Recommendations for the incorporation of biomarkers into Alzheimer clinical trials: an overview

Morris, John C.; Selkoe, Dennis J.

doi:10.1016/j.neurobiolaging.2011.09.005

Cited by 32 publications

(25 citation statements)

References 15 publications

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“…For A␤, therapies include both passive and active A␤ immunotherapy, ␤-secretase inhibitors, ␥-secretase inhibitors, and ␥-secretase modulators. Aside from measures of cognition, neuroimaging for amyloid with Pittsburgh compound B and CSF biomarkers such as A␤42 and p-Tau levels are the only biomarkers available to determine drug efficacy (83). Given that amyloid plaques appear not to correlate with dementia and may not represent the ideal target, and it is unclear whether low CSF A␤42 levels will be reversible with long term treatment, the relevance of these biomarkers for therapeutic trials is unclear.…”

Section: Discussionmentioning

confidence: 99%

Levels of Soluble Apolipoprotein E/Amyloid-β (Aβ) Complex Are Reduced and Oligomeric Aβ Increased with APOE4 and Alzheimer Disease in a Transgenic Mouse Model and Human Samples*

Tai

Bilousova

Jungbauer

et al. 2013

Journal of Biological Chemistry

137

146

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Background: An ELISA was developed to determine the role of apoE/A␤ on soluble A␤ accumulation. Results: In AD transgenic mouse brain and human synaptosomes and CSF, levels of soluble apoE/A␤ are lower and oligomeric A␤ levels are higher with APOE4 and AD. Conclusion: Isoform-specific apoE/A␤ levels modulate soluble oligomeric A␤ levels. Significance: ApoE/A␤ and oligomeric A␤ represent a mechanistic approach to AD biomarkers.

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Section: Discussionmentioning

confidence: 99%

Levels of Soluble Apolipoprotein E/Amyloid-β (Aβ) Complex Are Reduced and Oligomeric Aβ Increased with APOE4 and Alzheimer Disease in a Transgenic Mouse Model and Human Samples*

Tai

Bilousova

Jungbauer

et al. 2013

Journal of Biological Chemistry

137

146

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“…7 There are hypothesized models of ordered change in validated biomarkers that occur during the AD process.…”

Section: Discussionmentioning

confidence: 99%

“…4,5 New guidelines and diagnostic criteria for AD 6 now recognize a preclinical phase of the disease, detectable with imaging and CSF biomarkers. 7 There are hypothesized models of ordered change in validated biomarkers that occur during the AD process. 8 Only limited data have been available to indicate that cognitively normal older adults with positive AD biomarkers of presumptive preclinical AD are at increased risk of developing cognitive impairment and dementia.…”

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confidence: 99%

Preclinical Alzheimer disease and risk of falls

et al. 2013

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Objective: We determined the rate of falls among cognitively normal, community-dwelling older adults, some of whom had presumptive preclinical Alzheimer disease (AD) as detected by in vivo imaging of fibrillar amyloid plaques using Pittsburgh compound B (PiB) and PET and/or by assays of CSF to identify Ab 42 , tau, and phosphorylated tau. Methods:We conducted a 12-month prospective cohort study to examine the cumulative incidence of falls. Participants were evaluated clinically and underwent PiB PET imaging and lumbar puncture. Falls were reported monthly using an individualized calendar journal returned by mail. A Cox proportional hazards model was used to test whether time to first fall was associated with each biomarker and the ratio of CSF tau/Ab 42 and CSF phosphorylated tau/Ab 42 , after adjustment for common fall risk factors. Results:The sample (n 5 125) was predominately female (62.4%) and white (96%) with a mean age of 74.4 years. When controlled for ability to perform activities of daily living, higher levels of PiB retention (hazard ratio 5 2.95 [95% confidence interval 1.01-6.45], p 5 0.05) and of CSF biomarker ratios (p , 0.001) were associated with a faster time to first fall. Conclusions:Presumptive preclinical AD is a risk factor for falls in older adults. This study suggests that subtle noncognitive changes that predispose older adults to falls are associated with AD and may precede detectable cognitive changes. Falls remain the leading cause of long-term disability, premature institutionalization, injury, and injury-related mortality in the older adult population.1 Persons with Alzheimer disease (AD) dementia have an increased risk of serious falls.2 Gait changes and falls have been associated with non-AD dementias.3 However, gait change may also be associated with AD and may precede cognitive changes.4,5 New guidelines and diagnostic criteria for AD 6 now recognize a preclinical phase of the disease, detectable with imaging and CSF biomarkers. 7 There are hypothesized models of ordered change in validated biomarkers that occur during the AD process.8 Only limited data have been available to indicate that cognitively normal older adults with positive AD biomarkers of presumptive preclinical AD are at increased risk of developing cognitive impairment and dementia.9,10 However, a stage of preclinical AD has been validated by AD biomarkers in asymptomatic individuals who carry a deterministic mutation for AD.11 By definition, older adults with presumptive preclinical AD do not have cognitive symptoms as recognized by current clinical methods. However, other changes may be detectable and could yield important information about the spectrum of clinical features of the disease. Physical changes such as weight loss 12 and frailty 13 have been identified in cognitively normal individuals who later develop AD dementia. Because motor slowing precedes cognitive impairment during the typical From the Program in Occupational Therapy (S.L.S., H.H., J.C.M.), and

