ApoE-4 and Age at Onset of Alzheimer's Disease

Objective: To explore the impact of apoE-4 on Alzheimer's disease (AD) and its age at onset. Design: A genetic linkage study using affected relative pairs, predominantly siblings. Setting: Three academic medical centers ascertained subjects from memory disorder clinics, nursing homes, and the local community. Subjects: 310 families including 679 subjects with AD by NINCDS/ADRDA and/or Khachaturian criteria and 231 unaffected subjects. Outcome measure: ApoE genotype. Analytic methods: Association, affected pedigree member, sibling pair, and lod score analyses. Results: ApoE-4 was strongly associated with AD in this sample (allele frequency = 0.46 vs. 0.14 in controls, p < 0.000001). Results of lod score, affected pedigree member analysis, and sib-pair analysis also supported apoE-4 as a risk factor for AD. When the sample was stratified on family mean age at onset, the risk conferred by apoE-4 was most marked in the 61 to 65 age group. Individuals with two copies of apoE-4 had a significantly lower age at onset than those with one or no copies (66.4 vs. 72.0, p < 0.001), but individuals with one copy did not differ from those with none. Within families, the individual with the earliest age at onset had, on average, significantly more apoE-4 alleles (p < 0.0001) than the individual with the latest onset. Discussion: This work supports previous reports of an association between apoE-4 and the development of AD and demonstrates that apoE-4 exerts its maximal effect before age 70. These findings have important implications for the potential use of apoE genotyping for diagnosis and prediction of disease. They also underscore the need to identify additional genetic factors involved in AD with onset beyond age 70 years. NEUROLOGY 1997;48: 139-147

[1]  E. Masood.  Swedish council is dismissed amid claims of malpractice , 1995, Nature.

[2]  J. Growdon,et al.  Risk of dementia among relatives of Alzheimer's disease patients in the MIRAGE study , 1996, Neurology.

[3]  C. Filley.  Diagnosis of Alzheimer's disease. , 1988, Colorado medicine.

[4]  T. Rasmussen,et al.  Rasmussen's encephalitis and the new hat , 1996, Neurology.

[5]  G. Assmann,et al.  Apolipoprotein E Polymorphism and Coronary Artery Disease , 1983, Arteriosclerosis.

[6]  J. Gunn.  Pandora and the problem of evil , 1996, The Lancet.

[7]  T. Kinoshita,et al.  Apolipoprotein E allele in centenarians , 1996, Neurology.

[8]  Bradley T. Hyman,et al.  Reduced apolipoprotein ϵ4 allele frequency in the oldest old Alzheimer's patients and cognitively normal individuals , 1994, Neurology.

[9]  C. Sing,et al.  Apolipoprotein E polymorphism and atherosclerosis: insight from a study in octogenarians. , 1988, Transactions of the American Clinical and Climatological Association.

[10]  J. Growdon,et al.  Transmission and age‐at‐onset patterns in familial Alzheimer's disease , 1990, Neurology.

[11]  G. Schellenberg,et al.  Association of an apolipoprotein CII allele with familial dementia of the Alzheimer type. , 1987, Journal of neurogenetics.

[12]  M. Savolainen,et al.  Apolipoprotein E and B polymorphisms--longevity factors assessed in nonagenarians. , 1994, Atherosclerosis.

[13]  B. Angelin,et al.  Apolipoprotein E polymorphism in a healthy Swedish population: variation of allele frequency with age and relation to serum lipid concentrations. , 1993, Clinical chemistry.

[14]  M. Pericak-Vance,et al.  Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[15]  J. Meyer,et al.  Lecithin and memory training in suspected Alzheimer's disease. , 1982, Journal of gerontology.

[16]  M. Pericak-Vance,et al.  Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease , 1991, Nature.

[17]  B. Tycko,et al.  The apolipoprotein ε4 allele in patients with Alzheimer's disease , 1993, Annals of neurology.

[18]  R. Tanzi,et al.  Genetic studies of Alzheimer's disease: Lessons learned and future imperatives , 1994, Neurobiology of Aging.

[19]  K. Davis,et al.  Familial aggregation in Alzheimer's disease , 1988, Neurology.

[20]  G. Schellenberg,et al.  Candidate gene for the chromosome 1 familial Alzheimer's disease locus , 1995, Science.

[21]  R. Rosenberg.  Autosomal dominant cerebellar phenotypes , 1990, Neurology.

[22]  P. Froguel,et al.  Genetic associations with human longevity at the APOE and ACE loci , 1994, Nature Genetics.

[23]  A. D. Roses,et al.  Association of apolipoprotein E allele €4 with late-onset familial and sporadic Alzheimer’s disease , 2006 .

[24]  R. Sulkava,et al.  Lack of association of apolipoprotein E allele ϵ4 with late‐onset Alzheimer's disease among Finnish centenarians , 1995, Neurology.

[25]  Kong Sk,et al.  Analysis of areal features in population structure , 1988 .

[26]  J. Growdon,et al.  Assessment of genetic risk for alzheimer's disease among first‐degree relatives , 1989, Annals of neurology.

[27]  K. Lange,et al.  The affected-pedigree-member method of linkage analysis. , 1988, American journal of human genetics.

[28]  S. Pocock,et al.  Statistical problems in the reporting of clinical trials. A survey of three medical journals. , 1987, The New England journal of medicine.

[29]  J. Haines,et al.  Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. , 1993, Science.

[30]  S. Gauthier,et al.  Predictive value of apolipoprotein E genotyping in Alzheimer's disease: Results of an autopsy series and an analysis of several combined studies , 1994, Annals of neurology.

[31]  R. Daroff.  A new look and feel , 1996, Neurology.

[32]  R. Penn,et al.  Neurosurgical horizons in Parkinson's disease , 1993, Neurology.

[33]  D. T. Vernier,et al.  Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. , 1990, Journal of lipid research.

[34]  D. Deregt,et al.  ELISA reliable for detection of antibodies to BHV1. , 1993, The Canadian veterinary journal = La revue veterinaire canadienne.

[35]  López Piñero Jm,et al.  New material and information about the History of the plants of New Spain by Francisco Hernandez , 1994 .

[36]  R H Myers,et al.  Apolipoprotein E epsilon4 association with dementia in a population-based study: The Framingham study. , 1996, Neurology.

[37]  S. Cassidy,et al.  Principles and Practice of Medical Genetics , 1992 .

[38]  Strategies for promoting child health. , 1990 .

[39]  J. Haines,et al.  Apolipoprotein E, survival in Alzheimer's disease patients, and the competing risks of death and Alzheimer's disease , 1995, Neurology.

[40]  R. Lovell-Badge,et al.  Setbacks on the road to sexual fulfilment , 1994, Nature Genetics.

[41]  D. Drachman,et al.  Apolipoprotein E ε4 allele and the lifetime risk of Alzheimer's disease : what physicians know, and what they should know , 1995 .

[42]  Thomas Tobin.  An abortion referendum in Ireland. , 1983, The Georgetown University right-to-life journal.

[43]  A. Roses.  Apolipoprotein E genotyping in the differential diagnosis, not prediction, of Alzheimer's disease , 1995, Annals of neurology.

[44]  B. Tycko,et al.  Apolipoprotein E and alzheimer's disease: Ethnic variation in genotypic risks , 1995, Annals of neurology.

[45]  P. Garzone,et al.  Alzheimer’s Disease and Other Dementias , 2020, Acupuncture for Brain.

[46]  A. Hofman,et al.  Apolipoprotein E4 allele in a population–based study of early–onset Alzheimer's disease , 1994, Nature Genetics.