Date Published: August 9, 2017
Publisher: BioMed Central
Author(s): Paul S. Aisen, Jeffrey Cummings, Clifford R. Jack, John C. Morris, Reisa Sperling, Lutz Frölich, Roy W. Jones, Sherie A. Dowsett, Brandy R. Matthews, Joel Raskin, Philip Scheltens, Bruno Dubois.
Basic research advances in recent years have furthered our understanding of the natural history of Alzheimer’s disease (AD). It is now recognized that pathophysiological changes begin many years prior to clinical manifestations of disease and the spectrum of AD spans from clinically asymptomatic to severely impaired. Defining AD purely by its clinical presentation is thus artificial and efforts have been made to recognize the disease based on both clinical and biomarker findings. Advances with biomarkers have also prompted a shift in how the disease is considered as a clinico-pathophysiological entity, with an increasing appreciation that AD should not only be viewed with discrete and defined clinical stages, but as a multifaceted process moving along a seamless continuum. Acknowledging this concept is critical to understanding the development process for disease-modifying therapies, and for initiating effective diagnostic and disease management options. In this article, we discuss the concept of a disease continuum from pathophysiological, biomarker, and clinical perspectives, and highlight the importance of considering AD as a continuum rather than discrete stages. While the pathophysiology of AD has still not been elucidated completely, there is ample evidence to support researchers and clinicians embracing the view of a disease continuum in their study, diagnosis, and management of the disease.
In the century since Alois Alzheimer discovered Alzheimer’s disease (AD), scientists have made remarkable strides in understanding the illness , although it was not until the 1980s that two key molecular culprits in disease pathophysiology, amyloid beta (Aβ) and tau proteins, were identified [2, 3].
Based on currently available information, AD is best conceptualized as a biological and clinical continuum covering both the preclinical (clinically asymptomatic individuals with evidence of AD pathology) and clinical (symptomatic) phases of AD. In the broadest sense, a continuum is defined as a seamless sequence in which adjacent elements (severities) are not perceptibly different from each other, although the extremes are distinct. In AD, this equates to disease progression from an asymptomatic phase, through a long preclinical period during which pathophysiological changes are reflected by increasing biomarker evidence of disease, to the symptomatic phase, during which biomarker changes continue and symptoms of cognitive and then functional impairment become increasingly evident, with the eventual loss of independence and death. These changes in the individual components of the continuum occur in a sequential but overlapping manner.
The etiology of AD is complex and much remains to be fully elucidated. The close link between genetic mutations and disorders associated with AD (mutations of presenilin 1 (PS1), presenilin 2 (PS2), amyloid beta precursor protein (APP), and Trisomy 21) and the accumulation of Aβ strongly implicates this molecule as a pathological driver in AD, but there is controversy over whether Aβ accumulation alone indicates inevitable progression to AD. Furthermore, evidence indicates that Aβ accumulation alone is probably insufficient to produce symptoms [5–7]. At some point during the disease course, additional factors are involved in determining regional neurodegeneration . Tau pathology has been suggested as a facilitator of the downstream effects of amyloid . Other investigators have proposed that synaptic, mitochondrial, metabolic, inflammatory, neuronal, cytoskeletal, myelin, and other age-related alterations may also play a role in the pathogenesis of AD .
The AD continuum is composed of multiple interconnected components (pathophysiological processes, biomarker findings, and clinical symptoms), each occurring on its own trajectory, with individual trajectories generally parallel to each other but with some temporal offsets. The trajectories are influenced by modulating factors and, for both biomarkers and clinical symptoms, are dependent upon the sensitivity of the measurement.
For the clinician, applying the continuum concept of AD raises several points of importance for counseling and prognostic discussions. AD can be diagnosed without dementia; an understanding of the biomarker changes is equally important to understanding clinical manifestations; and an appreciation for the temporal course of AD from preclinical biomarker evidence of disease through the presence of clinical symptoms is critical for effective disease diagnosis and management.
