These results demonstrate a significant relationship between executive dysfunction and IADL impairment independent of diagnosis, global cognitive impairment, memory performance, depression, and apathy. Moreover, executive dysfunction was linearly or quadratically related to IADL impairment within each diagnostic group (NC, MCI, and mild AD). This relationship has previously been demonstrated in AD and other dementias4, 10
, but our findings also suggest that executive dysfunction impacts daily function in subjects with milder clinical impairment. In fact, these results demonstrate that a significant proportion of subjects with MCI and mild AD have executive dysfunction, earlier in the disease course than typically reported. This subset of MCI subjects with significant executive dysfunction have greater functional impairment and are bordering on dementia. It is very important to identify such individuals and treat them as early as possible in order to preserve their tenuous level of independence.
The current study assessed the relationship between executive dysfunction and IADL impairment in aging across a continuum of cognitive function from normal cognition to mild AD. Initially, the entire sample was assessed, followed by a focus on the MCI subjects alone. In the initial analysis, a general linear regression model was used, accounting for standard demographics, diagnosis, global cognitive impairment, memory performance, depression, and apathy. The model was also realistic in terms of curvilinear effects and interactions with diagnostic group. This model demonstrated that diagnosis accounts for more of the variance of IADL than executive dysfunction, but the latter was still independently predictive of IADL impairment. Additionally, the interaction of executive function and diagnosis in their relation to IADL was not significant. Both measures of executive function (TMT-B-A and DSym) were statistically significantly associated with IADL. Strictly speaking, the relationship with TMT-B-A was curvilinear reaching a peak and then declining because of a possible selection artifact: subjects with high TMT-B scores (worse executive function) and high FAQ scores (worse IADL) may have been too impaired to be included in the study; this in turn could have resulted in an over-representation in the high TMT-B scores (worse executive function) and low FAQ scores (better IADL), and the observed artifactual “bend” and decline instead of rise in the curve (see ).
Since the CDR, which closely relates to IADL in mildly impaired subjects, played a major role in determining diagnosis in the ADNI population, a strong relationship between diagnostic group and IADL impairment was expected. On the other hand, the CDR was one of many factors taken into account in assigning a diagnosis to the subjects participating in ADNI. The other factors included questionnaires assessing behavior, the MMSE, and neuropsychological tests assessing memory, attention, executive function, language, and visuospatial function.
When assessing MCI subject only, a linear regression model accounting for standard demographics, global cognitive impairment, memory performance, depression, and apathy, showed a significant association between IADL impairment and executive dysfunction for DSym only. TMT-B-A was not significantly associated with IADL impairment.
For the current study, we used two measures of executive function (TMT-B-A and DSym) to assess the relationship with IADL. TMT-B, with or without controlling for TMT-A, has been used widely in assessing the relationship between executive function and IADL5, 8, 26
. For the analyses of the current study we used a difference score between TMT-B and TMT-A (TMT-B-A), thus correcting for processing speed and visuomotor scanning, resulting in a purer executive function measure of set shifting27
. When assessing the entire sample (NC, MCI, and mild AD), TMT-B-A was significantly associated with IADL. However, when assessing the MCI subjects only, it was not. This may be due to a proportionally large number of subjects reaching the ceiling on TMT-B (exceeding the time limit of 300 seconds) while having relatively low or floor scores on FAQ. This was especially notable in the MCI group. The lack of a significant result for TMT-B-A may also be partly the result of lower power due to the smaller sample size. In the analysis of the full sample, strength is borrowed across diagnostic groups. On the other hand, DSym was significantly associated with IADL when assessing the entire sample, as well as MCI only. DSym is more of a processing speed task. Processing speed has been shown to relate to early cognitive decline in the elderly, well before dementia ensues32
. This may partly explain why DSym retained its significant association even when assessing the MCI subjects alone. Additionally, some argue that most tests of executive function are associated with perceptual speed and reasoning33
, thus reinforcing the use of DSym in the current analyses.
