| 1. |
- Alagaratnam, Jasmini, et al.
(författare)
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Correlation between cerebrospinal fluid and plasma neurofilament light protein in treated HIV infection: results from the COBRA study.
- 2022
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Ingår i: Journal of neurovirology. - : Springer Science and Business Media LLC. - 1538-2443 .- 1355-0284. ; 28:1, s. 54-63
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Tidskriftsartikel (refereegranskat)abstract
- Cerebrospinal fluid (CSF) neurofilament light protein (NfL) is a marker of central nervous system neuro-axonal injury. A novel, ultra-sensitive assay can determine plasma NfL. In untreated people-with-HIV (PWH), CSF and plasma NfL are strongly correlated. We aimed to assess this correlation in PWH on suppressive antiretroviral treatment (ART) and lifestyle-similar HIV-negative individuals enrolled into the COmorBidity in Relation to AIDS (COBRA) study. Differences in paired CSF (sandwich ELISA, UmanDiagnostics) and plasma (Simoa digital immunoassay, Quanterix™) NfL between PWH and HIV-negative participants were tested using Wilcoxon's test; associations were assessed using Pearson's correlation. CSF and plasma NfL, standardised to Z-scores, were included as dependent variables in linear regression models to identify factors independently associated with values in PWH and HIV-negative participants. Overall, 132 PWH (all with plasma HIV RNA<50 copies/mL) and 79 HIV-negative participants were included. Neither CSF (median 570 vs 568pg/mL, p=0.37) nor plasma (median 10.7 vs 9.9pg/mL, p=0.15) NfL differed significantly between PWH and HIV-negative participants, respectively. CSF and plasma NfL correlated moderately, with no significant difference by HIV status (PWH: rho=0.52; HIV-negative participants: rho=0.47, p (interaction)=0.63). In multivariable regression analysis, higher CSF NfL Z-score was statistically significantly associated with older age and higher CSF protein, and higher plasma NfL Z-score with older age, higher serum creatinine and lower bodyweight. In conclusion, in PWH on ART, the correlation between CSF and plasma NfL is moderate and similar to that observed in lifestyle-similar HIV-negative individuals. Consideration of renal function and bodyweight may be required when utilising plasma NfL.
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| 2. |
- Banerjee, Gargi, et al.
(författare)
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Cerebrospinal Fluid Biomarkers in Cerebral Amyloid Angiopathy.
- 2020
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Ingår i: Journal of Alzheimer's disease : JAD. - 1875-8908. ; 74:4, s. 1189-1201
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Tidskriftsartikel (refereegranskat)abstract
- There is limited data on cerebrospinal fluid (CSF) biomarkers in sporadic amyloid-β (Aβ) cerebral amyloid angiopathy (CAA).To determine the profile of biomarkers relevant to neurodegenerative disease in the CSF of patients with CAA.We performed a detailed comparison of CSF markers, comparing patients with CAA, Alzheimer's disease (AD), and control (CS) participants, recruited from the Biomarkers and Outcomes in CAA (BOCAA) study, and a Specialist Cognitive Disorders Service.We included 10 CAA, 20 AD, and 10 CS participants (mean age 68.6, 62.5, and 62.2 years, respectively). In unadjusted analyses, CAA patients had a distinctive CSF biomarker profile, with significantly lower (p<0.01) median concentrations of Aβ38, Aβ40, Aβ42, sAβPPα, and sAβPPβ. CAA patients had higher levels of neurofilament light (NFL) than the CS group (p<0.01), but there were no significant differences in CSF total tau, phospho-tau, soluble TREM2 (sTREM2), or neurogranin concentrations. AD patients had higher total tau, phospho-tau and neurogranin than CS and CAA groups. In age-adjusted analyses, differences for the CAA group remained for Aβ38, Aβ40, Aβ42, and sAβPPβ. Comparing CAA patients with amyloid-PET positive (n=5) and negative (n=5) scans, PET positive individuals had lower (p<0.05) concentrations of CSF Aβ42, and higher total tau, phospho-tau, NFL, and neurogranin concentrations, consistent with an "AD-like" profile.CAA has a characteristic biomarker profile, suggestive of a global, rather than selective, accumulation of amyloid species; we also provide evidence of different phenotypes according to amyloid-PET positivity. Further replication and validation of these preliminary findings in larger cohorts is needed.
