Risk of dementia among relatives of Alzheimer's disease patients in the MIRAGE study

Abstract

Despite recent advances in the molecular genetics of Alzheimer's disease (AD), several fundamental questions concerning risk of illness are unresolved, namely, if Mendelian factors account for the incidence of the disease, and if AD is an inevitable consequence of the aging process. This study was designed to address these issues and other aspects of familial aggregation of the disorder. A consecutive sample of 1,694 patients who met criteria for a diagnosis of probable or definite AD were ascertained in 13 centers participating in the Multi-Institutional Research in Alzheimer Genetic Epidemiology (MIRAGE) project. Lifetime risk and age at onset of AD among various strata of 12,971 first-degree relatives was estimated using survival analysis procedures. The lifetime risk of AD in first-degree relatives was 39.0% +/- 2.1% by age 96 years. Age-specific risk of AD declined after age 90 and the data set included 61 apparently unaffected persons who survived to age 96 without becoming demented. Female relatives had a higher risk of AD than male relatives at all ages. By age 80, children of conjugal AD couples had a cumulative risk of 54%, 1.5 times greater than the sum of the risks to children having affected mothers or fathers, and nearly 5 times greater than the risk to children having normal parents. Children of affected fathers had a cumulative risk that was 1.4 times the corresponding risk to children of affected mothers. Risk assessment in early-onset and late-onset families, using various strategies for determining the age cut-off, yielded contradictory results. These data suggest the following: (1) the lifetime risk among relatives does not support a simple autosomal dominant inheritance pattern of disease; (2) women are innately more susceptible to AD than men; (3) the proportion of hereditary cases may be higher in men than women; (4) distinction between early- onset and late-onset forms of AD has little meaning in the absence of a biological marker; (5) the risk of AD decreases after age 90; and (6) AD therefore may not be an inevitable concomitant of the aging process, a conclusion that has profound implications for basic and applied AD research. The age- and sex-specific lifetime risks derived from this study are sufficiently robust to be a reliable source of information for counseling relatives of AD patients.

Incorporating ethnicity into genetic risk assessment for Alzheimer disease: the REVEAL study experience

“…The MIRAGE study is the largest genetic epidemiological study of its kind to date, focusing on both African American and white families. 13,14,65 As a result, it provided a potential basis for clarifying risk profiles for African Americans and risk estimates to FDRs of persons with AD. The study found significantly higher risk for dementia among FDRs of African Americans compared with whites (RR 1.6; 95% CI 1.4 -1.9).…”

“…The MIRAGE study recruited patients with AD from 17 specialty clinics between May 1991 and March 2001, using methods published elsewhere. 14,65,79 The dementia risk models stratified by ethnicity as presented by Green et al 13 provided a basis for creating AD models for the REVEAL study.…”

Genetic susceptibility testing versus family history–based risk assessment: Impact on perceived risk of Alzheimer disease

“…Risk estimates were formulated using two sources: (1) agespecific incidence curves for first-degree relatives of individuals affected by AD from a genetic epidemiology study of AD families [17][18] ; and (2) odds ratio estimates reported in a metaanalysis encompassing 40 studies worldwide. 19 Bayes' rule was used to stratify risk according to APOE genotype.…”

“…7 AD is one of many complex disorders with a genetic component and given the inherent uncertainties of risk information and the rapidly advancing field of genetics, experts in the field have noted a need for multidisciplinary research focused on communication and risk perception in genetic testing: "The expected increasing uncertainty of the implications of the '-omics' era will necessitate a true integration of the field of genetic counseling with health education and communication sciences." 8 Currently, most asymptomatic individuals who request a risk assessment for AD are offered a probability based on epidemiologically based risk estimates, 17 yet epidemiologically derived risk estimates may have a minimal impact upon risk perception. 9 Little is known about the impact of receiving genetic test results, specifically negative results, as part of a risk assessment for a common complex disorder like AD.…”

Epidemiology of Alzheimer’s Disease

“…Those who have more than one first-degree relative with Alzheimer's disease are at even higher risk of developing the disease [48]. When diseases run in families, heredity (genetics), shared environmental and /or lifestyle factors or both may play a role.…”