Mild cognitive impairment (MCI) refers to the clinical state between normal cognition and probable Alzheimer’s disease (AD), but persons diagnosed with MCI may progress to non-AD forms of dementia, remain MCI until death, or recover to normal cognition. Risk factors for these various clinical changes, which we term “transitions,” may provide targets for therapeutic interventions. Therefore, it is useful to develop new approaches to assess risk factors for these transitions. Markov models have been used to investigate the transient nature of MCI represented by amnestic single-domain and mixed MCI states, where mixed MCI comprised all other MCI subtypes based on cognitive assessments. The purpose of this study is to expand this risk model by including a clinically determined MCI state as an outcome. Analyses show that several common risk factors play different roles in affecting transitions to MCI and dementia. Notably, APOE-4 increases the risk of transition to clinical MCI but does not affect the risk for a final transition to dementia, and baseline hypertension decreases the risk of transition to dementia from clinical MCI.
Mild cognitive impairment (MCI) often refers to the clinical condition between normal cognition and probable Alzheimer’s disease (AD). However, persons diagnosed with MCI may progress to non-AD forms of dementia, remain MCI until death, and in some instances recover to a normal cognitive state [
In a previous study we investigated MCI as defined by cognitive test performance alone. Here, we have added a clinical consensus-based MCI state as defined by the Second International Working Group on MCI [
Subjects in the current study are from the Biologically Resilient Adults in Neurological Studies (BRAiNS) at the University of Kentucky’s Alzheimer’s Disease Center (UK ADC), a longitudinal cohort of 1,030 individuals with ongoing recruitment established in 1989 [
Annual cognitive test-based assessments taken on a cohort of initially cognitively normal subjects participating in the BRAiNS project are used to classify subjects into one of three states: normal, test-based amnestic MCI (aMCITB), or test-based mixed MCI (mMCITB) (Table
Criteria for state classification.
State | Definition |
---|---|
Normal cognition | No cognitive test score more than 1.5 standard deviations (SD) below the age-adjusted mean; absence of MCICC or Dementia (see below) |
Test-based amnestic MCI (aMCITB) | At least one score more than 1.5 SD below the age-adjusted mean on the following measures of episodic memory: Wechsler Logical Memory, Benton Visual Retention Test (number correct or number of errors), a word list (Consortium to Establish a Registry in Alzheimer’s Disease word list or California Verbal Learning Test ) total learning score, delayed recall score, savings score, and the maximum recalled minus delayed recall score |
Test-based mixed MCI (mMCITB) | At least one score more than 1.5 SD below the age-adjusted mean on the following measures of language and executive function: phonemic or category verbal fluency, Boston Naming Test (15-item), and Trail Making Tests A or B |
Clinical consensus-based MCI (MCICC) | A cognitive complaint by the subject or informant, or evidence for longitudinal decline on cognitive test performance (at least 1.5 SD decline); generally intact global cognition; no or minimal functional impairment; not demented by DSM-IV criteria; neurodegenerative etiology suspected |
Dementia | Meeting DSM-IV criteria for dementia, or NINCDS/ARDRA criteria for possible or probable AD, or NINDS-AIREN criteria for possible or probable vascular dementia, or DLB Consortium criteria for Lewy body disease |
Classification into clinical consensus-based MCI (MCICC) results from a diagnosis of MCI, which is determined according to the consensus guidelines on MCI developed by the Second International Working Group on MCI [ a cognitive complaint by the subject or informant, or evidence for longitudinal decline on cognitive test performance (at least 1.5 SD decline); generally intact global cognition; no or minimal functional impairment; not demented by DSM-IV criteria.
Additionally, MCICC is restricted to those individuals for whom a neurodegenerative etiology is suspected. The NACC diagnostic criteria designate patients with cognitive impairments but without a presumed degenerative etiology as “cognitive impairment, not MCI” [
Between their annual assessments, subjects may die or become demented, and these states are treated as completely absorbing competing states. MCICC is treated as a quasi-absorbing state, as subjects do not move backward to a transient state (i.e., normal cognition, aMCITB, or mMCITB), but they may become demented or die.
For 19 subjects, review of the longitudinal record revealed apparent back transitions from MCICC to normal: nine subjects were diagnosed with MCICC, reverted to normal, and then reconverted to MCICC, three of whom eventually became demented; six subjects had a single diagnosis of MCICC between several diagnoses of normal cognition on either side; and four subjects had a single diagnosis of MCICC at their initial evaluation following the UK ADC’s implementation of the NACC Uniform Data Set (UDS) cognitive and clinical testing protocol [
The conditional distribution of the cognitive status at any assessment given the status at the prior assessment is assumed to have the Markov property. That is, the status at the current assessment depends only on the status at the prior assessment [
Flow diagram of transitions possible between subject visits. Normal cognition is the base state for transitions made from normal cognition, test-based amnestic MCI, and test-based mixed MCI; clinical consensus MCI is the base state otherwise.
