In patients with mild cognitive impairment, the rate of conversion to clinical dementia is as high as 20% per year. There is strong evidence linking the presence of the E4 allele of apolipoprotein E (APOE) and clinical dementia. Some investigators think APOE allele status may provide insight into a patient’s prognosis. The large, ongoing InDDEx study (Investigation in the Delay to Diagnosis of Alzheimer’s Disease with Exelon) provides an opportunity to investigate this hypothesis.

The large multicenter, placebo-controlled double-blind InDDEx study includes individuals with mild cognitive impairment. The primary endpoint is the effect of rivastigmine on the time to clinical diagnosis of dementia. In addition to taking cognitive and behavioral assessments, investigators have conducted genotyping to identify patients with 0, 1 or 2 APOE E4 genes.

Genotyping results for 494 patients in the InDDEx study revealed that 9% (44 patients) carried 2 APOE E4 alleles, while 31% (154 patients) had 1 APOE E4 allele, and the remaining 60% had none.

Those patients with APOE E4 alleles had relatively worse cognitive scores at baseline. For example, baseline Mini-Mental State Exam scores were relatively lower in patients with 2 APOE E4 alleles versus patients with no APOE E4 alleles.

Likewise, baseline Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) scores showed the same pattern. Patients with 2 APOE E4 alleles were significantly more impaired at baseline compared with patients who had no APOE E4 alleles. This was true for the overall ADAS-cog score as well as sub-item scores, including word recall, delayed word recall and word recognition.

Other measures of cognition, including Buschke free and cued recall, as well as NYU delayed paragraph recall, again showed increasing problems with increased number of APOE E4 alleles. On the other hand, the cognitive findings at baseline did not carry over to measures of behavior or depression. There were no significant differences according to presence or absence of APOE E4 alleles.

Interestingly, in this study, patients with APOE E4 alleles had a clear deficit in activities of daily living scores versus those patients who did not. Physicians do not expect patients with mild cognitive impairment to have significant impairments in physical function, Dr. Farlow noted.

Investigators also evaluated hippocampal volume in a subgroup of 272 patients. Hippocampal atrophy is one factor that may predict conversion from mild cognitive impairment to dementia.

Magnetic resonance imaging data showed a highly significant difference according to APOE E4 allele status. There was evidence of considerably more atrophy in the group of patients that had 2 APOE E4 alleles at baseline, compared with the non-APOE E4 population.

Dr. Farlow said these study results are consistent with previous work suggesting that patients with the APOE E4 genotype are much more likely to progress to dementia earlier as opposed to patients who do not have this genotype.

The data may also support the hypothesis that APOE E4 status may have considerable prognostic value in patients with mild cognitive impairment. Future analysis of the InDDEx study data will include conversion rates to clinical dementia. This will show whether APOE genotype is a valid marker for prognosis in patients with mild cognitive impairment.