Brain amyloidosis ascertainment from cognitive, imaging, and peripheral blood protein measures

Apostolova, Liana G.; Hwang, Kristy; Ávila, David; Elashoff, David; Kohannim, Omid; Teng, Edmond; Sokolow, Sophie; Jack, Clifford R.; Shaw, Leslie M.; Trojanowski, John Q.; Weiner, Michael W.; Thompson, Paul M.

doi:10.1212/wnl.0000000000001231

Cited by 41 publications

(39 citation statements)

References 42 publications

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“…This is likely because measuring Aβ deposition can be expensive and requires either access to a PET facility (amyloid PET) or experience in performing lumbar puncture, which is regarded as an invasive procedure (CSF Aβ). Further, proxy measures of Aβ based on peripheral blood proteins, which would be less costly and invasive, are not yet able to definitively identify abnormal Aβ levels[42]. A pathway-specific PRS could be used to identify patients with a higher genetic risk of having elevated Aβ deposits who may be candidates for Aβ accumulation screening.…”

Section: Discussionmentioning

confidence: 99%

Pathway-Specific Polygenic Risk Scores as Predictors of Amyloid-β Deposition and Cognitive Function in a Sample at Increased Risk for Alzheimer’s Disease

Darst

Koscik

Racine

et al. 2016

JAD

118

180

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Polygenic risk scores (PRSs) have been used to combine the effects of variants with small effects identified by genome-wide association studies. We explore the potential for using pathway-specific PRSs as predictors of early changes in Alzheimer’s disease (AD)-related biomarkers and cognitive function. Participants were from the Wisconsin Registry for Alzheimer’s Prevention, a longitudinal study of adults who were cognitively asymptomatic at enrollment and enriched for a parental history of AD. Using genes associated with AD in the International Genomics of Alzheimer’s Project’s meta-analysis, we identified clusters of genes that grouped into pathways involved in β-amyloid (Aβ) deposition and neurodegeneration: Aβ clearance, cholesterol metabolism, and immune response. Weighted pathway-specific and overall PRSs were developed and compared to APOE alone. Mixed models were used to assess whether each PRS was associated with cognition in 1,200 individuals, cerebral Aβ deposition measured using amyloid ligand (Pittsburgh compound B) positron emission imaging (PET) in 168 individuals, and cerebrospinal fluid (CSF) Aβ deposition, neurodegeneration, and tau pathology in 111 individuals, with replication performed in an independent sample. We found that PRSs including APOE appeared to be driven by the inclusion of APOE, suggesting that the pathway-specific PRSs used here were not more predictive than an overall PRS or APOE alone. However, pathway-specific PRSs could prove to be useful as more knowledge is gained on the genetic variants involved in specific biological pathways of AD.

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Section: Discussionmentioning

confidence: 99%

Pathway-Specific Polygenic Risk Scores as Predictors of Amyloid-β Deposition and Cognitive Function in a Sample at Increased Risk for Alzheimer’s Disease

Darst

Koscik

Racine

et al. 2016

JAD

118

180

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“…Kiddle et al similarly reported a signature that was associated with neocortical Aβ deposition, identifying 13 markers which were able to explain over 30 % of the between subject variation observed in neocortical Aβ deposition [60]. Other studies with the same aim of inferring neocortical Aβ deposition from a blood biomarker signature have reported efficacies of between 58 and 78% [61][62][63]. A replication study by Voyle and colleagues found pancreatic polypeptide and IgM to correlate with neocortical Aβ deposition, with IgM also correlating with neocortical Aβ deposition within cognitively normal participants [63].…”