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| 3. |
- Cunningham, Emma L, et al.
(författare)
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CSF Beta-amyloid 1-42 Concentration Predicts Delirium Following Elective Arthroplasty Surgery in an Observational Cohort Study.
- 2019
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Ingår i: Annals of surgery. - 1528-1140. ; 269:6, s. 1200-1205
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Tidskriftsartikel (refereegranskat)abstract
- To test the hypothesis that APOE ε4 status and cerebrospinal fluid (CSF) Aβ42, T-tau and P-tau would independently predict the risk of postoperative delirium.Delirium following surgery is common and associated with adverse outcomes. Age and cognitive impairment are consistent risk factors for postoperative delirium.This observational cohort study recruited 282 participants aged 65 years or older, without a diagnosis of dementia, admitted for primary elective hip or knee arthroplasty. Cognitive tests were undertaken preoperatively, blood and CSF were sampled at the time of spinal anesthesia, and participants were assessed daily postoperatively for delirium.Increasing age (P = 0.04), preoperative comorbidity (P = 0.03), type of surgery (P = 0.05), intravenous opioid usage (P = 0.04), and low CSF Aβ42 (P < 0.01) were independent predictors of postoperative delirium.This study is the first to show an independent association between CSF Aβ42 and delirium incidence in an elective surgical population, suggesting that postoperative delirium may indicate incipient Alzheimer disease.
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| 4. |
- Garland, Patrick, et al.
(författare)
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Neurofilament light predicts neurological outcome after subarachnoid haemorrhage.
- 2021
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 144:3, s. 761-768
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Tidskriftsartikel (refereegranskat)abstract
- To improve outcome prediction following subarachnoid haemorrhage (SAH), we sought a biomarker integrating early brain injury and multiple secondary pathological processes in a prospective study of 42 non-traumatic SAH patients and 19 control individuals. Neurofilament light (NF-L) was elevated in CSF and serum following SAH. CSF and serum NF-L on Days 1-3 post-SAH strongly predicted modified Rankin score at 6 months, independent of World Federation of Neurosurgical Societies (WFNS) score. NF-L from Day 4 onwards also had a profound impact on outcome. To link NF-L to a SAH-specific pathological process, we investigated NF-L's relationship with extracellular haemoglobin. Most CSF haemoglobin was not complexed with haptoglobin, yet was able to be bound by exogenous haptoglobin i.e. haemoglobin was scavengeable. CSF scavengeable haemoglobin was strongly predictive of subsequent CSF NF-L. Next, we investigated NF-L efflux from the brain after SAH. Serum and CSF NF-L correlated positively. The serum/CSF NF-L ratio was lower in SAH versus control subjects, in keeping with glymphatic efflux dysfunction after SAH. CSF/serum albumin ratio was increased following SAH versus controls. The serum/CSF NF-L ratio correlated negatively with the CSF/serum albumin ratio, indicating that transfer of the two proteins across the blood-brain interface is dissociated. In summary, NF-L is a strong predictive marker for SAH clinical outcome, adding value to the WFNS score, and is a promising surrogate end point in clinical trials.
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| 5. |
- Guerreiro, Rita, et al.
(författare)
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Genetic Variants and Related Biomarkers in Sporadic Alzheimer's Disease.
- 2015
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Ingår i: Current genetic medicine reports. - : Springer Science and Business Media LLC. - 2167-4876. ; 3, s. 19-25
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Tidskriftsartikel (refereegranskat)abstract
- From a neuropathological perspective, elderly patients who die with a clinical diagnosis of sporadic Alzheimer's disease (AD) are a heterogeneous group with several different pathologies contributing to the AD phenotype. This poses a challenge when searching for low effect size susceptibility genes for AD. Further, control groups may be contaminated by significant numbers of preclinical AD patients, which also reduces the power of genetic association studies. Here, we discuss how cerebrospinal fluid and imaging biomarkers can be used to increase the chance of finding novel susceptibility genes and as a means to study the functional consequences of risk alleles.
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| 6. |
- Paterson, Ross W, et al.
(författare)
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Biomarker Modelling of Early Molecular Changes in Alzheimer's Disease.
- 2014
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Ingår i: Molecular diagnosis & therapy. - : Springer Science and Business Media LLC. - 1179-2000 .- 1177-1062. ; 18:2, s. 213-227
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Forskningsöversikt (refereegranskat)abstract
- The preclinical phase of Alzheimer's disease (AD) occurs years, possibly decades, before the onset of clinical symptoms. Being able to detect the very earliest stages of AD is critical to improving understanding of AD biology, and identifying individuals at greatest risk of developing clinical symptoms with a view to treating AD pathophysiology before irreversible neurodegeneration occurs. Studies of dominantly inherited AD families and longitudinal studies of sporadic AD have contributed to knowledge of the earliest AD biomarkers. Here we appraise this evidence before reviewing novel, particularly fluid, biomarkers that may provide insights into AD pathogenesis and relate these to existing hypothetical disease models.
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| 7. |
- Paterson, Ross W, et al.
(författare)
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Cerebrospinal fluid in the differential diagnosis of Alzheimer's disease: clinical utility of an extended panel of biomarkers in a specialist cognitive clinic
- 2018
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Ingår i: Alzheimer's research & therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 10, s. 1-11
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Tidskriftsartikel (refereegranskat)abstract
- Cerebrospinal fluid (CSF) biomarkers are increasingly being used to support a diagnosis of Alzheimer's disease (AD). Their clinical utility for differentiating AD from non-AD neurodegenerative dementias, such as dementia with Lewy bodies (DLB) or frontotemporal dementia (FTD), is less well established. We aimed to determine the diagnostic utility of an extended panel of CSF biomarkers to differentiate AD from a range of other neurodegenerative dementias.We used immunoassays to measure conventional CSF markers of amyloid and tau pathology (amyloid beta (Aβ)1-42, total tau (T-tau), and phosphorylated tau (P-tau)) as well as amyloid processing (AβX-38, AβX-40, AβX-42, soluble amyloid precursor protein (sAPP)α, and sAPPβ), large fibre axonal degeneration (neurofilament light chain (NFL)), and neuroinflammation (YKL-40) in 245 patients with a variety of dementias and 30 controls. Patients fulfilled consensus criteria for AD (n=156), DLB (n=20), behavioural variant frontotemporal dementia (bvFTD; n=45), progressive non-fluent aphasia (PNFA; n=17), and semantic dementia (SD; n=7); approximately 10% were pathology/genetically confirmed (n=26). Global tests based on generalised least squares regression were used to determine differences between groups. Non-parametric receiver operating characteristic (ROC) curves and area under the curve (AUC) analyses were used to quantify how well each biomarker discriminated AD from each of the other diagnostic groups (or combinations of groups). CSF cut-points for the major biomarkers found to have diagnostic utility were validated using an independent cohort which included causes of AD (n=104), DLB (n=5), bvFTD (n=12), PNFA (n=3), SD (n=9), and controls (n=10).There were significant global differences in Aβ1-42, T-tau, T-tau/Aβ1-42 ratio, P-tau-181, NFL, AβX-42, AβX-42/X-40 ratio, APPα, and APPβ between groups. At a fixed sensitivity of 85%, AβX-42/X-40 could differentiate AD from controls, bvFTD, and SD with specificities of 93%, 85%, and 100%, respectively; for T-tau/Aβ1-42 these specificities were 83%, 70%, and 86%. AβX-42/X-40 had similar or higher specificity than Aβ1-42. No biomarker or ratio could differentiate AD from DLB or PNFA with specificity >50%. Similar sensitivities and specificities were found in the independent validation cohort for differentiating AD and other dementias and in a pathology/genetically confirmed sub-cohort.CSF AβX-42/X-40 and T-tau/Aβ1-42 ratios have utility in distinguishing AD from controls, bvFTD, and SD. None of the biomarkers tested had good specificity at distinguishing AD from DLB or PNFA.
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| 8. |
- Paterson, Ross W, et al.
(författare)
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Dissecting IWG-2 typical and atypical Alzheimer's disease: insights from cerebrospinal fluid analysis.