A previous meta-analysis of studies evaluating the relationship between executive dysfunction and IADL impairment showed that tests for screening global cognitive performance, such as the MMSE, related most strongly to IADL, significantly more so than any individual cognitive domain26
. However, that analysis also suggested that among the various cognitive domains, executive function is most closely related to IADL. The current study showed an association between IADL impairment and global cognitive impairment measured by the MMSE for AD subjects only. It also demonstrated a relationship between IADL impairment and memory impairment measured by a word-list delayed recall test (RAVLT) for all subjects (NC, MCI, and mild AD); this was previously reported in non-demented subjects5
. The current study showed an association between worsening apathy and IADL impairment for all subjects, which was previously reported in AD patients4, 6
. The results of the current study were also in line with previous longitudinal studies, which have shown that baseline executive dysfunction predicts worsening IADL over time and progression to clinical AD5, 11
. In addition to these findings, the current study demonstrated a strong relationship between executive dysfunction and IADL impairment, independent of global cognitive impairment, memory impairment, and apathy, thus supporting the distinct role of executive dysfunction in IADL impairment.
In this study, we also performed an analysis in which we divided amnestic MCI subjects into two groups based on presence or absence of significant executive dysfunction. We used a cut-off of 1.5 standard deviations below reported norms for executive function performance in order to obtain a clinically relevant dichotomy. This is a similar approach to that used in the ADNI standard research criteria for amnestic MCI when determining significant memory impairment. About one fifth of the amnestic MCI subjects had significant executive dysfunction in addition to memory impairment and were labeled MCI Executive, while the rest of the subjects had memory impairment but no significant executive dysfunction and were labeled MCI Non-Executive. This dichotomy should not be confused with the non-amnestic MCI model, in which MCI subjects have cognitive impairment in one or more domains that are not memory, such as executive function; in the current analysis all MCI subjects had memory impairment. The results of this analysis demonstrated that the MCI Executive group had significantly greater IADL impairment when compared to the MCI Non-Executive group, thus reinforcing the results of our primary analyses. Of note, the effect size (Cohen’s “d”) for this association was small (0.4), which makes it is difficult to interpret the results in a clinical context, as is often the case with such analyses of large databases. However, many relevant covariates were included in the regression model used, thus controlling for other clinically relevant factors.
In recent years, clinical trials assessing the efficacy of cholinesterase inhibitors in the treatment of MCI did not show a significant response when using less rigorous amnestic MCI criteria34, 35
. Another trial evaluating donepezil for the treatment of MCI used more rigorous amnestic MCI criteria36
, identical to those used in ADNI. This trial showed significant acute effects up to 18 months, but at 3 years donepezil did not significantly decrease the conversion rate from MCI to dementia. Therefore, using the approach presented here, which also accounts for executive dysfunction, may prove valuable in selecting subjects for clinical trials, who are more likely to represent prodromal AD and perhaps more likely to respond to treatment. It has been previously reported that memory impairment and executive dysfunction in non-demented subjects have been the best cognitive predictors of progression to AD5
, which further supports our findings. However, using such restrictive criteria will also make it tougher to recruit subjects for clinical trials and might not be as easily generalizable to the larger community-dwelling elderly population. Furthermore, in amnestic MCI subjects with or without executive dysfunction, the annual conversion rate to clinical AD is already 10–15% (compared to 1–2% for normal elderly controls)37
. We hypothesize that subjects with amnestic MCI plus executive dysfunction might account for the higher rate of progression, and will investigate this hypothesis in longitudinal datasets.
As illustrated in , the MCI Executive subjects were more impaired in global cognitive function (MMSE), memory (RAVLT delayed recall), and IADL (FAQ), as well as less educated than the MCI Non-Executive subjects. Thus, the MCI Executive subjects are especially likely to represent the gray zone between MCI and mild AD, which is often encountered clinically. As such, the ADNI protocol has an overlap in their criteria for MCI and mild AD, which reflects the continuum of these conditions. Furthermore, it could very well be that at the hands of different clinicians, some of the subjects in the MCI Executive group would have been diagnosed with mild AD.
