In a randomly sampled population-based cohort, the baseline prevalence of MCI varied by definition,15
as would be expected with any syndromic entity. Over one-year follow-up, the same MCI definitions led to different proportions of progression (worsening), reversion (improvement), and stability. As the various criterion sets overlap only partially, individuals can be classified as impaired by one definition and as normal by another. For example, with the Mayo Criteria defined as including CDR <1, MCI individuals could be either CDR=0 or CDR=0.5; among these, only those at CDR=0.5 can revert to CDR=0. Similarly, by designating worsening as progression to CDR >=1, we could be underestimating progression by not including worsening from CDR=0 to CDR=0.5.
With the above caveats, across MCI definitions, relatively small proportions (0–3%) progressed to dementia defined as CDR >=1 but at significantly higher rates than those with normal cognition. Progression was most likely to be seen among the definitions emphasizing memory. Larger proportions (1–20%) were found to worsen when the outcome was defined as severe cognitive impairment; again, MCI definitions with amnestic components showed had the highest progression. Within the purely cognitive classification, multi-domain amnestic impairment showed more progression than single-domain amnestic impairment, while non-amnestic impairments had the lowest progression.
Greater proportions of individuals with baseline MCI showed improvement, compared to worsening, at one-year followup. With CDR=0 as the outcome, the range of reversion was about a quarter of those with baseline CDR=0.5 alone. When reversion was characterized as normal cognition, the lowest proportion reverted from amnestic multi-domain MCI (which also had the highest proportion progressing to severe cognitive impairment). While reversion in the purely cognitive definition could be attributed to instability of measurement or intra-individual variability, the same phenomenon was also observed for our functional (CDR) and combined cognitive-functional (Mayo and IWG) definitions.
However, the most frequent outcome was stability, i.e. no change in MCI status. These proportions ranged from 72% to 88% for stable CDR, and from 33% to 79% for stable MCI by broad cognitive classification. The single-domain MCIs, whether amnestic or non-amnestic, were the least likely to remain cognitively unchanged while the CDR=0.5 group was the most likely to remain cognitively unchanged.
Our cohort study indicates, as have previous studies,4,8,10–12
that the MCI syndrome is a heterogeneous entity at the population level regardless of definition. A small proportion progresses to dementia or severe cognitive impairment, a somewhat larger proportion reverts to normal, while the majority remain unchanged. Most individuals with mild impairment remain at least mildly impaired. Some individuals who meet MCI criteria may have always functioned at a mildly impaired level, invoking the concept of “accidental MCI.”24
The heterogeneity in outcome observed here is greater than reported from clinical settings, where individuals seek care for cognitive impairment, and where progression occurs at the rate of 12–15% annually.13
Heterogeneity in outcome suggests heterogeneity in the underlying pathology. MCI definitions reflecting impairment in memory predicted more progression, and less reversion, than impairment in other domains, regardless of whether the definition is neuropsychological, functional, or both. Since memory deficits are the hallmark of dementing disorders such as Alzheimer’s disease (AD), MCI definitions centered on memory may be identifying individuals in the early stages of these disorders, which may be in the minority at the population level.
Finally, our data indicate that mild impairment in one domain, memory or otherwise, is more likely to predict reversion to normal than mild impairment in two or more domains, as was also observed in another population study.25
This source of variation could represent heterogeneity in etiology and/or in stage along the course of a given disease. For example, an individual with a non-progressive condition, e.g., depression, medication side-effects, or hypoxia, might suffer transient or reversible cognitive impairment reflecting resolution of the underlying condition. Alternatively, a person at a very early stage of AD might not manifest cognitive deficits unless a second condition is also present; if the second condition resolves, improvement might be noted temporarily. Further, a person with any progressive dementia may experience lability or “wobble” in function and performance early in the disease course, before the deficits become more pervasive and sustained, and this intra-individual variability itself may reflect underlying brain disease.26
Compared to single-domain impairments, impairment in two domains suggests a greater likelihood of underlying disease, which has reached a later stage, closer to the dementia threshold. Even within the normal range of cognition, poorer neuropsychological test scores predict subsequent decline in CDR.20
In our cohort, as in clinical practice, a minority of individuals did not return for followup assessment at one year because of death, relocation, illness, or elective dropout. At study entry, these individuals had been older, less educated, and more cognitively impaired than those who were followed up. Had they remained in the study, and experienced worsening in large enough proportions, they may have increased the progression rates for most but not all MCI definitions.
While one year is a relatively short period in which to observe MCI outcomes, it mirrors clinical practice where the first annual followup is often essential to validate the original diagnosis. While longer prospective studies usually report annual progression rates averaged over multiple years, 5,8,12, 14
the annual rate changes over time.12
Repeated assessments of this cohort over a longer followup period will clarify these patterns and identify the profiles of individuals whose mild impairments are likely to develop into dementia eventually. The incorporation of biomarker and risk factor assessments may further improve the characterization of MCI at the population level.
Population-based cohorts suffer less selection bias and are more representative of the community than specialty clinic samples. Being large, they are powered to detect relatively small effects. However, participants recruited randomly from the community are not necessarily concerned about their cognition; their subjective reports (“complaints”) are not spontaneously offered but rather elicited by standardized questions, and may vary in clinical and prognostic significance. Normal or mildly impaired individuals in the community who are not seeking care for cognitive difficulties may not have surrogate informants more knowledgeable than themselves about their own everyday functioning. Dementia ratings based on participants’ self-reports plus raters’ observations may differ from ratings based on family reports typically obtained in specialty clinics. In most population studies, participants are assessed using standardized protocols implemented by research personnel who, while highly trained, are not expert clinicians exercising judgment regarding help-seeking patients in the clinic. Classification is based on statistical or actuarial criteria, which in clinical settings could be overridden by expert clinical judgment. Thus, both heterogeneity in the participant pool and methodological factors can account for variance in proportions with progression and reversion in MCI between clinical and community studies, with results fairly consistent within these groups of studies. 27
Population-based data illustrate the importance of validating research criteria at the community level before they are recommended for clinical practice.