The base state is normal cognition while a participant’s prior state is normal cognition, aMCITB, or mMCITB; once a participant has moved into MCICC, the base state then becomes MCICC. The model is additive, which means in practice that although we assume the risk factors are independent of the
Covariates of interest include age at assessment (centered at 78, the sample median), sex (1 = female, 0 = male), education (two levels: ≤12 years, >12 years), presence (1) or absence (0) of any copies of the APOE-4 allele, presence (1) or absence (0) of family history of dementing illness among first degree relatives, and presence (1) or absence (0) of hypertension at study entry. Hypertension status at entry was derived from participant responses to the question “have you ever been told by a doctor or nurse that you have high blood pressure?” Use of medications was also recorded; however, reported use of an antihypertensive medication did not supersede a participant’s response of “no” since anti-hypertensives are used to treat other illnesses. Also included as covariates (when the base state is normal cognition) are two indicator variables for (1 = yes, 0 = no) aMCITB and mMCITB; normal cognition is the reference category. Race was not included as a covariate because almost all of the included subjects (99%) are Caucasian.
Study participants contribute an average of 10.8 annual assessments (median = 10 assessments, mode = 10 assessments) with the average time between assessments at approximately 13 months (Table
Subject characteristics (
Characteristic | Summary |
---|---|
Age at entry, | |
Female, % | 64.3 |
Family history of dementia, % | 41.3 |
At least one APOE-4 allele, % | 30.0 |
>12 years of education, % | 88.1 |
History of hypertension at entry, % | 36.6 |
Hypertension treated with medication, % | 86.5 |
Number of assessments (mean ± SD) | |
Time between assessments, |
Table
One-step transition matrix (number of assessments [% of prior visit state]).
Prior visit | Current visit | |||||
---|---|---|---|---|---|---|
Normal | Amnestic MCITB | Mixed MCITB | Clinical Consensus MCI | Dementia | Death | |
Normal | 2192 (68.3) | 478 (14.9) | 385 (12.0) | 34 (1.1) | 19 (0.6) | 100 (3.1) |
Amnestic MCITB | 448 (59.3) | 148 (19.6) | 108 (14.3) | 23 (3.1) | 10 (1.3) | 18 (2.4) |
Mixed MCITB | 341 (33.0) | 88 (8.5) | 453 (43.8) | 47 (4.5) | 27 (2.6) | 79 (7.6) |
Clinical Consensus MCI | 101 (66.9) | 34 (22.5) | 16 (10.6) |
A number of risk factors alter the probability of transition to an MCI state (Table
Estimated relative risks and 95% confidence intervals for one-step transitions to test-based amnestic MCI (aMCITB), test-based mixed MCI (mMCITB), or clinical consensus MCI (MCICC) versus the base state of normal cognition (bolding denotes statistical significance).
Risk factor* | aMCITB versus Normal | mMCITB versus Normal | MCICC versus Normal |
---|---|---|---|
Age | 1.07 (1.05–1.08) | ||
Female sex (versus male) | 1.01 (0.82–1.24) | 0.71 (0.46–1.09) | |
Family history of dementia (yes versus no) | 0.81 (0.65–1.00) | 1.04 (0.66–1.64) | |
≥one APOE-4 allele (versus none) | 1.04 (0.83–1.31) | 1.12 (0.89–1.40) | |
≤12 years of education (versus >12 years) | 1.24 (0.89–1.74) | 1.79 (1.33–2.42) | |
History of hypertension (yes versus no) | 0.95 (0.76–1.18) | 1.04 (0.84–1.28) | 0.79 (0.42–1.49) |
aMCITB at prior assessment (versus normal) | 1.15 (0.91–1.45) | 1.00 (0.77–1.29) | |
mMCITB at prior assessment (versus normal) | 0.76 (0.57–1.02) |
*As risk factors do not depend on the prior state, covariate effects are the same regardless of whether transitions occur from a prior state of normal cognition, aMCITB, or mMCITB.
Demographic risk factors for transition to the MCICC state (versus remaining in or returning to a normal state) are older age (
In the absence of MCICC, risk factors for dementia include older age (
Participants in this sample who transitioned from MCICC to dementia (
Estimated relative risks and 95% confidence intervals for one-step transitions to dementia or death without dementia versus the base state of normal cognition or clinical consensus MCI (MCICC) (bolding denotes statistical significance).
