Rapid Review of Minimum Clinically Important Differences in Alzheimer’s Disease

     Alzheimer’s Disease (AD) is characterized by the extracellular accumulation of amyloid-beta plaques and intracellular micro-tubule associated protein tau tangles, resulting in a progressive neurodegenerative disorder that clinically manifests most often as amnestic pattern of cognitive decline.(1-5) AD leads to progressive functional decline and is the leading cause of Dementia after mixed-dementia with concomitant cerebrovascular disease.(5-7) 

     For decades the treatment of Alzheimer’s Disease has centered on largely supportive measures and cognitive enhancing pharmacotherapies, namely cholinesterase inhibitors and NMDA receptor antagonists, but these interventions are not disease modifying. Lecanumab, an IgG immunotherapy targeting soluble protofibrils of amyloid-beta, is a new immunotherapy for early AD that accelerates the removal of amyloid-Beta and slows the rate of cognitive decline by 27% at 18 months.(8) This novel immunotherapy may offer some hope in altering the clinical progression of Alzheimer’s Disease and may have a disease modifying effect.(8) The recent United States Food and Drug Association (FDA) approval of Lecanumab necessitates the rapid mobilization of resources and dissemination of education to clinicians who may be caring for patient’s with Alzheimer’s Disease who are potentially eligible for Lecanumab.  

     One critical aspect of preparedness for the widespread implementation, use and monitoring of Lecanemab and other potential future and emerging immunotherapies such as Donanemab, is an understanding of what might constitute the minimum clinically meaningful change in established functional or cognitive outcomes in Alzheimer’s Disease. While new and emerging immunotherapies might appear to slow the progression of cognitive and functional decline, it is not clear whether these changes, albeit statistically significant, are clinically significant.(9, 10) Overall, there is no clear consensus on what change in outcome measures would constitute the minimal clinically important difference (MCID).(9-11) Some evidence even suggests that the MCID may also depend on the stage and severity of AD.(12) The MCID can be defined through anchor based and distribution-based methods.(9, 13-15) Anchor-based MCID methodology examines the association between scores on an administered instrument and another independent measure used as the anchor of clinical meaningfulness.(13) The two requirements of an anchor-based approach must be that the anchor must be interpretable and, second, that there must be an association between the target and the anchor.(13) Anchor based methods to determine MCID in trials of AD appears to be the most appropriate approach to employ. Some of the most validated and widely used instruments of cognition and functionality in AD clinical trials include Mini-mental State Examination [MMSE]; Clinical Dementia Rating scale sum of boxes (CDR-SB); Alzheimer’s Disease Cooperative Study Activities of Daily Living Scale (ADCS-ADL); and the Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog). Using an anchor-based approach, these validated scales would ultimately be anchored against an independent metric, that is, the expert clinician’s impression of whether or not the patient with Alzheimer’s Disease experienced a clinically meaningful decline over the follow up period.(9, 13-15) The determination of the MCID in the cognitive or functional rating scale would be done by ascertaining the change in the cognitive or functional scale score that this clinically meaningful change ultimately corresponds to.  

     To the best of our knowledge, there has been no systematic review summarizing MCIDs using either anchor based or distribution-based methods to define MCID in established cognitive and functional outcomes in Alzheimer’s Disease clinical trials. In light of the FDA’s recent approval of Lecanumab, a rapid systematic review summarizing MCIDs across relevant outcomes in AD is necessary and would likely have great impact as an adjunctive resource for clinicians monitoring and evaluating clinically meaningful changes in those receiving new immunotherapies for AD.    

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