| 1. |
- Giannisis, Andreas, et al.
(författare)
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Plasma apolipoprotein E levels in longitudinally followed patients with mild cognitive impairment and Alzheimer's disease
- 2022
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Ingår i: Alzheimer's Research & Therapy. - : BioMed Central (BMC). - 1758-9193. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Low levels of plasma apolipoprotein E (apoE) and presence of the APOE epsilon 4 allele are associated with an increased risk of Alzheimer's disease (AD). Although the increased risk of AD in APOE epsilon 4-carriers is well-established, the protein levels have received limited attention. Methods: We here report the total plasma apoE and apoE isoform levels at baseline from a longitudinally (24 months) followed cohort including controls (n = 3 9), patients with stable amnestic mild cognitive impairment during 24 months follow up (MCI-MCI, n = 3 0) , patients with amnestic MCI (aMCI) that during follow-up were clinically diagnosed with AD with dementia (ADD) (MCI-ADD, n = 28), and patients with AD with dementia (ADD) at baseline (ADD, n = 28). We furthermore assessed associations between plasma apoE levels with cerebrospinal fluid (CSF) AD biomarkers and alpha-synuclein, as well as both CSF and plasma neurofilament light chain (NfL), YKL-40 and kallikrein 6. Results: Irrespective of clinical diagnosis, the highest versus the lowest apoE levels were found in APOE epsilon 2/epsilon 3 versus APOE epsilon 4/epsilon 4 subjects, with the most prominent differences exhibited in females. Total plasma apoE levels were 32% and 21% higher in the controls versus MCI-ADD and ADD patients, respectively. Interestingly, MCI-ADD patients exhibited a 30% reduction in plasma apoE compared to MCI-MCI patients. This decrease appeared to be associated with brain amyloid-beta (A beta(42)) pathology regardless of disease status as assessed using the Amyloid, Tau, and Neurodegeneration (A/T/N) classification. In addition to the association between low plasma apoE and low levels of CSF A beta(42), lower apoE levels were also related to higher levels of CSF total tau (t-tau) and tau phosphorylated at Threonine 181 residue (p-tau) and NfL as well as a worse performance on the mini-mental-state-examination. In MCI-ADD patients, low levels of plasma apoE were associated with higher levels of CSF alpha-synuclein and kallikrein 6. No significant correlations between plasma apoE and the astrocytic inflammatory marker YKL40 were observed. Conclusions: Our results demonstrate important associations between low plasma apoE levels, A beta pathology, and progression from aMCI to a clinical ADD diagnosis.
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| 2. |
- Patra, Kalicharan, et al.
(författare)
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Assessment of kallikrein 6 as a cross-sectional and longitudinal biomarker for Alzheimer's disease
- 2018
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Ingår i: Alzheimer's Research & Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Background: Kallikrein 6 (KLK6) is known to be an age-related protease expressed at high levels in the central nervous system. It was previously shown to be involved in proteolysis of extracellular proteins implicated in neurodegenerative diseases such as Alzheimer's disease (AD), prompting validation of KLK6 as a potential biomarker of disease. However, analyses of both plasma and cerebrospinal fluid (CSF) levels of KLK6 in patients with AD have been inconclusive. We present a detailed analysis of KLK6 in plasma and CSF in two separate cohorts in a cross-sectional and a longitudinal clinical setting. Methods: The cross-sectional cohort included control subjects without dementia and patients with AD, and the longitudinal cohort included patients with MCI and patients with AD followed over a 2-year period. Plasma and CSF levels of KLK6 were quantified by use of a previously developed and validated enzyme-linked immunosorbent assay. Statistical analyses were performed to compare KLK6 levels between diagnostic groups and to identify potential associations between KLK6 level, age, apolipoprotein E (APOE) genotype, total apoE level and the classical CSF AD biomarkers. Results: In the cross-sectional setting, KLK6 levels in plasma but not in CSF were significantly higher in the AD group than in control subjects. CSF but not plasma KLK6 levels were positively correlated with age in both the cross-sectional and longitudinal settings. In both cohorts, the CSF KLK6 levels were significantly and positively correlated with the CSF levels of core AD biomarkers. Total plasma and CSF apoE levels were positively associated with KLK6 in the cross-sectional study. Finally, during the 2-year monitoring period of the longitudinal cohort, CSF KLK6 levels increased with disease progression over time in the investigated patient groups. Conclusions: In two separate cohorts we have confirmed the previously reported correlation between age and CSF levels of KLK6. Increased plasma KLK6 levels in patients with AD with a more advanced disease stage suggest KLK6 as a potential biomarker in patients with AD with more severe dementia. Significant correlations between KLK6 levels and core CSF AD biomarkers suggest molecular links between KLK6 and AD-related pathological processes.