While we know that pathological changes begin long before symptoms appear, determining whether biomarker evidence of pathophysiological changes in the preclinical stage implies definite progression to clinical disease during an individual’s lifetime is difficult. Individual biomarkers do not provide definitive prognostic information. Recently, there have been efforts to improve diagnostic accuracy and ability to predict those at risk for clinical symptoms by considering a combination of biomarker findings. Jack et al.  proposed that diagnosis should be based on both the presence and absence of seven biomarkers in three categories (amyloid, tau, and neurodegeneration (A/T/N)). Dubois et al.  proposed that diagnosis be based on both Aβ and tau pathology. Using these criteria, the authors went further to differentiate between a “state” and a “stage”. In simple terms, a state is considered asymptomatic at risk of AD (cognitively normal and amyloid or tau positive but not both) or AD (amyloid and tau positive), while a stage refers to the degree of disease progression within a given state (e.g., clinical AD, preclinical AD, MCI due to AD or prodromal AD, dementia due to AD). Conceptualizing AD as a continuum may favor describing the state as dichotomous and the stage as continuous.
Clinical assessment still provides the central approach to patient evaluation and should incorporate history taking from both patients and knowledgeable informants, supplemented by the use of cognitive and functional assessment tools. For detection of AD in the primary care setting, brief cognitive screening tools with adequate sensitivity may be helpful, although careful history taking from the individual and the family is essential. Tools that may be considered include questionnaires that probe for early change (e.g., Eight-item Interview to Differentiate Aging and Dementia (AD8), Cognitive Function Instrument (CFI)), brief global cognitive screens (e.g., MMSE), and more specific tests of episodic memory impairment indicative of hippocampal dysfunction (five-word test) (Table 2). For formal diagnosis in specialist practice, a more detailed clinical assessment, including neuropsychological testing, may be considered. Table 2 provides examples of other tools and their use within the AD continuum. While attributes of a specific tool dictate where it will be most useful, there is no consensus as to which tool is most appropriate for a specific clinical environment or time point along the continuum. In the future, we will certainly see computerized testing reaching clinical practice as well as the general population at large. While batteries will provide standardized and more rapid testing, they have not yet been developed sufficiently to be adopted widely.Table 2Examples of clinical tools used and when in the disease course they are most usefulExamples of toolsBrief tools for general settingNeuropsychological testingClinical trialsClinically normal/SCICFI ADCS-PACCa FCI MCI due to AD/prodromal ADMIS FCSRT FCSRT AD8 RBANS ADCOMa GPCOG CVLT FCI Mini-cog RBANS Five-word test [64, 65]CFI MoCA ACE III MMSE DementiaMMSE ADAS-Cog ADAS-Cog ACE III RBANS CDR RBANS ADCS-ADL SIB SIB aComposite tools—comprised of select items from existing scalesACE III Addenbrooke’s Cognitive Examination-III, AD Alzheimer’s disease, AD8 Eight-item Informant Interview to Differentiate Aging and Dementia, ADAS-Cog Alzheimer’s Disease Assessment Scale—cognitive subscale, ADCOM AD composite, ADCS Alzheimer’s Disease Cooperative Study, ADL activities of daily living, CDR Clinical Dementia Rating, CFI Cognitive Function Instrument, CVLT California Verbal Learning Test, FCI Financial Capacity Instrument, FCSRT Free and Cued Selective Reminding Test, GPCOG General Practitioner Assessment of Cognition, MCI mild cognitive impairment, MIS Memory Impairment Screen, MMSE Mini-Mental State Examination, MoCA Montreal Cognitive Assessment, PACC Preclinical Alzheimer Cognitive Composite, RBANS Repeatable Battery for the Assessment of Neuropsychological Status, SIB Severe Impairment Battery, SCI subjective clinical impairment
In the development of therapeutic interventions, there has generally been a shift in focus from AD dementia to MCI due to AD/prodromal AD and earlier; there is a need for a parallel shift in the diagnostic domain, beyond the research environment, to encourage lifestyle modifications and participation in clinical trials. An appreciation of the disease continuum engenders an awareness of our need to consider both diagnosis and therapies in a similar manner, along a continuum. That is, an individual treatment or management option may be most appropriate at a defined stage along the continuum, but its use will likely extend beyond this stage, and there will be overlap among the various treatment and management options such that more than one may be appropriate at any point on the continuum. This will be particularly relevant as new DMTs with different mechanisms of action become available.
While we have traditionally described AD in terms of clinically apparent stages, we now have enough understanding of the disease course from pathophysiological, biomarker, and clinical perspectives to appreciate the need to consider AD as a continuum. That is, a process in which pathophysiological changes accumulate and eventually culminate in clinically apparent disease, which then progresses with gradual worsening of cognitive and functional abilities; there are no firm boundaries between the various clinical stages. Based on what we know today, we have endeavored to describe important characteristics along the AD continuum from disease inception to advanced clinical disease. As noted throughout, there is considerable individual variation along the continuum.