Patients with AD, while typically conceptualised as having an illness primarily of episodic memory, may manifest more prominent dysfunction in other cognitive domains, sometimes as the most salient feature of the illness. Threads of clinical research going back two decades have investigated the clinical heterogeneity of AD and the possibility of consistent clinical subtypes.7 9 15
Based on our own experience having seen individuals with such disparate forms of AD, we sought here to compare the characteristics of very mild AD patients with disproportionate executive dysfunction to those with predominant amnesia. We found that the executive predominant and memory predominant subgroups were reliably identifiable in two separate patient groups in the ADNI sample (MCI and AD, both CDR 0.5), indicating that even at a very mild stage of the illness such distinct clinical subtypes are not uncommon, consistent with a previous investigation of dysexecutive MCI.10
The subgroups were defined on the basis of performance on two neuropsychological tests but exhibited consistent generalisable deficits in these cognitive domains on multiple tests (separate from those used to define the subgroups). Furthermore, the executive predominant subgroup was more impaired than the memory predominant subgroup in daily life with respect to judgement and problem solving and showed a trend towards more rapid overall 2 year clinical decline. In addition to investigating these clinical characteristics, as first steps towards exploring biological differences between these subgroups, we found that the APOE-ε4 allele was considerably over-represented in the memory predominant subgroup (nearly twice as frequent) compared with the executive predominant subgroup, and that the executive predominant subgroup exhibited more prominent cortical atrophy in lateral frontoparietal regions than the memory predominant subgroup.
Although executive, language, visuospatial or behavioural symptoms may dominate the clinical picture of atypical forms of AD, executive dysfunction may not stand out as much as a primary feature because it colours performance in many other domains, particularly memory. Individuals with prominent executive dysfunction may appear to be globally impaired on neuropsychological tests although careful probing of cognitive domains using tasks with reduced executive demand may indicate relative preservation of memory, language or visuospatial function. For example, deficits in free recall, which have been heavily employed as indicators of amnesia in AD research,16
clearly reflect not only memory but also executive and lexical search processes involved in retrieval.17 18
For this reason, we chose to operationalise the definition of amnesia in this study using a recognition discriminability index which represents the individual's ability to correctly recognise previously encountered information as old while identifying information not previously encountered as new. This type of memory task is usually considered to be subserved by the temporolimbic episodic memory system(s) and to be low with respect to demands on executive function, as reflected by relative sparing of performance in frontal lesion patients.19
In contrast, executive function was operationalised using the letter–number sequencing task of the Trail Making Test, adjusted for speed on the rote number sequencing task. This type of executive task is thought to be subserved by frontoparietal executive control systems.20
We employed an approach using two individual, widely used tests because we hope that this will enable the efficient investigation of this issue in other large samples in which similar tests are used, and because future studies could add these two tests with little additional burden.
Based on these two distinct psychometric performance measures, we identified very mild AD patients with much more prominent (difference of at least 2 SDs) executive dysfunction than memory impairment and others with much more impaired memory than executive function. We specifically did not require normal performance in either domain, as has been done previously,10
because this investigation was focused on the predominance of dysfunction within a particular cognitive domain in patients who have multiple cognitive deficits rather than impairment solely within a single domain. We investigated the generalisability of these findings in two ways. Firstly, the executive predominant and memory predominant clinical subgroups were also identified in the MCI patient sample. Secondly, factor analyses were performed separately in the AD and MCI patient groups on other psychometric tasks not used to define the clinical subgroups and identified three similar factors representing Lexical/Executive function, Episodic Memory and Processing Speed/Working Memory. In both the MCI and AD patient groups, the phenotypes generalised to these factors with the executive predominant subgroups of both MCI and AD patient groups performing worse on these other measures of Lexical/Executive function and the memory predominant subgroups both performing worse on other measures of Episodic Memory. These findings are similar to those reported previously for dysexecutive MCI patient subgroups10
and for patients with mild to moderate AD,7
but their replication in two separate samples in the present study support the idea that they are broadly generalisable.
One might question our classification of MCI patients from the ADNI cohort as having a dysexecutive phenotype as all patients were diagnosed with traditional amnestic MCI21
for inclusion in the cohort. However, just as with mild clinical AD, these patients may still have disproportionate executive impairment despite concomitant amnesia. Furthermore, a free recall memory measure (Wechsler Memory Scale Logical Memory II) was used to operationalise objective memory impairment to qualify for the a-MCI diagnosis. Thus it is possible that those with prominent executive impairment displayed free recall deficits at least partly on this basis rather than due to the loss of integrity of temporolimbic structures. Indeed, this group performed less than 0.5 SDs below that of healthy controls on the recognition memory measure, suggesting a relative preservation of the mnemonic aspects of episodic memory.
