Evidence for apolipoprotein E ε4 association in early-onset Alzheimer's patients with late-onset relatives (original) (raw)
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Annals of Neurology, 1995
Numerous studies have shown that the risk of Alzheimer's disease (AD) is associated with the dose of the € 4 allele of apolipoprotein E (ApoE). However, more than one third of AD patients lack ~4 and many persons having ~4 survive cognitively intact to old age. We evaluated the lifetime risk of disease in 3,999 first-degree relatives of 549 probands who met the criteria for probable or definite AD and whose ApoE genotypes were known. ApoE genotypes for relatives were not determined. After age 65 the risk among relatives was proportional, as much as 7 to 10% at age 85, to the number of ~4 alleles present in the proband. Risks to relatives of ApoE 212 and 2/3 probands were nearly identical at all ages to risks for relatives of ApoE 3 / 3 probands. The expected proportion of relatives having at least one € 4 allele was calculated for each genotype group based on the distribution of parents, sibs, and offspring in the sample. Among relatives in the ApoE 3 / 3 group, the lifetime risk for AD by age 90 was three times greater than the expected proportion of ~4 carriers, suggesting that factors other than ApoE contribute to AD susceptibility. Furthermore, the 44% risk of AD by age 93 among relatives of ApoE 414 probands indicates that as many as 50(%' of people having at least one ~4 allele do not develop AD. We also found that among male relatives, risk of AD in the ApoE 314 group was similar to that for the ApoE 313 group but significantly less than the risk for the ApoE 414 group. In contrast, among female relatives the risk for the ApoE 314 group was nearly twice that for the ApoE 3 / 3 group and identical to the risk for the ApoE 414 group. These findings are consistent with a sex-modification effect of the E4 isoform on disease susceptibility. SA, Volicer L. Wells JM, van Broeckhoven C, G r o w d o n JH. Haines JL. Apolipoprotein E genotype i n patients with Alzheimer's disease: implications for the risk of dementia among relatives. Ann Neurol 1995;38:797-808
Frequency of the apolipoprotein E ε2 allele is diminished in sporadic Alzheimer disease
Neuroscience Letters, 1994
Recent data have demonstrated genetic disequilibrium between inheritance of the apolipoprotein E (apoE) e4 allele and increased risk of Alzheimer disease. We tested the idea that inheritance of other allelic variations of apoE might also increase or decrease the risk of developing Alzheimer disease. We studied apoE genotypes in a large clinic based population of Alzheimer disease patients and age-compatible, tested control individuals. We confirm the genetic disequilibrium between apoE e4 and Alzheimer disease and now report that inheritance of apoE e2, another common variant of the apolipoprotein E gene, is negatively associated with risk of developing Alzheimer disease.
Lack of association between apolipoprotein E allele e 4 and sporadic Alzheimer's disease
Neurobiology of Aging, 1994
Apolipoprotein E (apoE) is a protein involved in the transport of lipids and a component of Alzheimer's disease (AD) plaques. There are three common alleles of the apoE gene, designated ~2, E3 and e 4. An association between familial and sporadic AD and the e4 allele was recently reported. We have investigated Swedish Alzheimer patients and controls. The e4 allele frequency in familial and sporadic cases and in controls was 47, 22 and 18%, respectively. There was no significant difference between sporadic AD and controls but in familial cases the increased e4 allele frequency previously reported was confirmed.
American journal of human genetics, 1996
Apolipoprotein E (APOE) genotype is the single most important determinant to the common form of Alzheimer disease (AD) yet identified. Several studies show that family history of AD is not entirely accounted for by APOE genotype. Also, there is evidence for an interaction between APOE genotype and gender. We carried out a complex segregation analysis in 636 nuclear families of consecutively ascertained and rigorously diagnosed probands in the Multi-Institutional Research in Alzheimer Genetic Epidemiology study in order to derive models of disease transmission which account for the influences of APOE genotype of the proband and gender. In the total group of families, models postulating sporadic occurrence, no major gene effect, random environmental transmission, and Mendelian inheritance were rejected. Transmission of AD in families of probands with at least one epsilon 4 allele best fit a dominant model. Moreover, single gene inheritance best explained clustering of the disorder in ...