- 2015
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Ingår i: Journal of neurology. - : Springer Science and Business Media LLC. - 1432-1459 .- 0340-5354. ; 262, s. 2722-2730
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Tidskriftsartikel (refereegranskat)abstract
- Pathobiological factors underlying phenotypic diversity in Alzheimer's disease (AD) are incompletely understood. We used an extended cerebrospinal fluid (CSF) panel to explore differences between "typical" with "atypical" AD and between amnestic, posterior cortical atrophy, logopenic aphasia and frontal variants. We included 97 subjects fulfilling International Working Group-2 research criteria for AD of whom 61 had "typical" AD and 36 "atypical" syndromes, and 30 controls. CSF biomarkers included total tau (T-tau), phosphorylated tau (P-tau), amyloid β1-42, amyloid βX-38/40/42, YKL-40, neurofilament light (NFL), and amyloid precursor proteins α and β. The typical and atypical groups were matched for age, sex, severity and rate of cognitive decline and had similar biomarker profiles, with the exception of NFL which was higher in the atypical group (p=0.03). Sub-classifying the atypical group into its constituent clinical syndromes, posterior cortical atrophy was associated with the lowest T-tau [604.4 (436.8-675.8) pg/mL], P-tau (79.8±21.8pg/L), T-tau/Aβ1-42 ratio [2.3 (1.4-2.6)], AβX-40/X-42 ratio (22.1±5.8) and rate of cognitive decline [1.9 (0.75-4.25) MMSE points/year]. Conversely, the frontal variant group had the highest levels of T-tau [1185.4 (591.7-1329.3) pg/mL], P-tau (116.4±45.4pg/L), T-tau/Aβ1-42 ratio [5.2 (3.3-6.9)] and AβX-40/X-42 ratio (27.9±7.5), and rate of cognitive decline. Whilst on a group level IWG-2 "typical" and "atypical" AD share similar CSF profiles, which are very different from controls, atypical AD is a heterogeneous entity with evidence for subtle differences in amyloid processing and neurodegeneration between different clinical syndromes. These findings also have practical implications for the interpretation of clinical CSF biomarker results.
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| 9. |
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| 10. |
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| 11. |
- Sverrisdóttir, Oddný Ósk, et al.
(författare)
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Direct Estimates of Natural Selection in Iberia Indicate Calcium Absorption Was Not the Only Driver of Lactase Persistence in Europe
- 2014
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Ingår i: Molecular biology and evolution. - : Oxford University Press (OUP). - 0737-4038 .- 1537-1719. ; 31:4, s. 975-983
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Tidskriftsartikel (refereegranskat)abstract
- Lactase persistence (LP) is a genetically determined trait whereby the enzyme lactase is expressed throughout adult life. Lactase is necessary for the digestion of lactose-the main carbohydrate in milk-and its production is downregulated after the weaning period in most humans and all other mammals studied. Several sources of evidence indicate that LP has evolved independently, in different parts of the world over the last 10,000 years, and has been subject to strong natural selection in dairying populations. In Europeans, LP is strongly associated with, and probably caused by, a single C to T mutation 13,910 bp upstream of the lactase (LCT) gene (-13,910*T). Despite a considerable body of research, the reasons why LP should provide such a strong selective advantage remain poorly understood. In this study, we examine one of the most widely cited hypotheses for selection on LP-that fresh milk consumption supplemented the poor vitamin D and calcium status of northern Europe's early farmers (the calcium assimilation hypothesis). We do this by testing for natural selection on -13,910*T using ancient DNA data from the skeletal remains of eight late Neolithic Iberian individuals, whom we would not expect to have poor vitamin D and calcium status because of relatively high incident UVB light levels. None of the eight samples successfully typed in the study had the derived T-allele. In addition, we reanalyze published data from French Neolithic remains to both test for population continuity and further examine the evolution of LP in the region. Using simulations that accommodate genetic drift, natural selection, uncertainty in calibrated radiocarbon dates, and sampling error, we find that natural selection is still required to explain the observed increase in allele frequency. We conclude that the calcium assimilation hypothesis is insufficient to explain the spread of LP in Europe.
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| 12. |
- Toombs, Jamie, et al.
(författare)
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Amyloid-beta 42 adsorption following serial tube transfer.
- 2014
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Ingår i: Alzheimer's research & therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- Cerebrospinal fluid (CSF) amyloid-beta 38 (Aβ38), 40 (Aβ40), 42 (Aβ42) and total tau (T-tau) are finding increasing utility as biomarkers of Alzheimer's disease (AD). The purpose of this study was to determine whether measured CSF biomarker concentrations were affected by transfer of CSF between tubes, and whether addition of a non-ionic surfactant mitigates any observed effects.
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| 13. |
- Toombs, Jamie, et al.
(författare)
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Identification of an important potential confound in CSF AD studies: aliquot volume.