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“…In one example, mice expressing an APP mutation that causes AD in humans underwent rapid formation and stabilization of Aβ oligomers accompanied by profound synaptic and neuronal loss in the absence of fibrillar amyloid plaques in the cortex (Tomiyama et al, 2010). In light of numerous such studies implicating a pathogenic role of soluble Aβ oligomers and the evidence that lowered Aβ 42 monomer levels in CSF represents the earliest biomarker for AD (Bateman et al, 2012; Craig-Schapiro et al, 2009; Fagan et al, 2009; Golde et al, 2011; Morris and Selkoe, 2011), the search for such oligomers in biological fluids, primarily in human cerebrospinal fluid (CSF), has intensified in recent years (Benilova et al, 2012). The recent report that a Phase 3 trial of the Aβ-specific monoclonal antibody solanezumab produced a small but significant cognitive benefit in patients with mild AD (Doody, 2012) has made it even more critical to understand the earliest changes in the economy of synaptotoxic Aβ oligomers in the brain and biological fluids.…”

Section: Introductionmentioning

confidence: 99%

Soluble Aβ Oligomers Are Rapidly Sequestered from Brain ISF In Vivo and Bind GM1 Ganglioside on Cellular Membranes

Hong

Ostaszewski

Yang

et al. 2014

Neuron

179

151

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SUMMARY Soluble Aβ oligomers contribute importantly to synaptotoxicity in Alzheimer's disease, but their dynamics in vivo remain unclear. Here, we found that soluble Aβ oligomers were sequestered from brain interstitial fluid onto brain membranes much more rapidly than non-toxic monomers and were recovered in part as bound to GM1 ganglioside on membranes. Aβ oligomers bound strongly to GM1 ganglioside, and blocking the sialic acid residue on GM1 decreased oligomer-mediated LTP impairment in mouse hippocampal slices. In a hAPP transgenic mouse model, substantial levels of GM1-bound Aβ42 were recovered from brain membrane fractions. We also detected GM1-bound Aβ in human CSF, and its levels correlated with Aβ42, suggesting its potential as a biomarker of Aβ-related membrane dysfunction. Together, these findings highlight a novel mechanism whereby hydrophobic Aβ oligomers become sequestered onto GM1 ganglioside and presumably other lipids on neuronal membranes, where they may induce progressive functional and structural changes.

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Recommendations for the incorporation of biomarkers into Alzheimer clinical trials: an overview

Cited by 32 publications

References 15 publications

Levels of Soluble Apolipoprotein E/Amyloid-β (Aβ) Complex Are Reduced and Oligomeric Aβ Increased with APOE4 and Alzheimer Disease in a Transgenic Mouse Model and Human Samples*

Levels of Soluble Apolipoprotein E/Amyloid-β (Aβ) Complex Are Reduced and Oligomeric Aβ Increased with APOE4 and Alzheimer Disease in a Transgenic Mouse Model and Human Samples*

Preclinical Alzheimer disease and risk of falls

Soluble Aβ Oligomers Are Rapidly Sequestered from Brain ISF In Vivo and Bind GM1 Ganglioside on Cellular Membranes

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