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| 3. |
- Patra, Kalicharan, et al.
(författare)
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Plasma Apolipoprotein E Monomer and Dimer Profile and Relevance to Alzheimer's Disease
- 2019
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 71:4, s. 1217-1231
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Tidskriftsartikel (refereegranskat)abstract
- The APOE epsilon 4 gene variant is the strongest genetic risk factor for Alzheimer's disease (AD), whereas APOE epsilon 3 conventionally is considered as 'risk neutral' although APOE epsilon 3-carriers also develop AD. Previous studies have shown that the apolipoprotein E3 (apoE3) isoform occurs as monomers, homodimers and heterodimers with apolipoprotein A-II in human body fluids and brain tissue, but the relevance of a plasma apoE3 monomer/dimer profile to AD is unknown. Here we assessed the distribution of monomers, homodimers and heterodimers in plasma from control subjects and patients with mild cognitive impairment (MCI) and AD with either a homozygous APOE epsilon 3 (n = 31 control subjects, and n = 14 MCI versus n = 5 AD patients) or APOE epsilon 4 genotype (n = 1 control subject, n = 21 MCI and n = 7 AD patients). Total plasma apoE levels were lower in APOE epsilon 4-carriers and overall correlated significantly to CSF A beta(42), p(Thr181)-tau and t-tau levels. Apolipoprotein E dimers were only observed in the APOE epsilon 3-carriers and associated with total plasma apoE levels, negatively correlated to apoE monomers, but were unrelated to plasma homocysteine levels. Importantly, the APOE epsilon 3-carrying AD patients versus controls exhibited a significant decrease in apoE homodimers (17.8 +/- 9.6% versus 26.7 +/- 6.3%, p = 0.025) paralleled by an increase in apoE monomers (67.8 +/- 18.3% versus 48.5 +/- 11.2%, p = 0.008). In the controls, apoE monomers and heterodimers were significantly associated with plasma triglycerides; the apoE heterodimers were also associated with levels of high-density lipoprotein cholesterol. The physiological relevance of apoE dimer formation needs to be further investigated, though the distribution of apoE in monomers and dimers appears to be of relevance to AD in APOE epsilon 3 subjects.
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| 4. |
- Swift, Imogen J, et al.
(författare)
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A systematic review of progranulin concentrations in biofluids in over 7,000 people-assessing the pathogenicity of GRN mutations and other influencing factors.
