Opportunities for using genetic information to either diagnose, predict, or communicate risk for disease are ever increasing, with clinical genetic testing being offered for a wide variety of health problems, including breast cancer, colon cancer, Huntington’s disease, and Alzheimer’s disease (AD). In addition, these opportunities are more and more in the public eye, as some companies market genetic testing directly to consumers (Hudson, Javitt, Burke, & Byers, 2007), and genetic information is highlighted in popular media (e.g., the Jolie  effect). As a result of this scientific innovation, aggressive marketing, and ubiquitous media attention, health care providers may be increasingly faced with consumer inquiries regarding genetic risk and genetic testing. Psychiatric-mental health (PMH) specialists, whether practicing in community or institutional settings, are no exception. The purpose of this article is to discuss the current recommendations related to genetic testing and AD as well as the implications for nurses who provide specialty mental health services.
Overview of Alzheimer’s Disease
AD is the most common cause of irreversible dementia (now classified as a neurocognitive disorder in the Diagnostic and Statistical Manual of Mental Disorders, fifth edition [American Psychiatric Association, 2013]), accounting for nearly 60% of all dementia (Alzheimer’s Association, 2013), and affects more than 5.2 million individuals in the United States across diverse populations (Alzheimer’s Association, 2013). AD now also has the dubious distinction of being one of the leading causes of death (Tejada-Vera, 2013). The onset of AD is typically insidious and usually occurs after age 60 to 65 (Alzheimer’s Association, 2013). However, a small percentage of individuals develop symptoms prior to age 60, labeled as early-onset AD (Alzheimer’s Association, 2013). The duration of AD is variable, ranging from 2 to 25 years, with an average life expectancy after AD onset of 8 to 10 years (Helzner et al., 2008). The cognitive, functional, and behavioral changes characteristic of AD are associated with substantial burden for both formal and informal caregivers.
Genetics of Alzheimer’s Disease
The existing and anticipated individual, family, and societal impact of AD has prompted aggressive research efforts to determine the etiology of the disorder to develop preventive, curative, or both interventions. This research has included extensive efforts to explore the genetic basis of AD—an ongoing and active area of research.
The overall heritability of AD, as estimated by early family-based studies, is approximately 74% (Gatz et al., 2006), meaning 74% of the observed variability in AD is attributed to inherited genetic factors. AD continues to be widely accepted as both multi-factorial (influenced by both genetic and environmental factors) as well as genetically heterogeneous (multiple genetic factors contribute to the development of, and risk for, the disease). This view has been substantiated by the identification of genes involved in both the early and late forms of the disease as summarized below.
In the early 1990s, three genes were identified that play a causative role in AD in a small percentage of families (approximately 5%) with onset at early ages and autosomal dominant patterns of inheritance (Goate et al., 1991; Levy-Lahad et al., 1995; Mullan et al., 1992). Specifically, mutations in the presenilin 1 (PSEN1) gene account for the largest percentage (20% to 70%) of all early-onset familial AD. Mutations in the amyloid precursor protein (APP) gene account for approximately 10% to 15% of all cases of early-onset familial AD. Presenilin 2 (PSEN2) gene mutations are rare and account for less than 5% of all early-onset familial AD. These initial gene discoveries have since been replicated, with continued efforts underway to study the function of these genes in relationship to the pathophysiology of AD (Ridge, Ebbert, & Kauwe, 2013). For the most part, the clinical symptoms of early-onset AD are largely indistinguishable from late-onset AD.
Another prominent factor in the genetics of AD is the apolipoprotein E (APOE) gene. A strong relationship between a common variant with this gene, APOE-ε4, and increased risk for AD with earlier ages at onset was first identified in 1991 (Pericak-Vance et al., 1991). This finding has been widely replicated and confirmed through a meta-analysis (Bertram, McQueen, Mullin, Blacker, & Tanzi, 2007). In contrast to the causative genes described earlier, APOE is a susceptibility gene, meaning that the APOE-ε4 variant increases risk for disease, but is neither necessary nor sufficient by itself to cause disease.
Efforts are ongoing to identify, catalog, and understand other risk genes for AD using both candidate gene and genome-wide approaches (Hollingworth, Harold, Jones, Owen, & Williams, 2011). A candidate gene approach is a hypothesis-driven approach to gene discovery—examining targeted genes that are hypothesized to play a role in AD based on the biological pathways implicated in AD pathogenesis. In contrast, genome-wide approaches are hypothesis-free and examine all genes within the genome. Genome-wide strategies have also been used to identify genes that modify risk for AD (Bertram et al., 2008). Genetic association studies based on both approaches are cataloged in the online AlzGene database, which is currently being updated with new database software and is anticipated to be completed in 2013 (Alzheimer Research Forum, 2011; Bertram et al., 2007). The goal of the database is to provide an unbiased, centralized, and regularly updated collection of genetic association studies that can be searched by registered users.
