Environment Modifies ApoE E4-Related Risk of Alzheimer’s Disease

Potentially modifiable environmental factors protect against Alzheimer’s disease in older adults carrying the apolipoprotein E e4 allele, a major susceptibility gene for the late-onset form of the disease and also a risk factor for other types of dementia.

In a cohort study of 932 cognitively healthy people aged 75 years or older, those carrying the ApoE e4 allele had a higher risk of developing Alzheimer’s disease than did noncarriers during a 9-year follow-up, researchers reported at the Alzheimer’s Association International Conference 2012.

Carriers who had more education or a high level of leisure-time activities, and those who did not have any vascular risk factors, were roughly half as likely to develop the disease as other carriers.

Having all three protective factors largely offset the risk of carrying the e4 allele in terms of developing any type of dementia. Together, they delayed the onset of dementia by about 1.2 years.

“Here, we show evidence that man can conquer nature,” commented first author Dr. Weili L. Xu, an epidemiologist and a postdoctoral researcher at the Aging Research Center of the Karolinska Institute, Stockholm, and Stockholm University.

“The risk effect of e4 on dementia may be attenuated by these potential protective factors. They seem to delay dementia onset in a way that e4 and non-e4 carriers have similar dementia-free survival time. Our study provides further evidence not only for the combined effect of genetic and environmental factors on dementia, but also the possibility that environmental factors may diminish genetic risk,” she maintained.

“As 70% of dementia cases occur in elderly people aged 75-plus, gaining 1 year without dementia is of great importance,” she added.

The findings could be interpreted differently, however, noted session attendee Dr. Richard B. Lipton. “What you said was that environmental factors can protect against the effect of genes, but the other way of looking at it is that environmental factors seem more important in genetically vulnerable subgroups, because the effect of education and low cardiovascular risk didn’t look very protective in the e4-negatives,” said Dr. Lipton of Albert Einstein College of Medicine, New York.

And session cochair Dr. James Mortimer of the University of South Florida, Tampa, commented that the 1.2-year delay in dementia onset “seems very modest, actually. I’m quite surprised, given the reasonably large effect sizes you presented.” He speculated that “this might have been due to age being such a dominant factor.”

Dr. Xu and her colleagues studied participants in the Kungsholmen Project, a population-based prospective cohort study on aging and dementia. Analyses were based on adults from the community who were at least 75 years of age at baseline and had normal cognitive function. ApoE genotyping identified 28% as carriers of the e4 allele.

After 9 years of follow-up, 39% of carriers had developed dementia (predominantly Alzheimer’s disease), compared with 33% of noncarriers. Even among carriers who were homozygous for e4, only slightly more than half developed dementia, suggesting that other factors were at play, she noted.

In adjusted analysis, compared with noncarriers, carriers had an elevated risk of Alzheimer’s disease (hazard ratio [HR], 1.52) and of any dementia (HR, 1.39).

In analyses restricted to carriers, however, the risk of Alzheimer’s disease was lower for those having more vs. less than 8 years of education (HR, 0.55); having a high vs. low level of leisure-time activities, a composite of social, mental, and physical activities (HR, 0.49); and lacking all of five common vascular risk factors vs. having any (HR, 0.61). The findings were similar for any dementia.

In stratified analyses, the three factors were protective for any form of dementia among noncarriers but more so among carriers, Dr. Xu said.

Compared with carriers lacking all three protective factors, carriers having all three had a sharply reduced risk of any dementia (HR, 0.62) that was similar to that of noncarriers lacking all three protective factors (HR, 0.75).

Dr. Xu disclosed no relevant conflicts of interest.

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