Modeling screening, prevention, and delaying of Alzheimer's disease: an early-stage decision analytic model

Furiak, Nicolas M; Klein, Robert W.; Kahle-Wrobleski, Kristin; Siemers, Eric; Sarpong, Eric; Klein, T.

doi:10.1186/1472-6947-10-24

Cited by 12 publications

(14 citation statements)

References 38 publications

(36 reference statements)

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“…The available validated diagnostics for AD are neither scalable for mass population screening nor sufficiently cost-effective to be practical [ 19 ]. For example, brain imaging can provide clear evidence of neurodegeneration but is restricted to specialist centers [ 20 ] and an imaging-based public health screening program would not be affordable [ 19 , 21 ]. There is a pressing need to stratify the older healthy population, using simple and cost-effective methods, to, for example, identify those appropriate to enrich clinical trials of novel AD treatments.…”

Section: Introductionmentioning

confidence: 99%

A novel multi-tissue RNA diagnostic of healthy ageing relates to cognitive health status

et al. 2015

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BackgroundDiagnostics of the human ageing process may help predict future healthcare needs or guide preventative measures for tackling diseases of older age. We take a transcriptomics approach to build the first reproducible multi-tissue RNA expression signature by gene-chip profiling tissue from sedentary normal subjects who reached 65 years of age in good health.ResultsOne hundred and fifty probe-sets form an accurate classifier of young versus older muscle tissue and this healthy ageing RNA classifier performed consistently in independent cohorts of human muscle, skin and brain tissue (n = 594, AUC = 0.83–0.96) and thus represents a biomarker for biological age. Using the Uppsala Longitudinal Study of Adult Men birth-cohort (n = 108) we demonstrate that the RNA classifier is insensitive to confounding lifestyle biomarkers, while greater gene score at age 70 years is independently associated with better renal function at age 82 years and longevity. The gene score is ‘up-regulated’ in healthy human hippocampus with age, and when applied to blood RNA profiles from two large independent age-matched dementia case–control data sets (n = 717) the healthy controls have significantly greater gene scores than those with cognitive impairment. Alone, or when combined with our previously described prototype Alzheimer disease (AD) RNA ‘disease signature’, the healthy ageing RNA classifier is diagnostic for AD.ConclusionsWe identify a novel and statistically robust multi-tissue RNA signature of human healthy ageing that can act as a diagnostic of future health, using only a peripheral blood sample. This RNA signature has great potential to assist research aimed at finding treatments for and/or management of AD and other ageing-related conditions.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-015-0750-x) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

A novel multi-tissue RNA diagnostic of healthy ageing relates to cognitive health status

et al. 2015

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“…The use of biomarkers for identification of individuals with AD prior to the appearance of clinical symptoms, the socalled pre-dementia phase of the disease [2], will be essential to the development of drugs for early intervention [3][4][5]. Furthermore, if sufficiently powered, some biomarkers could be used as part of a screening program for at-risk elderly people [6].…”

Section: Introductionmentioning

confidence: 99%

A Blood Gene Expression Marker of Early Alzheimer's Disease

Lunnon

Sattlecker

Furney

et al. 2013

JAD

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A marker of Alzheimer's disease (AD) that can accurately diagnose disease at the earliest stage would significantly support efforts to develop treatments for early intervention. We have sought to determine the sensitivity and specificity of peripheral blood gene expression as a diagnostic marker of AD using data generated on HT-12v3 BeadChips. We first developed an AD diagnostic classifier in a training cohort of 78 AD and 78 control blood samples and then tested its performance in a validation group of 26 AD and 26 control and 118 mild cognitive impairment (MCI) subjects who were likely to have an AD-endpoint. A 48 gene classifier achieved an accuracy of 75% in the AD and control validation group. Comparisons were made with a classifier developed using structural MRI measures, where both measures were available in the same individuals. In AD and control subjects, the gene expression classifier achieved an accuracy of 70% compared to 85% using MRI. Bootstrapping validation produced expression and MRI classifiers with mean accuracies of 76% and 82%, respectively, demonstrating better concordance between these two classifiers than achieved in a single validation population. We conclude there is potential for blood expression to be a marker for AD. The classifier also predicts a large number of people with MCI, who are likely to develop AD, are more AD-like than normal with 76% of subjects classified as AD rather than control. Many of these people do not have overt brain atrophy, which is known to emerge around the time of AD diagnosis, suggesting the expression classifier may detect AD earlier in the prodromal phase. However, we accept these results could also represent a marker of diseases sharing common etiology.

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“…The treatment effectiveness of ChEIs for MCI patients was derived from a recent Cochrane review study [ 36 ] where authors reported evidence of minor benefits (effects for year 1 and year 3 were borderline significant; effects for year 2 were significant) with limitations and uncertainty, and further concluded that ChEI treatment is not recommended for MCI patients due to weak evidence. Compared with other similar studies using a hypothetical treatment effectiveness (RR 0.5) [ 29 – 31 , 70 , 71 , 73 ], however, our assumption was relatively conservative (RR 0.84) and was based on point estimates reported from the most recent review evidence. Moreover, by applying the empirical data, our approach should better reflect what the real potential treatment benefits might be, acknowledge the debate of whether we should treat MCI patients or not based on the current evidence, and reflect that if a decision must be made, it should be made based on the available evidence [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

Using Cerebrospinal Fluid Biomarker Testing to Target Treatment to Patients with Mild Cognitive Impairment: A Cost-Effectiveness Analysis

Michaud

Kane

McCarten

et al. 2017

PharmacoEconomics Open

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ObjectiveCerebrospinal fluid (CSF) biomarkers are shown to facilitate a risk identification of patients with mild cognitive impairment (MCI) into different risk levels of progression to Alzheimer’s disease (AD). Knowing a patient’s risk level provides an opportunity for earlier interventions, which could result in potential greater benefits. We assessed the cost effectiveness of the use of CSF biomarkers in MCI patients where the treatment decision was based on patients’ risk level.MethodsWe developed a state-transition model to project lifetime quality-adjusted life-years (QALYs) and costs for a cohort of 65-year-old MCI patients from a US societal perspective. We compared four test-and-treat strategies where the decision to treat was based on a patient’s risk level (low, intermediate, high) of progressing to AD with two strategies without testing, one where no patients were treated during the MCI phase and in the other all patients were treated. We performed deterministic and probabilistic sensitivity analyses to evaluate parameter uncertainty.ResultsTesting and treating low-risk MCI patients was the most cost-effective strategy with an incremental cost-effectiveness ratio (ICER) of US$37,700 per QALY. Our results were most sensitive to the level of treatment effectiveness for patients with mild AD and for MCI patients. Moreover, the ICERs for this strategy at the 2.5th and 97.5th percentiles were US$18,900 and US$50,100 per QALY, respectively.ConclusionBased on the best available evidence regarding the treatment effectiveness for MCI, this study suggests the potential value of performing CSF biomarker testing for early targeted treatments among MCI patients with a narrow range for the ICER.Electronic supplementary materialThe online version of this article (doi:10.1007/s41669-017-0054-z) contains supplementary material, which is available to authorized users.

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Modeling screening, prevention, and delaying of Alzheimer's disease: an early-stage decision analytic model

Cited by 12 publications

References 38 publications

A novel multi-tissue RNA diagnostic of healthy ageing relates to cognitive health status

A novel multi-tissue RNA diagnostic of healthy ageing relates to cognitive health status

A Blood Gene Expression Marker of Early Alzheimer's Disease

Using Cerebrospinal Fluid Biomarker Testing to Target Treatment to Patients with Mild Cognitive Impairment: A Cost-Effectiveness Analysis

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