Correspondence

Age-Related Memory Decline and the APOE ε4 Effect

N Engl J Med 2009; 361:1996-1997November 12, 2009

Article

To the Editor:

Cognitive decline is a complex multifactorial process, and so it is important to exclude as many potentially confounding variables as possible when assessing the influence of a single factor. In their longitudinal study, Caselli and colleagues (July 16 issue)1 apparently did not take into account some such variables, including alcohol consumption, mentally stimulating activities, and smoking.2-4 In addition, physical inactivity is reported to be a risk factor for cognitive decline, especially among persons carrying the apolipoprotein E (APOE) ε4 allele.5

Jie-Yu Chuang, M.D.
Tri-Service General Hospital, Taipei, Taiwan
simone@mail.ndmctsgh.edu.tw

5 References

1
Caselli RJ, Dueck AC, Osborne D, et al. Longitudinal modeling of age-related memory decline and the APOE ε4 effect. N Engl J Med 2009;361:255-263
Full Text | Web of Science | Medline

2
Anstey KJ, Mack HA, Cherbuin N. Alcohol consumption as a risk factor for dementia and cognitive decline: meta-analysis of prospective studies. Am J Geriatr Psychiatry 2009;17:542-555
CrossRef | Web of Science | Medline

3
Wilson RS, Mendes De Leon CF, Barnes LL, et al. Participation in cognitively stimulating activities and risk of incident Alzheimer disease. JAMA 2002;287:742-748
CrossRef | Web of Science | Medline

4
Peters R, Poulter R, Warner J, Beckett N, Burch L, Bulpitt C. Smoking, dementia and cognitive decline in the elderly: a systematic review. BMC Geriatr 2008;8:36-36
CrossRef | Medline

5
Schuit AJ, Feskens EJ, Launer LJ, Kromhaut D. Physical activity and cognitive decline: the role of the apolipoprotein ε4 allele. Med Sci Sports Exerc 2001;33:772-777
Web of Science | Medline

To the Editor:

Caselli et al. note that accelerated memory decline among persons with the APOE ε4 allele may be caused by subclinical Alzheimer's disease. Subclinical and clinical vascular cognitive impairment are also prevalent among older adults. There is some evidence that cerebrovascular impairment and cognitive impairment have common risk factors.1 Indeed, diabetes, hypertension, and the APOE ε4 genotype independently contribute to cognitive decline in late middle age and beyond.2 Caselli et al. investigated the temporal effect of APOE ε4 on cognition, but they do not provide information on the vascular risk factors of the subjects, and so the possibility that these risk factors could have had an effect on the reported memory decline cannot be ruled out.

Lei Ma, M.D.
Gang Zhao, M.D.
Feng Xia, M.D.
Xijing Hospital, Xi'an, China
zhaogang@fmmu.edu.cn

2 References

1
Libon DJ, Heilman KM. Assessing the impact of vascular disease in demented and nondemented patients. Stroke 2008;39:783-784
CrossRef | Web of Science | Medline

2
Knopman DS, Mosley TH, Catellier DJ, et al. Fourteen-year longitudinal study of vascular risk factors, APOE genotype, and cognition: the ARIC MRI Study. Alzheimers Dement 2009;5:207-214
CrossRef | Web of Science | Medline

Author/Editor Response

We, too, are concerned about the multiple factors that might influence cognitive trajectories. There is little question regarding the potentially adverse influences of substance abuse and stroke, and so persons who reported a history of substance abuse or stroke were excluded from the study. Furthermore, anyone in whom mild cognitive impairment or dementia developed at any time, for any reason, was excluded.

In our cohort, there was no difference between APOE ε4 carriers and noncarriers with respect to the prevalence of hypertension (24.7% vs. 27.7%, P=0.35 by the chi-square test). Diabetes mellitus was uncommon but less prevalent among APOE ε4 carriers than among noncarriers (3.4% vs. 8.4%, P=0.007 by the chi-square test), so it seems unlikely to explain the earlier age of onset of cognitive decline and the difference in the rate of decline among APOE ε4 carriers as compared with noncarriers. Although we did not quantitatively assess physical or mental activity, there was a trend toward a lower mean body-mass index in carriers than in noncarriers (26.6 vs. 27.4, P=0.09 by the t-test) and a lower prevalence of obesity (15.6% vs. 24.9%, P=0.02 by the chi-square test). With regard to mental activity, among subjects in the APOE cohort, ε4 carriers had slightly more intellectually demanding occupations than noncarriers according to the Dictionary of Occupational Titles (DOT)1 (specific vocational preparation, P=0.05, and total general educational development, P=0.03; DOT information was not obtained from the other cohort in our study), so again these factors would not explain our observations. These observations concur with neuropathological2 and imaging3 data that collectively characterize a presymptomatic stage of Alzheimer's disease and indicate that its neuropsychological onset (within the sensitivity of the score on the long-term memory portion of the Auditory Verbal Learning Test) is between 55 and 60 years of age. Whether other factors accelerate or delay the onset of this decline remains to be determined, but we are hopeful that our findings may provide a platform for such future research.

Richard J. Caselli, M.D.
Amylou C. Dueck, Ph.D.
Mayo Clinic Arizona, Scottsdale, AZ
caselli.richard@mayo.edu

Eric M. Reiman, M.D.
Banner Alzheimer's Institute, Phoenix, AZ

3 References

1
Dictionary of occupational titles. 4th ed. Washington, DC: Department of Labor, Employment and Training Administration, 1991.

2
Kok E, Haikonen S, Luoto T, et al. Apolipoprotein E-dependent accumulation of Alzheimer disease-related lesions begins in middle age. Ann Neurol 2009;65:650-657
CrossRef | Web of Science | Medline

3
Reiman EM, Chen K, Liu X, et al. Fibrillar amyloid-beta burden in cognitively normal people at 3 levels of genetic risk for Alzheimer's disease. Proc Natl Acad Sci U S A 2009;106:6820-6825
CrossRef | Web of Science | Medline

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