Allele doses of apolipoprotein E type ε4 in sporadic late-onset Alzheimer's disease
American Journal of Medical Genetics, 1995
Apoliprotein E, type €4 allele (ApoE-~4) is associated with late-onset sporadic Alzheimer's disease (AD). W e have found that the cumulative probability of remaining unaffected over time decreases for each dose of ApoE-~4 in sporadic, late-onset French AD. The effect of genotypes on age at onset of AD was analyzed using the product limit method, to compare unaffected groups during aging. KEY WORDS: Alzheimer's disease, apolipoprotein E, €4 allele, allelic €4 dose, sporadic and late-onset form, age at onset 0 1995 Wiley-Liss, Inc.
Annals of Neurology, 1995
It was suggested that in contrast to the E4 allele, the E2 allele of the apolipoprotein E gene (APOE"2) has a protective effect for late-onset Alzheimer's disease and early-onset Alzheimer's disease (EOAD). We studied the role of the APOE*2 allele in the pathogenesis of EOAD in a Dutch population-based study of 175 probable EOAD patients with onset age at or before 65 years and 532 age-matched controls. In our population, there was no evidence for a protective effect of the APOE"2 allele on the risk of EOAD. However, our data show that among EOAD patients, survival for APOE"2 carriers was significantly reduced. When restricting the analysis to patients ascertained early after diagnosis at a stage of disease when mortality is low, our data suggest an increased risk of EOAD for subjects with APOE2E2, APOE2E3, APOE3E4, and APOE4E4 genotypes.
Dementia and Geriatric Cognitive Disorders, 2004
The presence of the apolipoprotein E (APOE) Â4 allele is a definite risk factor for the onset of Alzheimer's disease (AD). Its presence seems to affect especially the memory in the early stage of the disease, but the effect on the progression of the disease and survival is still controversial. Some longitudinal studies could be influenced by variables other than APOE, such as the response to medical treatment, rehabilitation therapy and inclusion of patients at different stages of progression at baseline. Moreover, the inclusion in the same study sample of patients of different ages at onset of the disease (below 65 or above 80 years) appears arbitrary. In our study, we evaluated a population of newly diagnosed untreated AD patients at their first neuropsychological examination and with the onset of their first symptoms not longer than 3 years ago. In order to analyse the different effects of the APOE Â4 allele on the different ages at the onset of the disease, we split the study sample into two groups: (1) subjects under 65 years [early-onset AD (EOAD); n = 30] and subjects over 70 years [late-onset AD (LOAD); n = 41], excluding subjects with an age of onset between 66 and 69 years. Our results show that the APOE Â4 allele carriers are characterised by a different neuropsychological pattern at the disease onset; however, only in the EOAD group is this effect significant: in EOAD, the Â4 allele carriers obtained worse performances in learning, long-term verbal memory and general intelligence tasks. On the contrary, in LOAD patients, the pattern of cognitive impairment at the onset is not dependent on the possession of an Â4 allele in the genotype. Such data could suggest a careful control of the study sample concerning age at the onset of the disease since APOE could play a different role in EOAD and LOAD mainly due to the different pathogenic mechanism at the onset and evolution of AD.
Dementia and Geriatric Cognitive Disorders, 2004
The presence of the apolipoprotein E (APOE) Â4 allele is a definite risk factor for the onset of Alzheimer's disease (AD). Its presence seems to affect especially the memory in the early stage of the disease, but the effect on the progression of the disease and survival is still controversial. Some longitudinal studies could be influenced by variables other than APOE, such as the response to medical treatment, rehabilitation therapy and inclusion of patients at different stages of progression at baseline. Moreover, the inclusion in the same study sample of patients of different ages at onset of the disease (below 65 or above 80 years) appears arbitrary. In our study, we evaluated a population of newly diagnosed untreated AD patients at their first neuropsychological examination and with the onset of their first symptoms not longer than 3 years ago. In order to analyse the different effects of the APOE Â4 allele on the different ages at the onset of the disease, we split the study sample into two groups: