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Dysexecutive versus amnesic phenotypes of very mild Alzheimer's disease are associated with distinct clinical, genetic and cortical thinning characteristics
  1. Bradford C Dickerson1,2,3,4,
  2. David A Wolk5,6,7,
  3. the Alzheimer's Disease Neuroimaging Initiative
  1. 1Frontotemporal Dementia Unit, Boston, Massachusetts, USA
  2. 2Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
  3. 3Massachusetts Alzheimer's Disease Research Center, Boston, Massachusetts, USA
  4. 4Athinoula A Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
  5. 5Department of Neurology, University of Pennsylvania, Philadelphia, USA
  6. 6Alzheimer's Disease Core Center, Philadelphia, USA
  7. 7Penn Memory Center, University of Pennsylvania, Philadelphia, USA
  1. Correspondence to Dr B Dickerson, MGH Frontotemporal Dementia Unit, 149 13th St, Suite 2691, Charlestown, MA 02129, USA; bradd{at}


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.

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  • Funding This work was primarily funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI, Principal Investigator: Michael Weiner; NIH grant No U01 AG024904). ADNI is funded by the National Institute of Ageing, the National Institute of Biomedical Imaging and Bioengineering (NIBIB) and the Foundation for the National Institutes of Health, through generous contributions from the following companies and organisations: Pfizer Inc, Wyeth Research, Bristol-Myers Squibb, Eli Lilly and Company, GlaxoSmithKline, Merck & Co Inc, AstraZeneca AB, Novartis Pharmaceuticals Corporation, the Alzheimer's Association, Eisai Global Clinical Development, Elan Corporation plc, Forest Laboratories and the Institute for the Study of Ageing (ISOA), with participation from the US Food and Drug Administration. The grantee organisation is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. This analysis was also supported by grants from the NIA R01-AG29411, R21-AG29840, P50-AG005134, K23-AG028018, P30AG010124 and the Alzheimer's Association.

  • Competing interests None.

  • Ethics approval This study was conducted with the approval of the multiple institutions.

  • Provenance and peer review Not commissioned; externally peer reviewed.