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Apolipoprotein E ε4 allele predicted an accelerated rate of cognitive decline in Alzheimer's disease
  1. David Burke, BMed, FRANZCP
  1. New South Wales Institute of Psychiatry, Sydney, New South Wales, Australia

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Question In patients newly diagnosed with Alzheimer's disease (AD), what effect do different apolipoprotein E (APOE) genotypes have on the rate of cognitive decline?


Inception cohort followed up for 1–6 years (mean 2.47 y).


Health maintenance organisation in Seattle, Washington, USA.


201 patients who were diagnosed with AD within the previous year based on National Institute of Neurological and Cognitive Disorders and Stroke-Alzheimer's Disease and Related Disorders Association and DSM-III-R criteria. Patients with other central nervous system conditions or major psychiatric disorders were excluded.

Assessment of prognostic factors

Patients were grouped according to their APOE genotype: ε2/3 (n=14), ε3/3 (n=75), ε3/4 (n=82), and ε4/4 (n=30).

Main outcome measure

Annual rate of cognitive decline assessed by the Dementia Rating Scale (DRS) total scores derived from 5 subscales: attention, memory, initiation and perseveration, conceptualisation, and construction.

Main results

All patients had baseline and ≥1 DRS total score. At the mean DRS score of 105 for this patient sample, the ε4/4 group had a greater rate of decline than the ε2/3 group (p<0.003); the differences in rate of decline were less pronounced compared with the ε3/3 group (p<0.076) and the ε3/4 group (p<0.055) (table). At a DRS score of 80, the rate of decline in the ε4/4 group was greater than the ε2/3 group (p<0.001) and the ε3/4 group (p<0.021), with a smaller difference compared with the ε3/3 group (p<0.174) (table). At both cutoff points the rate of decline was slower in the ε2/3 group than the ε3/3 and ε3/4 groups. In addition, older age predicted a slower rate of decline (p<0.001).

Annual rate of cognitive decline among genotype groups at a mean of 2.5 years


Patients newly diagnosed with Alzheimer's disease who were homozygous for the apolipoprotein E ε4 allele had an increased rate of cognitive decline compared with other genotypes. Patients with the ε2/3 allele had a slower rate of decline.


The search for biological markers to confirm the clinical diagnosis of AD has been prompted by the assumption that new treatments are most likely to slow or halt disease progression rather than reverse existing damage. Human APOE, previously known for its role in cholesterol transport and plasma lipoprotein metabolism, has emerged as a major genetic risk factor for AD.

The APOE ε4 allele has been shown to confer an increased risk of AD, occurring in up to 50% of cases.1 From a clinicopathological viewpoint, the APOE ε4 allele appears to lower the age of onset of AD and increase the amount of Aβ deposition in the brain.2 Few studies support the implications of genotype differences in disease severity or rate of decline.3, 4 In that context, this study contributes to knowledge on the molecular genetics of AD.

This study by Craft et al includes the largest inception cohort of patients with AD in whom longitudinal data and APOE status have been reported. Another strength of the study is the use of the DRS to measure decline, using its broad range of scores, and therefore avoiding the floor effects of other instruments (eg, Mini Mental State Examination). Furthermore, the study was able to examine the effects of APOE genotype status on disease progression, and detected statistically significant differences in the rate of decline between the ε4/4 group (fastest) and the ε2/3 group (slowest), and similar (intermediate) rates for the ε3/4 and ε3/3 groups. Finally, the results were robust to the manipulation of age at onset as a covariate or as a correlate of rate of decline.

The study provides further evidence for the hypothesis that APOE plays a mechanistic part in the neuropathologic progression of AD, as well as in its onset. The findings support the previously established clinical utility of APOE testing5; and suggest a possible role for APOE testing as a prognostic indicator in some patients presenting with dementia.



  • Sources of funding: NIA R01 AG-10880; Alzheimer's Disease Patient Registry; Alzheimer's Association; Department of Veterans Affairs.

  • For correspondence: Dr S Craft, Geriatric Research, Education, and Clinical Center (182B), VA Puget Sound Health Care System, 1660 South Columbian Way, Seattle, WA 98108, USA. Fax +1 206 764 2569.

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