Clinical genetics and genetic counseling in Alzheimer disease

Because of growing evidence for genetic causes of Alzheimer disease, clinicians are often asked about risks for this disorder among relatives of patients. This paper briefly reviews the evidence for genetic and other causes of Alzheimer disease, including specifically its typical late-onset variant. Several recent developments in the molecular genetics of early-onset Alzheimer disease are described briefly. These findings, however, may not apply to more typical, late-onset Alzheimer disease. Genetic studies of the latter disorder are complicated by the censorship of any inherited predisposition to disease by death from other causes. Hence, heritable disease may be apparent only in families with large numbers of elderly relatives at risk. Relying on empiric observations of risk among relatives from several recent studies of pooled Alzheimer families, curves are presented describing theoretic age-specific risks in relatives of patients and unaffected controls. Real (current) lifetime risks of Alzheimer disease are then estimated by modification of the theoretic figures with corresponding current age-specific mortality characteristics of the U.S. population. The lifetime incidence among relatives of patients with Alzheimer disease is estimated to be 19%, or three to four times the risk among control relatives. Because both mortality of and risk for Alzheimer disease change rapidly with advancing age, it may be possible to reduce the current morbidity from Alzheimer disease by 50% if onset can be postponed by only 5 years.