- 2024
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Ingår i: Alzheimer's Research & Therapy. - 1758-9193. ; 16:1
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Tidskriftsartikel (refereegranskat)abstract
- Pathogenic heterozygous mutations in the progranulin gene (GRN) are a key cause of frontotemporal dementia (FTD), leading to significantly reduced biofluid concentrations of the progranulin protein (PGRN). This has led to a number of ongoing therapeutic trials aiming to treat this form of FTD by increasing PGRN levels in mutation carriers. However, we currently lack a complete understanding of factors that affect PGRN levels and potential variation in measurement methods. Here, we aimed to address this gap in knowledge by systematically reviewing published literature on biofluid PGRN concentrations.Published data including biofluid PGRN concentration, age, sex, diagnosis and GRN mutation were collected for 7071 individuals from 75 publications. The majority of analyses (72%) had focused on plasma PGRN concentrations, with many of these (56%) measured with a single assay type (Adipogen) and so the influence of mutation type, age at onset, sex, and diagnosis were investigated in this subset of the data.We established a plasma PGRN concentration cut-off between pathogenic mutation carriers and non-carriers of 74.8ng/mL using the Adipogen assay based on 3301 individuals, with a CSF concentration cut-off of 3.43ng/mL. Plasma PGRN concentration varied by GRN mutation type as well as by clinical diagnosis in those without a GRN mutation. Plasma PGRN concentration was significantly higher in women than men in GRN mutation carriers (p=0.007) with a trend in non-carriers (p=0.062), and there was a significant but weak positive correlation with age in both GRN mutation carriers and non-carriers. No significant association was seen with weight or with TMEM106B rs1990622 genotype. However, higher plasma PGRN levels were seen in those with the GRN rs5848 CC genotype in both GRN mutation carriers and non-carriers.These results further support the usefulness of PGRN concentration for the identification of the large majority of pathogenic mutations in the GRN gene. Furthermore, these results highlight the importance of considering additional factors, such as mutation type, sex and age when interpreting PGRN concentrations. This will be particularly important as we enter the era of trials for progranulin-associated FTD.
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| 5. |
- Twohig, Daniel, et al.
(författare)
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The relevance of cerebrospinal fluid α-synuclein levels to sporadic and familial Alzheimer's disease
- 2018
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Ingår i: Acta neuropathologica communications. - : Springer Science and Business Media LLC. - 2051-5960. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Accumulating evidence demonstrating higher cerebrospinal fluid (CSF) -synuclein (Syn) levels and Syn pathology in the brains of Alzheimer's disease (AD) patients suggests that Syn is involved in the pathophysiology of AD. To investigate whether Syn could be related to specific aspects of the pathophysiology present in both sporadic and familial disease, we quantified CSF levels of Syn and assessed links to various disease parameters in a longitudinally followed cohort (n=136) including patients with sporadic mild cognitive impairment (MCI) and AD, and in a cross-sectional sample from the Dominantly Inherited Alzheimer's Network (n=142) including participants carrying autosomal dominant AD (ADAD) gene mutations and their non-mutation carrying family members.Our results show that sporadic MCI patients that developed AD over a period of two years exhibited higher baseline Syn levels (p=0.03), which inversely correlated to their Mini-Mental State Examination scores, compared to cognitively normal controls (p=0.02). In the same patients, there was a dose-dependent positive association between CSF Syn and the APOE epsilon 4 allele. Further, CSF Syn levels were higher in symptomatic ADAD mutation carriers versus non-mutation carriers (p=0.03), and positively correlated to the estimated years from symptom onset (p=0.05) across all mutation carriers. In asymptomatic (Clinical Dementia Rating<0.5) PET amyloid-positive ADAD mutation carriers CSF Syn was positively correlated to C-11-Pittsburgh Compound-B (PiB) retention in several brain regions including the posterior cingulate, superior temporal and frontal cortical areas. Importantly, APOE epsilon 4-positive ADAD mutation carriers exhibited an association between CSF Syn levels and mean cortical PiB retention (p=0.032). In both the sporadic AD and ADAD cohorts we found several associations predominantly between CSF levels of Syn, tau and amyloid-(1-40).Our results suggest that higher CSF Syn levels are linked to AD pathophysiology at the early stages of disease development and to the onset of cognitive symptoms in both sporadic and autosomal dominant AD. We conclude that APOE epsilon 4 may promote the processes driven by Syn, which in turn may reflect on molecular mechanisms linked to the asymptomatic build-up of amyloid plaque burden in brain regions involved in the early stages of AD development.
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