Modeling test and treatment strategies for presymptomatic Alzheimer disease.

James F Burke,Roger L Albin,Rodney A Hayward,Kenneth M Langa,Pedro Antonio Valdes-Sosa

doi:10.1371/journal.pone.0114339

Abstract

ObjectivesIn this study, we developed a model of presymptomatic treatment of Alzheimer disease (AD) after a screening diagnostic evaluation and explored the circumstances required for an AD prevention treatment to produce aggregate net population benefit.MethodsMonte Carlo simulation methods were used to estimate outcomes in a simulated population derived from data on AD incidence and mortality. A wide variety of treatment parameters were explored. Net population benefit was estimated in aggregated QALYs. Sensitivity analyses were performed by individually varying the primary parameters.FindingsIn the base-case scenario, treatment effects were uniformly positive, and net benefits increased with increasing age at screening. A highly efficacious treatment (i.e. relative risk 0.6) modeled in the base-case is estimated to save 20 QALYs per 1000 patients screened and 221 QALYs per 1000 patients treated.ConclusionsHighly efficacious presymptomatic screen and treat strategies for AD are likely to produce substantial aggregate population benefits that are likely greater than the benefits of aspirin in primary prevention of moderate risk cardiovascular disease (28 QALYS per 1000 patients treated), even in the context of an imperfect treatment delivery environment.

Highlights

[1] The net benefit per 1000 patients screened was substantial higher for older populations (52 quality-adjusted life years (QALYs) saved in 75 year-olds vs. 20 QALYS saved in 55 year-olds)
The benefit per patient treated was even higher for younger patients than older patients
This base-case scenario represented a best-case scenario for presymptomatic screening/treatment – such that there was even modest net benefit even in ‘‘false positive’’ patients. This apparent paradox was due to the definition of sensitivity and specificity used in this study, which was the probability that an individual patient would develop Alzheimer disease (AD) 20 years subsequently

Summary

Introduction

Alzheimer disease (AD) is a largely untreatable major public health problem whose aggregate social costs approximate those of cancer and cardiovascular disease. [1, 2] With AD prevalence rising in both developed and developing nations due to population aging, AD constitutes an urgent global problem. [3, 4] Strong genetic evidence supports the amyloid hypothesis that excessive production or impaired catabolism of amyloidogenic fragments (Aß 40 and A42 peptides) of the amyloid precursor protein (APP) initiate pathogenic cascades causing neuronal dysfunction and degeneration. [5, 6] Trials of anti-amyloid therapies in those with AD, have been disappointing,[7, 8] with little evidence of clinical benefit despite some biomarker indications of diminished brain amyloid burden. [9, 10] These disappointing trial outcomes lead to a hypothesis that treatment in symptomatic AD subjects is too late. Presymptomatic AD screen and treat strategies will have to overcome other distinctive challenges (e.g., lower population prevalence of AD and the need to develop biomarkerbased screening tools) as well as challenges in common with cardiovascular disease prevention (e.g., risks of medications in an aging population, medication compliance). These challenges raise the possibility that that even wide implementation of an efficacious presymptomatic AD treatment may fail to deliver the anticipated major societal benefit

Objectives

Methods

Results

Conclusion