Risk factors* (normal is base state; no history of MCICC) | Dementia versus normal | Death versus normal |
---|---|---|
Age | ||
Female sex (versus male) | 1.87 (0.95–3.68) | |
Family history of dementia (yes versus no) | 1.66 (0.92–3.01) | 0.82 (0.57–1.17) |
≥one APOE-4 allele (versus none) | 0.97 (0.67 –1.42) | |
≤12 years of education (versus >12 years) | 0.75 (0.26–2.18) | 1.33 (0.80 –.22) |
History of hypertension (yes versus no) | 0.79 (0.42–1.49) | |
aMCITB at prior assessment (versus normal) | 1.85 (0.82–4.21) | 0.64 (0.38–1.08) |
mMCITB at prior assessment (versus normal) | ||
Risk factors (MCICCis base state) | Dementia versus MCICC | Death versus MCICC |
Age | 1.05 (0.98–1.13) | 1.03 (0.94–1.13) |
Female sex (versus male) | 1.75 (0.67–4.56) | 1.15 (0.65–3.76) |
Family history of dementia (yes versus no) | 2.88 (0.95–8.72) | 0.68 (0.15–3.03) |
≥one APOE-4 allele (versus none) | 0.69 (0.22–2.16) | 2.33 (0.61–8.90) |
≤12 years of education (versus >12 years) | 0.97 (0.27–3.46) | 0.55 (0.10–2.99) |
History of hypertension (yes versus no) | 0.70 (0.20–2.47) |
*As risk factors depend only on the base state, covariate effects in the top half of the table are the same whether transitions occur from a prior state of normal cognition, aMCITB, or mMCITB.
The addition of the MCICC state to the multistate Markov chain confirms the utility of cognitive testing in predicting true underlying cognitive impairment. Entry into aMCITB and particularly mMCITB, both of which are determined solely by poor performance on cognitive assessment, increases the risk of a diagnosis of MCICC at the next visit versus returning to normal. These results highlight the importance of objective criteria in MCI diagnosis and emphasize the role of cognitive testing, particularly of language and executive function, in early detection. Notably, poor performance limited to tests of episodic memory (aMCITB) in this population can resolve to normal performance at the next annual assessment as much as 60% of the time and progress to MCICC just 3% of the time (Table
These findings reflect a novel analysis of risk factors for MCI and dementia based on the current NACC UDS criteria that are used across AD centers in the United States [
Risk factors for one-step transitions into MCICC include age, low education, prior classification as either aMCITB or mMCITB, and the presence of at least one APOE-4 allele. APOE-4 is a known risk factor for AD, and although results for MCI have been mixed, a recent study of a nationally representative sample reported that APOE-4 was a reliable predictor of MCI versus normal cognition [
It is clear that once an individual has transitioned to MCICC, the risk of dementia increases dramatically. In this sample, 38.5% of individuals with MCICC have transitioned to dementia (at an estimated overall rate of 12.6% per year) compared to 11.8% of individuals with no history of MCICC (at an estimated overall rate of 0.16% per year). However, common risk factors for dementia (i.e., age, sex, education, family history, and APOE-4) do not predict whether an individual will remain in MCICC or transition to dementia, or death without dementia, at the next visit. Similar results have been reported in studies that have examined risk factors for progression of cognitive impairment. Tschanz et al. [
Participants who reported hypertension at baseline were significantly less likely to transition from MCICC to dementia at the next visit, which may indicate a primarily vascular rather than an AD or mixed AD and vascular etiology for MCICC in these patients. Several studies have shown that brain white matter changes are associated with cognitive decline in aging [
As with aMCITB, mMCITB, and MCICC, older age increases the probability of a transition to a dementia state. Baseline hypertension plays no role in transitions to aMCITB, mMCITB, MCICC, or dementia (in the absence of MCICC), predicting only transitions to death (modeled as a competing risk for dementia). This result agrees with our previous research [
All forms of MCI, and dementia as well, reflect a heterogeneous (and not completely understood) group of diseases including AD, hippocampal sclerosis, dementia with Lewy bodies, and vascular dementia [
Limitations of the current study include that the final outcome for many of the included subjects is unknown as they continue to be followed longitudinally. Additional followup may change the results observed here, though they have face validity. The generalizability of the results is also somewhat limited due to the sample’s demographic and geographic homogeneity, which would not be replicated in a population-based sample, and the nature of the longitudinal study, which requires brain donation at death. The volunteers are highly motivated and highly educated, and the frequency of both family history of dementia and APOE-4 is higher than what would be observed in the general population. Biomarker data (i.e., blood, cerebrospinal fluid, and neuroimaging) are for the most part unavailable on these subjects, and studies that have investigated risk factors for transition from clinical MCI to dementia have largely been focused on biomarkers [
Finally, a large portion of this University of Kentucky-based longitudinal cohort was not included in this study (
This research was partially funded with support from the following grants to the University of Kentucky’s Center on Aging: R01 AG038651-01A1 and P30 AG028383 from the National Institute on Aging, as well as a grant to the University of Kentucky’s Center for Clinical and Translational Science, UL1RR033173, from the National Center for Research Resources.