the diagnostic accuracy of the established AD biomarkers and CSF Aβ42 was shown to reflect cerebral amyloid pathology irrespective of the APOE genotype. In another multicentre cohort consisting of solely cognitively healthy subjects, we showed that the dose-dependent effect of APOE ε4 on CSF Aβ42 was absent in younger subjects and CSF Aβ42 concentrations started to drop around age 50 and even earlier in ε4-carriers, pinpointing the earliest disturbances in amyloid homeostasis, long before cognitive impairment becomes apparent. Taken together, the results from this thesis underline the usefulness of AD biomarkers as well as their robust diagnostic performance irrespective of the most prominent genetic risk factor. In addition, since biomarkers (in particular CSF Aβ42) can reflect pathological changes already in the preclinical stage of the disease, they could become valuable in future AD prevention, once disease-modifying therapies become available.
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| 6. |
- Lautner, Ronald, et al.
(författare)
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Biomarkers for microglial activation in Alzheimer's disease.
- 2011
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Ingår i: International journal of Alzheimer's disease. - : Hindawi Limited. - 2090-0252. ; 2011
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Tidskriftsartikel (refereegranskat)abstract
- Intensive research over the last decades has provided increasing evidence for neuroinflammation as an integral part in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD). Inflammatory responses in the central nervous system (CNS) are initiated by activated microglia, representing the first line of the innate immune defence of the brain. Therefore, biochemical markers of microglial activation may help us understand the underlying mechanisms of neuroinflammation in AD as well as the double-sided qualities of microglia, namely, neuroprotection and neurotoxicity. In this paper we summarize candidate biomarkers of microglial activation in AD along with a survey of recent neuroimaging techniques.
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| 7. |
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| 8. |
- Lautner, Ronald, et al.
(författare)
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Preclinical effects of APOE epsilon 4 on cerebrospinal fluid A beta 42 concentrations
- 2017
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Ingår i: Alzheimers Research & Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Background: From earlier studies it is known that the APOE epsilon 2/epsilon 3/epsilon 4 polymorphism modulates the concentrations of cerebrospinal fluid (CSF) beta-amyloid(1-42) (A beta 42) in patients with cognitive decline due to Alzheimer's disease (AD), as well as in cognitively healthy controls. Here, in a large cohort consisting solely of cognitively healthy individuals, we aimed to evaluate how the effect of APOE on CSF A beta 42 varies by age, to understand the association between APOE and the onset of preclinical AD. Methods: APOE genotype and CSF A beta 42 concentration were determined in a cohort comprising 716 cognitively healthy individuals aged 17-99 from nine different clinical research centers. Results: CSF concentrations of A beta 42 were lower in APOE epsilon 4 carriers than in noncarriers in a gene dose-dependent manner. The effect of APOE epsilon 4 on CSF A beta 42 was age dependent. The age at which CSF A beta 42 concentrations started to decrease was estimated at 50 years in APOE epsilon 4-negative individuals and 43 years in heterozygous APOE epsilon 4 carriers. Homozygous APOE epsilon 4 carriers showed a steady decline in CSF A beta 42 concentrations with increasing age throughout the examined age span. Conclusions: People possessing the APOE epsilon 4 allele start to show a decrease in CSF A beta 42 concentration almost a decade before APOE epsilon 4 noncarriers already in early middle age. Homozygous APOE epsilon 4 carriers might deposit A beta 42 throughout the examined age span. These results suggest that there is an APOE epsilon 4-dependent period of early alterations in amyloid homeostasis, when amyloid slowly accumulates, that several years later, together with other downstream pathological events such as tau pathology, translates into cognitive decline.
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| 9. |
- Lautner, Ronald, et al.
(författare)
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Preclinical effects of APOE ϵ4 on cerebrospinal fluid Aβ42 concentrations
- 2017
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Ingår i: Alzheimer's Research and Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: From earlier studies it is known that the APOE ϵ2/ϵ3/ϵ4 polymorphism modulates the concentrations of cerebrospinal fluid (CSF) beta-amyloid1-42 (Aβ42) in patients with cognitive decline due to Alzheimer's disease (AD), as well as in cognitively healthy controls. Here, in a large cohort consisting solely of cognitively healthy individuals, we aimed to evaluate how the effect of APOE on CSF Aβ42 varies by age, to understand the association between APOE and the onset of preclinical AD. Methods: APOE genotype and CSF Aβ42 concentration were determined in a cohort comprising 716 cognitively healthy individuals aged 17-99 from nine different clinical research centers. Results: CSF concentrations of Aβ42 were lower in APOE ϵ4 carriers than in noncarriers in a gene dose-dependent manner. The effect of APOE ϵ4 on CSF Aβ42 was age dependent. The age at which CSF Aβ42 concentrations started to decrease was estimated at 50 years in APOE ϵ4-negative individuals and 43 years in heterozygous APOE ϵ4 carriers. Homozygous APOE ϵ4 carriers showed a steady decline in CSF Aβ42 concentrations with increasing age throughout the examined age span. Conclusions: People possessing the APOE ϵ4 allele start to show a decrease in CSF Aβ42 concentration almost a decade before APOE ϵ4 noncarriers already in early middle age. Homozygous APOE ϵ4 carriers might deposit Aβ42 throughout the examined age span. These results suggest that there is an APOE ϵ4-dependent period of early alterations in amyloid homeostasis, when amyloid slowly accumulates, that several years later, together with other downstream pathological events such as tau pathology, translates into cognitive decline.
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| 10. |
- Mattsson, Niklas, et al.
(författare)
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Effects of APOE ε4 on neuroimaging, cerebrospinal fluid biomarkers, and cognition in prodromal Alzheimer's disease
- 2018
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Ingår i: Neurobiology of Aging. - : Elsevier BV. - 0197-4580 .- 1558-1497. ; 71, s. 81-90
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Tidskriftsartikel (refereegranskat)abstract
- Apolipoprotein (APOE) ε4 is a major genetic risk factor for Alzheimer's disease (AD), but its importance for the clinical and biological heterogeneity in AD is unclear, particularly at the prodromal stage. We analyzed 151 prodromal AD patients (44 APOE ε4-negative and 107 APOE ε4-positive) from the BioFINDER study. We tested cognition, 18F-flutemetamol β-amyloid (Aβ) positron emission tomography, cerebrospinal fluid biomarkers of Aβ tau and neurodegeneration, and magnetic resonance imaging of white matter pathology and brain structure. Despite having similar cortical Aβ-load and baseline global cognition (mini mental state examination), APOE ε4-negative prodromal AD had more nonamnestic cognitive impairment, higher cerebrospinal fluid levels of Aβ-peptides and neuronal injury biomarkers, more white matter pathology, more cortical atrophy, and faster decline of mini mental state examination, compared to APOE ε4-positive prodromal AD. The absence of APOE ε4 is associated with an atypical phenotype of prodromal AD. This suggests that APOE ε4 may impact both the diagnostics of AD in early stages and potentially also effects of disease-modifying treatments.
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