The pathophysiological process underlying the clinical syndrome of MCI is known to be heterogeneous38–41
. It remains unknown whether subjects with amnestic MCI plus executive dysfunction are more likely to harbor high levels of amyloid pathology, and thus might demonstrate a better response to treatment targeting underlying AD pathology. A clinical-biomarker correlation using cerebrospinal fluid markers or clinical-imaging correlation, using positron emission tomography (PET) amyloid imaging, may help clarify this question.
There are other treatment implications of the impact of executive dysfunction on the ability to perform IADL. Symptomatic treatments, such as stimulants or dopaminergic agents, specifically targeting attention and executive function systems, might have significant impact on maintaining independence and decreasing caregiver burden. Behavioral interventions, specifically targeted at executive dysfunction symptoms, may also help maintain independence in these individuals. Identifying executive dysfunction early in the course of MCI may be critical for sustaining quality of life in non-demented elderly individuals.
The current study and analyses have several limitations. Subjects participating in ADNI were very carefully selected to neatly fit into the diagnostic groups of normal cognition for age, amnestic MCI, and mild AD. Subjects with significant cerebrovascular disease, psychiatric disorders, or major health issues were excluded. The cognitive profile of the MCI subjects was also carefully selected in order to represent subjects who are more likely to have AD as the underlying etiology of their impairments. Therefore, the ADNI population may not represent the full continuum of the cognitively impaired older population, which limits the generalizability of the findings of this study. This issue is further discussed above in the case of the even more restrictive and less generalizable population represented by the MCI Executive group obtained from the dichotomous MCI analysis. That said, the ADNI population does specifically represent a spectrum of subjects who are either at risk for AD or who are at the early stages of AD, as opposed to other causes of dementia. Another issue that the dichotomous MCI analysis brings to the foreground is the overlap in some of the criteria utilized in the MCI and mild AD diagnoses in the ADNI protocol. The same minimum criteria for memory impairment are used in both diagnoses and there is an overlap in the global cognitive impairment range of the MMSE and the global rating of the CDR. This reflects the sometimes arbitrary division between MCI and mild AD, while it is likely that in fact this represents a continuum. This is demonstrated by the performance of the MCI Executive subjects, who are closing in on the performance of the mild AD subjects. The current study has focused on executive function and has not explored other cognitive domain impairments in MCI, which may be as informative as memory impairment and executive dysfunction in assessing the relationship with IADL. On the other hand, prior studies have emphasized these two cognitive domains and global cognitive impairment in the assessment of IADL5, 26
, as well as relevant behavioral symptoms such as apathy4
, which were assessed in the current study. Finally, a ceiling effect was noted in one of the executive function measures used in the current study, TMT-B. There was also a floor effect noted in the IADL measure (FAQ) in the NC subjects. These ceiling and floor effects were addressed by modeling linear and curvilinear interactions of variables of interest with diagnosis in order to reach down and accurately model diagnostic group level differences, as well as differences in within group linear/quadratic relations as needed, being sensitive to the complexities of the data. In addition, the residual distributions reasonably conformed to test assumptions.
Few longitudinal studies demonstrating that executive dysfunction predicts functional impairment and progression to dementia have been done5, 42
. The initial three year follow-up phase of the ADNI longitudinal observational study is nearing its end. Future longitudinal analyses of the ADNI cohort and similar large well characterized cohorts will be necessary to determine whether executive dysfunction precedes IADL impairment in MCI and predicts progression to clinical AD. Functional impairment takes its toll on caregivers of AD patients and usually leads to the placement of the patient in an institution. Therefore, earlier detection and prediction of functional impairment with elements such as executive dysfunction is vital. The longitudinal studies described above will play a major role toward achieving this goal. This in turn will lead to better design of future clinical trials for the treatment of prodromal AD with a population of MCI subjects that are better characterized and suited for disease-modifying treatments targeting AD. Additionally, symptomatic treatment of executive dysfunction at early stages may also further delay IADL impairment and improve patients’ quality of life.