Genetic counseling and testing for Alzheimer disease: Joint practice guidelines of the American College of Medical Genetics and the National Society of Genetic Counselors

Abstract

Alzheimer disease is the most common cause of dementia. It occurs worldwide and affects all ethnic groups. The incidence of Alzheimer disease is increasing due, in part, to increased life expectancy and the aging baby boomer generation. The average lifetime risk of developing Alzheimer disease is 10–12%. This risk at least doubles with the presence of a first-degree relative with the disorder. Despite its limited utility, patients express concern over their risk and, in some instances, request testing. Furthermore, research has demonstrated that testing individuals for apoli-poprotein E can be valuable and safe in certain contexts. However, because of the complicated genetic nature of the disorder, few clinicians are prepared to address the genetic risks of Alzheimer disease with their patients. Given the increased awareness in family history thanks to family history campaigns, the increasing incidence of Alzheimer disease, and the availability of direct to consumer testing, patient requests for information is increasing. This practice guideline provides clinicians with a framework for assessing their patients’ genetic risk for Alzheimer disease, identifying which individuals may benefit from genetic testing, and providing the key elements of genetic counseling for AD.

How Should Clinicians Counsel a Woman with a Strong Family History of Early-Onset Alzheimer's Disease about Her Pregnancy?

“…AD is categorized as early onset (i.e., before age 65) or late onset (LOAD) [4]. The earlyonset form of the disease (EOAD) represents 10 percent of all AD cases [5].…”

“…Strikingly, the inherited genetic contribution to EOAD is estimated to be 92-100 percent [6]. Strictly speaking, EOAD is not synonymous with autosomal dominant AD, but because autosomal dominant AD is found almost exclusively in families with EOAD, this article will use these terms interchangeably [4].…”

“…Mutations in the APP and PSEN1 genes are completely penetrant, so people with the mutant allele will develop AD if they live a normal lifespan [4]. A person with either of these mutations has a 50 percent chance of passing the mutant allele on to each child [8].…”

“…A person with either of these mutations has a 50 percent chance of passing the mutant allele on to each child [8]. By contrast, mutations in PSEN2 are 95 percent penetrant [4]. Although mutations in any of the three known EOAD genes are causative, these mutations only account for 5-10 percent of all cases of EOAD [5].…”

“…In addition to mutations in the three EOAD genes, the ε4 allele of the apolipoprotein E (APOE) gene increases a person's susceptibility to developing both EOAD and LOAD [4].…”