Cerebrospinal Fluid YKL-40 and Neurogranin in Familial Alzheimer’s Disease: A Pilot Study

Þórðardóttir, Steinunn; Almkvist, Ove; Johansson, Charlotte; Zetterberg, Henrik; Blennow, Kaj; Graff, Caroline

doi:10.3233/jad-191261

Cited by 11 publications

(12 citation statements)

References 74 publications

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“…Gantenerumab and solanezumab had no effect on YKL-40 compared with placebo. Although increased YKL-40 level has been proposed to precede amyloid plaques, studies in sAD and DIAD have found no correlation with CSF Aβ42, ultimately leaving the treatment-related changes in YKL-40 levels a subject of future research.…”

Section: Discussionmentioning

confidence: 99%

Downstream Biomarker Effects of Gantenerumab or Solanezumab in Dominantly Inherited Alzheimer Disease

Wagemann,

Liu,

Wang

et al. 2024

JAMA Neurol

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ImportanceEffects of antiamyloid agents, targeting either fibrillar or soluble monomeric amyloid peptides, on downstream biomarkers in cerebrospinal fluid (CSF) and plasma are largely unknown in dominantly inherited Alzheimer disease (DIAD).ObjectiveTo investigate longitudinal biomarker changes of synaptic dysfunction, neuroinflammation, and neurodegeneration in individuals with DIAD who are receiving antiamyloid treatment.Design, Setting, and ParticipantsFrom 2012 to 2019, the Dominantly Inherited Alzheimer Network Trial Unit (DIAN-TU-001) study, a double-blind, placebo-controlled, randomized clinical trial, investigated gantenerumab and solanezumab in DIAD. Carriers of gene variants were assigned 3:1 to either drug or placebo. The present analysis was conducted from April to June 2023. DIAN-TU-001 spans 25 study sites in 7 countries. Biofluids and neuroimaging from carriers of DIAD gene variants in the gantenerumab, solanezumab, and placebo groups were analyzed.InterventionsIn 2016, initial dosing of gantenerumab, 225 mg (subcutaneously every 4 weeks) was increased every 8 weeks up to 1200 mg. In 2017, initial dosing of solanezumab, 400 mg (intravenously every 4 weeks) was increased up to 1600 mg every 4 weeks.Main Outcomes and MeasuresLongitudinal changes in CSF levels of neurogranin, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), chitinase 3–like 1 protein (YKL-40), glial fibrillary acidic protein (GFAP), neurofilament light protein (NfL), and plasma levels of GFAP and NfL.ResultsOf 236 eligible participants screened, 43 were excluded. A total of 142 participants (mean [SD] age, 44 [10] years; 72 female [51%]) were included in the study (gantenerumab, 52 [37%]; solanezumab, 50 [35%]; placebo, 40 [28%]). Relative to placebo, gantenerumab significantly reduced CSF neurogranin level at year 4 (mean [SD] β = −242.43 [48.04] pg/mL; P &lt; .001); reduced plasma GFAP level at year 1 (mean [SD] β = −0.02 [0.01] ng/mL; P = .02), year 2 (mean [SD] β = −0.03 [0.01] ng/mL; P = .002), and year 4 (mean [SD] β = −0.06 [0.02] ng/mL; P &lt; .001); and increased CSF sTREM2 level at year 2 (mean [SD] β = 1.12 [0.43] ng/mL; P = .01) and year 4 (mean [SD] β = 1.06 [0.52] ng/mL; P = .04). Solanezumab significantly increased CSF NfL (log) at year 4 (mean [SD] β = 0.14 [0.06]; P = .02). Correlation analysis for rates of change found stronger correlations between CSF markers and fluid markers with Pittsburgh compound B positron emission tomography for solanezumab and placebo.Conclusions and RelevanceThis randomized clinical trial supports the importance of fibrillar amyloid reduction in multiple AD-related processes of neuroinflammation and neurodegeneration in CSF and plasma in DIAD. Additional studies of antiaggregated amyloid therapies in sporadic AD and DIAD are needed to determine the utility of nonamyloid biomarkers in determining disease modification.Trial RegistrationClinicalTrials.gov Identifier: NCT04623242

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Section: Discussionmentioning

confidence: 99%

Downstream Biomarker Effects of Gantenerumab or Solanezumab in Dominantly Inherited Alzheimer Disease

Wagemann,

Liu,

Wang

et al. 2024

JAMA Neurol

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“…The standardized clinical examination included somatic, neurological, and psychiatric status, often an interview with a close informant, cognitive screening (MMSE) [ 12 ], cognitive assessment, Magnetic imaging, electric encephalography, and biochemical assessments of urine, blood, Cerebrospinal fluid markers (Abeta, total tau and phosphorylated tau), and fibroblast. Studies on non-cognitive outcomes have been reported elsewhere [ 13 , 14 ].…”