In addition to psychometric differences, the executive predominant subgroup exhibited greater impairment in the CDR Judgement and Problem Solving box, an indication of greater executive dysfunction in daily life. There was a trend towards slightly more impairment in the CDR Memory box in the memory predominant subgroup (). Comparable results were reported previously10
with respect to more prominent executive dysfunction in daily life in the dysexecutive MCI subgroup, as measured by the Dysexecutive Questionnaire.22
Furthermore, in the present study, the rate of clinical decline, as indicated by the 2 year change in CDR Sum of Boxes was slightly higher (trend level effect) in the executive predominant subgroup than in the memory predominant subgroup. To our knowledge, such results relating to prognostic implications of a dysexecutive AD phenotype have not been previously reported.
With respect to the potential biological underpinnings of these subtypes, we identified a much higher (nearly double) frequency of the APOE-ε4 allele in the memory predominant subgroup compared with the executive predominant subgroup. This was also observed previously by Pa et al with 52% ε4 carrier frequency in their amnesic MCI subgroup and 37% carrier frequency in their dysexecutive subgroup. However, one criticism of their finding, as they point out in the discussion, is that some of their dysexecutive MCI group may not have underlying AD pathology which would effectively dilute the carrier frequency. The fact that we found similar results limited to patients with a CSF profile consistent with AD mitigates against this argument.
It is possible that APOE genotype modulates the clinical phenotype of AD through its effects on large scale memory networks of the brain.23
For example, ε4 carriers have been found to have greater memory impairment and medial temporal atrophy than non-carriers.24
Conversely, a recent study found greater orbitofrontal and dorsal frontoparietal atrophy in non-carriers.25
As with our finding in AD patients with a prominant dysexecutive phenotype, other atypical presentations of AD also appear associated with a lower ε4 carrier status, suggesting that this gene may be less important as a risk factor for atypical phenotypes.26
With respect to underlying anatomical features, we found that our executive predominant AD subgroup demonstrated relatively greater dorsal frontoparietal cortical thinning than the memory predominant subgroup, who demonstrated a trend towards more prominent hippocampal atrophy. These dorsal frontoparietal regions are critical nodes in the ‘dorsal attention network,’ commonly activated in functional neuroimaging studies of working memory and attention.27 28
These findings regarding differences between the two subgroups are similar to those hypothesised previously but not found in the dysexecutive MCI study.10
Neuroanatomical differences between subgroups of patients with AD or other neurodegenerative diseases may be difficult to identify because they may be subtle, thus requiring a hypothesis driven approach such as that employed here.
Some limitations of this analysis include the focus on clinically probable AD and MCI, which likely includes individuals with non-Alzheimer pathologies. However, given that the emphasis of this analysis is on clinical phenotyping and that it was performed in the ADNI cohort, in which uniform and fairly strict clinical criteria were implemented, the results are potentially broadly generalisable to many patients with similar clinical characteristics. Future analyses will focus further on determining whether similar clinical subgroups can be identified in individuals with in vivo evidence of amyloid binding and similar characteristics that increase the likelihood of AD pathology. Another limitation is the focus on psychometric definitions of executive versus memory dysfunction; it would be ideal to perform such subgrouping by including the characteristics and severity of symptoms in daily life as part of the definition of the subgroup. A paucity of this type of data is being prospectively collected as part of ADNI, and the addition of instruments such as the dysexecutive questionnaire for prospective data collection would be valuable for future studies. The finding reported here regarding slightly more impaired judgement and problem solving suggests that instruments focusing on these issues will probably yield relevant results. Another limitation of the present analysis relates to the possibility of differential effects related to cerebrovascular disease or risk factors; although ADNI inclusion criteria require a Hachinski Ischaemic Scale score ≤4, which curtails the presence of significant vascular disease or risk factors, it would be of interest to investigate whether differences in the phenotypes or rates of progression reported here may relate to white matter hyperintensities or cerebrovascular risk factors.
Further investigations focused on morphometric and functional brain measures, in addition to neuropathology, will surely contribute in important ways to advancing our knowledge of the putative biological mechanisms of clinical phenotypic heterogeneity in AD. Refined data on AD clinical phenotypes will likely be valuable not only for clinical practice with respect to differential diagnosis and prognostication but also for recruitment of more homogenous patient groups for clinical trials of potential therapeutic interventions.