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The impact of apolipoprotein E4 on cause of death in Alzheimer's disease

From the Alzheimer's Disease Research Center (Drs. Hofstetter, Katzman, and Thal), Department of Neurosciences (Drs. Olichney, Galasko, Grundman, and Thal), University of California, San Diego, and Neurology Service, San Diego VA Medical Center (Drs. Sabbagh, Olichney, Galasko, and Thal), San Diego, CA.

Address correspondence and reprint requests to Dr. John M. Olichney, Department of Neurology (9127), VA Medical Center, 3350 La Jolla Village Dr., San Diego, CA, 92161.

Objective: We tested the hypothesis that the apolipoprotein E 4 (apoE4) allele is associated with an increased proportion of vascular-related mortality in Alzheimer's disease (AD).

Background: ApoE4 is associated with an increased risk of developing AD, with an earlier onset, and may predispose to vascular dementia as well. In the general population, apoE4 has been associated with increased coronary artery disease and shorter lifespan. There is a paucity of data regarding the effect of the apolipoprotein E (apoE) genotype upon the contributing causes of death in AD.

Methods: Death certificates of 114 AD cases were reviewed blind to apoE genotype. Deaths due to ischemic heart disease (IHD), cerebrovascular disease (CVD), vascular disease (either IHD or CVD), pneumonia, and other causes were analyzed as a function of apoE genotype. Logistic regression analyses were employed to control for age and gender effects.

Results: The likelihood of vascular disease contributing to death increased in association with the 4 allele (29% in cases without an 4 allele, 43% in cases with one 4 allele, 53% in 4/4 homozygous cases;p = 0.035 after corrections for age and gender). This increase appeared largely due to an increase in ischemic heart disease, which was reported more frequently on death certificates of cases with one or more4 allele (adjusted odds ratio [OR] = 1.85 per 4 allele;p < 0.05). There were nonsignificant trends for apoE4 to be associated with increased mortality related to cerebrovascular disease (OR = 1.45) and decreased mortality related to pneumonia (OR = 0.77) and AD itself(OR = 0.72). The 4/4 cases had significantly earlier age of onset (mean= 64.5 yr), earlier death, and longer duration of disease (mean = 10.1 yr). Cases with one or more 4 allele tended to have lower mean MMSE scores prior to death (6.6 versus 9.5) and were more often female (54% versus 45%).

Conclusions: The apoE4 allele appears to increase the risk of vascular and ischemic heart disease-related death in patients with AD.

Supported by NIH Grant AGO-5131 and a grant from the State of California(Alzheimer Disease and Diagnostic Treatment Centers).

Received July 9, 1996. Accepted in final form January 14, 1997.

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