Section: Panels Of Blood-based Biomarker-associated Disease Phenotypesmentioning

confidence: 99%

Blood-based molecular biomarkers for Alzheimer’s disease

2019

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A major barrier to the effective conduct of clinical trials of new drug candidates against Alzheimer's disease (AD) and to identifying patients for receiving future disease-modifying treatments is the limited capacity of the current health system to find and diagnose patients with early AD pathology. This may be related in part to the limited capacity of the current health systems to select those people likely to have AD pathology in order to confirm the diagnosis with available cerebrospinal fluid and imaging biomarkers at memory clinics. In the current narrative review, we summarize the literature on candidate blood tests for AD that could be implemented in primary care settings and used for the effective identification of individuals at increased risk of AD pathology, who could be referred for potential inclusion in clinical trials or future approved treatments following additional testing. We give an updated account of blood-based candidate biomarkers and biomarker panels for AD-related brain changes. Our analysis centres on biomarker candidates that have been replicated in more than one study and discusses the need of further studies to achieve the goal of a primary care-based screening algorithm for AD.

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“…The full texts of the remaining 40 publications were assessed for eligibility. A total of 28 studies were included in the qualitative synthesis of which 12 had a prospective study design [14, 16, 18, 19**, 20, 21, 22, 23, 24, 25**, 26, 27] and 16 had a cross-sectional design [28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43]. By hand search of reference lists and recent updates of included studies one additional publication was identified [44].…”

Section: Identification Of Study Reportsmentioning

confidence: 99%

“…Investigators of the ADNI cohort reported that plasma apoJ levels did not differ between individuals with MCI progressing to AD and individuals with MCI not progressing to AD [19**]. Although apoJ levels were significantly positively related to prevalent AD or all-cause dementia at baseline, apoJ levels did not predict incident all-cause dementia during 7 years of follow-up in the well-characterized population-based Rotterdam study [26].…”

Section: New Insights Into the Role Of Hdl-c And Apolipoproteins In Dmentioning

confidence: 99%

HDL-cholesterol and apolipoproteins in relation to dementia

Koch

Jensen

2016

Current Opinion in Lipidology

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Purpose of review Dementia is a major cause of disability and institutionalization. Besides age and APOE genotype, there are currently no established, clinically relevant, non-invasive markers of dementia. We conducted a literature search of recent observational epidemiological studies evaluating the relevance of high-density lipoprotein cholesterol (HDL-C) and apolipoproteins as biomarkers of future and prevalent risk of dementia. Recent findings HDL-C and apolipoproteins, such as apolipoprotein E (apoE) have been suggested to play important roles in brain function and have been associated with dementia and Alzheimer’s disease (AD) in observational studies. However, findings have been inconsistent, especially across study designs. In recent years, modern proteomic approaches have enabled the investigation of further apolipoproteins involved in the deposition and clearance of beta-amyloid, a determining factor for subsequent neurodegeneration. Summary Associations in cross-sectional studies are not always indicative of a prospective relationship. Large studies find that plasma HDL-C and apoE are inversely associated with dementia. Higher apoJ levels might be a marker of prevalent dementia, but were not associated with risk of future dementia. The investigation of HDL-C and apolipoproteins in relation to dementia represents an area of opportunity. Additional prospective studies that account for potential confounding factors and that explore potential effect modifiers such as APOE genotype and sex are needed to fully investigate the potential of these non-invasive measures in disease prediction.

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Brain amyloidosis ascertainment from cognitive, imaging, and peripheral blood protein measures

Abstract: This study provides Class II evidence that a classification algorithm based on cognitive, imaging, and peripheral blood protein measures identifies patients with brain amyloid on PiB-PET with moderate accuracy (sensitivity 68%, specificity 78%).

Cited by 41 publications

References 42 publications

Pathway-Specific Polygenic Risk Scores as Predictors of Amyloid-β Deposition and Cognitive Function in a Sample at Increased Risk for Alzheimer’s Disease

Pathway-Specific Polygenic Risk Scores as Predictors of Amyloid-β Deposition and Cognitive Function in a Sample at Increased Risk for Alzheimer’s Disease

Blood-based molecular biomarkers for Alzheimer’s disease

HDL-cholesterol and apolipoproteins in relation to dementia

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