Section: Methodsmentioning

confidence: 99%

The APOE ε4 Allele Affects Cognitive Functions Differently in Carriers of APP Mutations Compared to Carriers of PSEN1 Mutations in Autosomal-Dominant Alzheimer’s Disease

Almkvist

Graff

2021

Genes

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Mounting evidence shows that the APOE ε4 allele interferes with cognition in sporadic Alzheimer’s disease. Less is known about APOE in autosomal-dominant Alzheimer’s disease (adAD). The present study explored the effects on cognition associated with the gene–gene interactions between the APOE gene and the APP and PSEN1 genes in adAD. This study includes mutation carriers (MC) and non-carriers (NC) from adAD families with mutations in APP (n = 28 and n = 25; MC and NC, respectively) and PSEN1 (n = 12 and n = 15; MC and NC, respectively) that represent the complete spectrum of disease: AD dementia (n = 8) and mild cognitive impairment (MCI, n = 15 and presymptomatic AD, n = 17). NC represented unimpaired normal aging. There was no significant difference in the distribution of APOE ε4 (absence vs. presence) between the APP vs. PSEN1 adAD genes and mutation status (MC vs. NC). However, episodic memory was significantly affected by the interaction between APOE and the APP vs. PSEN1 genes in MC. This was explained by favorable performance in the absence of APOE ε4 in PSEN1 compared to APP MC. Similar trends were seen in other cognitive functions. No significant associations between APOE ε4 and cognitive performance were obtained in NC. In conclusion, cognitive effects of APOE–adAD gene interaction were differentiated between the PSEN1 and APP mutation carriers, indicating epistasis.

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“…Additionally, CSF YKL-40 levels may be associated with the progression of the disease as it increased longitudinally in mild cognitive impairment and Alzheimer's disease patients but not in persons with normal cognitive function [153] (Table 2). In a recent pilot study, longitudinal records demonstrated an elevation in CSF YKL-40 levels in mild cognitive impairment patients as they approach symptomatic Alzheimer's disease [191]. These observations were confirmed in a study of the ADNI cohort, where, longitudinally, there was an elevation of CSF YKL-40 levels in all the groups over the mean followup time of 4 years, although the change in the biomarker was significant only in mild cognitive-impaired Aβ-positive patients [190].…”

Section: Cerebrospinal Fluid Chitinase-3-like Proteinmentioning

confidence: 99%

Cerebrospinal Fluid Biomarkers of Alzheimer’s Disease: Current Evidence and Future Perspectives

et al. 2021

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Alzheimer’s disease is a progressive, clinically heterogeneous, and particularly complex neurodegenerative disease characterized by a decline in cognition. Over the last two decades, there has been significant growth in the investigation of cerebrospinal fluid (CSF) biomarkers for Alzheimer’s disease. This review presents current evidence from many clinical neurochemical studies, with findings that attest to the efficacy of existing core CSF biomarkers such as total tau, phosphorylated tau, and amyloid-β (Aβ42), which diagnose Alzheimer’s disease in the early and dementia stages of the disorder. The heterogeneity of the pathophysiology of the late-onset disease warrants the growth of the Alzheimer’s disease CSF biomarker toolbox; more biomarkers showing other aspects of the disease mechanism are needed. This review focuses on new biomarkers that track Alzheimer’s disease pathology, such as those that assess neuronal injury (VILIP-1 and neurofilament light), neuroinflammation (sTREM2, YKL-40, osteopontin, GFAP, progranulin, and MCP-1), synaptic dysfunction (SNAP-25 and GAP-43), vascular dysregulation (hFABP), as well as CSF α-synuclein levels and TDP-43 pathology. Some of these biomarkers are promising candidates as they are specific and predict future rates of cognitive decline. Findings from the combinations of subclasses of new Alzheimer’s disease biomarkers that improve their diagnostic efficacy in detecting associated pathological changes are also presented.

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Cerebrospinal Fluid YKL-40 and Neurogranin in Familial Alzheimer’s Disease: A Pilot Study

Cited by 11 publications

References 74 publications

Downstream Biomarker Effects of Gantenerumab or Solanezumab in Dominantly Inherited Alzheimer Disease

Downstream Biomarker Effects of Gantenerumab or Solanezumab in Dominantly Inherited Alzheimer Disease

The APOE ε4 Allele Affects Cognitive Functions Differently in Carriers of APP Mutations Compared to Carriers of PSEN1 Mutations in Autosomal-Dominant Alzheimer’s Disease

Cerebrospinal Fluid Biomarkers of Alzheimer’s Disease: Current Evidence and Future Perspectives

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