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- Kauwe, John S K, et al.
(författare)
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Fine mapping of genetic variants in BIN1, CLU, CR1 and PICALM for association with cerebrospinal fluid biomarkers for Alzheimer's disease.
- 2011
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 6:2
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Tidskriftsartikel (refereegranskat)abstract
- Recent genome-wide association studies of Alzheimer's disease (AD) have identified variants in BIN1, CLU, CR1 and PICALM that show replicable association with risk for disease. We have thoroughly sampled common variation in these genes, genotyping 355 variants in over 600 individuals for whom measurements of two AD biomarkers, cerebrospinal fluid (CSF) 42 amino acid amyloid beta fragments (Aβ(42)) and tau phosphorylated at threonine 181 (ptau(181)), have been obtained. Association analyses were performed to determine whether variants in BIN1, CLU, CR1 or PICALM are associated with changes in the CSF levels of these biomarkers. Despite adequate power to detect effects as small as a 1.05 fold difference, we have failed to detect evidence for association between SNPs in these genes and CSF Aβ(42) or ptau(181) levels in our sample. Our results suggest that these variants do not affect risk via a mechanism that results in a strong additive effect on CSF levels of Aβ(42) or ptau(181).
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| 2. |
- Levin, Johannes, et al.
(författare)
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α-Synuclein seed amplification assay detects Lewy body co-pathology in autosomal dominant Alzheimer's disease late in the disease course and dependent on Lewy pathology burden
- 2024
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Ingår i: Alzheimer's and Dementia. - 1552-5260.
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Amyloid beta and tau pathology are the hallmarks of sporadic Alzheimer's disease (AD) and autosomal dominant AD (ADAD). However, Lewy body pathology (LBP) is found in ≈ 50% of AD and ADAD brains. METHODS: Using an α-synuclein seed amplification assay (SAA) in cerebrospinal fluid (CSF) from asymptomatic (n = 26) and symptomatic (n = 27) ADAD mutation carriers, including 12 with known neuropathology, we investigated the timing of occurrence and prevalence of SAA positive reactivity in ADAD in vivo. RESULTS: No asymptomatic participant and only 11% (3/27) of the symptomatic patients tested SAA positive. Neuropathology revealed LBP in 10/12 cases, primarily affecting the amygdala or the olfactory areas. In the latter group, only the individual with diffuse LBP reaching the neocortex showed α-synuclein seeding activity in CSF in vivo. DISCUSSION: Results suggest that in ADAD LBP occurs later than AD pathology and often as amygdala- or olfactory-predominant LBP, for which CSF α-synuclein SAA has low sensitivity. Highlights: Cerebrospinal fluid (CSF) real-time quaking-induced conversion (RT-QuIC) detects misfolded α-synuclein in ≈ 10% of symptomatic autosomal dominant Alzheimer's disease (ADAD) patients. CSF RT-QuIC does not detect α-synuclein seeding activity in asymptomatic mutation carriers. Lewy body pathology (LBP) in ADAD mainly occurs as olfactory only or amygdala-predominant variants. LBP develops late in the disease course in ADAD. CSF α-synuclein RT-QuIC has low sensitivity for focal, low-burden LBP.
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| 3. |
- Sexton, Claire E., et al.
(författare)
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Novel avenues of tau research
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Ingår i: Alzheimer's and Dementia. - 1552-5260.
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Forskningsöversikt (refereegranskat)abstract
- INTRODUCTION: The pace of innovation has accelerated in virtually every area of tau research in just the past few years. METHODS: In February 2022, leading international tau experts convened to share selected highlights of this work during Tau 2022, the second international tau conference co-organized and co-sponsored by the Alzheimer's Association, CurePSP, and the Rainwater Charitable Foundation. RESULTS: Representing academia, industry, and the philanthropic sector, presenters joined more than 1700 registered attendees from 59 countries, spanning six continents, to share recent advances and exciting new directions in tau research. DISCUSSION: The virtual meeting provided an opportunity to foster cross-sector collaboration and partnerships as well as a forum for updating colleagues on research-advancing tools and programs that are steadily moving the field forward.
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| 4. |
- 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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