- 2013
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Ingår i: Clinical chemistry and laboratory medicine : CCLM / FESCC. - : Walter de Gruyter GmbH. - 1434-6621 .- 1437-4331. ; 51:12, s. 2311-2317
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Tidskriftsartikel (refereegranskat)abstract
- Abstract Background: Cerebrospinal fluid (CSF) amyloid beta 1-42 (Aβ1-42), total tau (T-tau) and phosphorylated tau181 (P-tau) are finding increasing utility as biomarkers of Alzheimer's disease (AD). The purpose of this study was to determine whether measured CSF biomarker concentrations were affected by aliquot storage volume and whether addition of detergent-containing buffer mitigates any observed effects. Methods: AD and control CSF was distributed into polypropylene tubes in aliquots of different volumes (50-1500 μL). Aβ1-42, T-tau and P-tau were measured with and without addition of Tween 20 (0.05%). Results: Measured concentrations of Aβ1-42 increased two-fold with aliquot storage volume. A volume increase of 10 µL caused an Aβ1-42 increase of 0.95 pg/mL [95% confidence interval (CI) 0.36-1.50, p=0.02] in controls, and 0.60 pg/mL (CI 0.23-0.98 pg/mL, p=0.003) in AD samples. Following addition of Tween 20, the positive relationship between Aβ1-42 and aliquot volume disappeared. T-tau and P-tau were not significantly affected. Conclusions: CSF aliquot storage volume has a significant impact on the measured concentration of Aβ1-42. The introduction of a buffer detergent at the initial aliquoting stage may be an effective solution to this problem.
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| 14. |
- Toombs, Jamie, et al.
(författare)
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In the blood: biomarkers for amyloid pathology and neurodegeneration in Alzheimer's disease.
- 2020
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Ingår i: Brain communications. - : Oxford University Press (OUP). - 2632-1297. ; 2:1
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Tidskriftsartikel (refereegranskat)abstract
- This scientific commentary refers to 'Plasma total-tau, neurofilament light chain and amyloid-β levels and risk of dementia: a population-based study' by de Wolf et al. (https://doi.org/10.1093/brain/awaa054), and 'Relationship of amyloid-b1-42 in blood and brain amyloid: Ginkgo Evaluation of Memory Study' by Lopez et al. (https://doi.org/10.1093/braincomms/fcz038), two papers that illustrate these latest developments.
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| 15. |
- Willumsen, Nanet, et al.
(författare)
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The PSEN1 E280G mutation leads to increased amyloid-β43 production in induced pluripotent stem cell neurons and deposition in brain tissue
- 2023
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Ingår i: Brain Communications. - : Oxford University Press (OUP). - 2632-1297. ; 5:1
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Tidskriftsartikel (refereegranskat)abstract
- Mutations in the presenilin 1 gene, PSEN1, which cause familial Alzheimer's disease alter the processing of amyloid precursor protein, leading to the generation of various amyloid-β peptide species. These species differ in their potential for aggregation. Mutation-specific amyloid-β peptide profiles may thereby influence pathogenicity and clinical heterogeneity. There is particular interest in comparing mutations with typical and atypical clinical presentations, such as E280G. We generated PSEN1 E280G mutation induced pluripotent stem cells from two patients and differentiated them into cortical neurons, along with previously reported PSEN1 M146I, PSEN1 R278I and two control lines. We assessed both the amyloid-β peptide profiles and presenilin 1 protein maturity. We also compared amyloid-β peptide profiles in human post-mortem brain tissue from cases with matched mutations. Amyloid-β ratios significantly differed compared with controls and between different patients, implicating mutation-specific alterations in amyloid-β ratios. Amyloid-β42:40 was increased in the M146I and both E280G lines compared with controls. Amyloid-β42:40 was not increased in the R278I line compared with controls. The amyloid-β43:40 ratio was increased in R278I and both E280G lines compared with controls, but not in M146I cells. Distinct amyloid-β peptide patterns were also observed in human brain tissue from individuals with these mutations, showing some similar patterns to cell line observations. Reduced presenilin 1 maturation was observed in neurons with the PSEN1 R278I and E280G mutations, but not the M146I mutation. These results suggest that mutation location can differentially alter the presenilin 1 protein and affect its autoendoproteolysis and processivity, contributing to the pathological phenotype. Investigating differences in underlying molecular mechanisms of familial Alzheimer's disease may inform our understanding of clinical heterogeneity.
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