Dysexecutive versus amnesic phenotypes of very mild Alzheimer's disease are associated with distinct clinical, genetic and cortical thinning characteristics

Abstract

Objective: To investigate whether some patients with very mild Alzheimer's disease (AD) demonstrate disproportionate executive dysfunction relative to amnesia and how this relates to functional impairment in daily life, future clinical decline, APOE genotype and regional cortical thickness measured from MRI scan data.

Methods: The Alzheimer's Disease Neuroimaging Initiative dataset was interrogated for a primary sample of patients with very mild AD dementia (n=100) and a secondary confirmatory sample of patients with mild cognitive impairment (n=396). An executive predominant subgroup was defined as having executive performance ≥2 SDs worse than memory performance and a memory predominant subgroup was defined conversely. A priori regions of interest from a previous study of an AD patient sample were used to obtain cortical thickness measures.

Results: Despite equivalent global measures of impairment (Mini-Mental State Examination, Clinical Dementia Rating (CDR) Sum of Boxes), executive predominant patients (n=88) were more impaired on other executive measures and in the CDR Judgement and Problem Solving box (p<0.005) while memory predominant patients (n=56) were more impaired on other memory measures (p<0.05). The APOE-ε4 allele was much more frequent in the memory predominant subgroup (p<0.0001). Frontoparietal cortical regions were thinner in the executive predominant group than in the memory predominant group (p<0.05).

Conclusions: A dysexecutive clinical phenotype of very mild AD is not rare and is associated with more problem solving difficulties and possibly more rapid progression compared with patients with a predominant amnesic phenotype. Executive predominant AD may reflect an alternative underlying pathophysiology related to genetic status, reflected in more prominent pathological alterations in frontoparietal regions subserving executive function. These findings, which deserve further investigation, may have implications for diagnosis, prognostication, monitoring and related issues involved in clinical research and care.

Figure 1

Distinct phenotypes of Alzheimer's disease (AD). An executive predominant AD subgroup can be identified and is also present in mild cognitive impairment (MCI) with relatively prominent executive dysfunction and much less impaired memory. A memory predominant AD subgroup can be identified and is also present in MCI with relatively prominent memory loss and unimpaired executive function. Performance data shown here are from tests used to define the groups. Error bars depict 1 SEM.

Figure 2

Clinical ratings of subgroups at baseline and follow-up. (A) Baseline Clinical Dementia Rating (CDR) Box score ratings in clinical subgroups. The executive predominant subgroup is more impaired in Judgement and Problem Solving than the memory predominant subgroup (p<0.005). (B) Change in CDR Sum of Boxes score in the two subgroups at the 2 year follow-up, demonstrating a trend towards more rapid progression in the executive predominant subgroup (p=0.07).

Figure 3

Per cent APOE-ε4 carriers in the memory predominant subgroups is nearly double that of the executive predominant subgroups (p<0.0001 in each diagnostic group), with remarkably similar values in very mild Alzheimer's disease (AD) dementia patients and in those with mild cognitive impairment (MCI) with a CSF A-beta profile similar to that of autopsy proven AD.

Figure 4

Magnitude of regional atrophy in the subgroups. Despite a trend towards slightly lesser hippocampal atrophy, the executive predominant subgroup shows much more prominent thinning in the superior frontal and superior parietal cortices than the memory predominant subgroup (p<0.05). Hippocampal volumes were suggestive of an opposite effect but not statistically significant. Brain image shows localisation of frontal and parietal regions of interest (ROI).