In addition to the genetic approaches described above, other efforts are ongoing to examine the biological basis of AD. For example, researchers continue to study the similarities and differences in the brains and underlying genetic mechanisms between AD and Down syndrome (Webb & Murphy, 2012). These efforts stem from longstanding observations that individuals with Down syndrome, resulting from an extra copy of chromosome 21, often develop neuropathology similar to AD with the associated cognitive impairment (Lai & Williams, 1989). This early evidence has progressed to recent efforts to examine potential therapeutic modalities for both diseases (Carroll, 2013).
Current Recommendations for Genetic Testing
AD is a common disorder with an overall lifetime population risk of 10% to 12% (Bird, 2013). This risk increases to approximately 25% for first-degree relatives of a simplex, or isolated, case of AD. This risk further increases to 50% in first-degree relatives of an affected individual in families exhibiting autosomal dominant inheritance. The identification of genetic factors that play both causative and susceptibility roles in AD opened the door to the availability of genetic testing as an option to aid diagnosis and potentially clarify these risks for family members of affected individuals.
Early-Onset AD and Predictive Genetic Testing
Predictive genetic testing is currently available for individuals at increased risk for AD based on a positive family history. Predictive genetic testing protocols for AD model the protocols developed for presymptomatic and predictive genetic testing in individuals at risk for Huntington’s disease. Ideally, this testing occurs within a specialty genetics setting so that individuals and families can take advantage of pre- and post-test genetic counseling. Genetics providers also have the resources to coordinate with the clinical laboratories that currently offer the appropriate testing and can guide clients in considering strategies for paying for the testing (e.g., self-pay versus insurance). The preferred and most cost-effective testing strategy is to identify the disease-causing gene mutation in an affected family member first (searching throughout the known early-onset genes for a mutation). Then, other family members can be tested for that specific mutation only. All clinicians can access a searchable online directory of laboratories that provide clinical and/or research-based genetic testing for a wide variety of disorders at http://www.genetests.org. Although there are no preventive strategies or cures for AD currently, individuals may choose predictive genetic testing for a variety of reasons, including decreasing uncertainty, potentially clarifying risk for oneself or one’s children, and future planning related to health care and housing needs.
Late-Onset AD and Susceptibility Genetic Testing
In contrast to early-onset AD, susceptibility testing for risk alleles in late-onset AD (e.g., APOE-ε4 allele) is not currently recommended clinically because of the lack of sensitivity and specificity of the genetic tests (i.e., poor clinical utility) and the resultant difficulty in presenting probabilistic information to consumers. Lifetime risks for developing AD according to gender and APOE genotype were developed by Breitner et al. (1999), and these risk estimates are currently being used in research studies to examine the short- and long-term effects of genetic testing for risk alleles (as opposed to causative mutations) (Eckert et al., 2006; Green et al., 2009; Roberts et al., 2003, 2005). In the meantime, current recommendations continue to advise against susceptibility testing in AD (Goldman et al., 2011). Despite these recommendations, some direct-to-consumer genetic testing companies are providing APOE results and risk estimates for AD to consumers, highlighting the need for additional research to examine the relative risks and merits of these types of information disclosures (McGuire & Burke, 2008). For additional nuanced discussions of genetic testing in AD for susceptibility genes, see Arribas-Ayllon (2011) and Roberts, Christensen, and Green (2011).
Other Considerations and Genetic Testing in AD
An array of other considerations related to genetic testing in AD are also noteworthy. For example, genetic testing, as in other late-onset disorders, is not recommended in asymptomatic children. The rationale in support of this recommendation is that genetic testing in children, especially in the absence of prevention or treatment options, decreases the autonomy of children to choose whether they wish to pursue this information. Ideally, predictive genetic testing in AD should only occur in the context of genetic counseling to assure individuals and families are informed of the benefits and risks associated with genetic testing. Given the anticipated rapid expansion in the number of individuals worldwide with AD, the development and testing of more streamlined ways of providing this counseling will be needed to meet demand (Green et al., 2007). This demand is likely to increase as a clearer understanding is gained of genes and the clinical usefulness of genetic information in informing risk estimations and driving medical and nursing interventions.
Whether in community or institutional settings, nurses who specialize in the care of individuals experiencing PMH problems will be increasingly faced with the impact of genes and genetic testing on the health and health care decision making of their clients. The skill sets of PMH specialty nurses are particularly salient in the context of genetic testing in AD, presenting opportunities to effect care in direct and supportive ways.
Several opportunities exist for PMH nurses (PMHNs) to participate directly in the provision of genetic services to individuals and families experiencing AD. In some settings, PMH specialists are part of interdisciplinary genetic counseling teams. In these situations, the PMH specialist may be conducting pre-test assessments of mental health status, providing anticipatory guidance about the potential psychosocial impact of genetic test results, and offering assistance with coping with genetic test results.
Another opportunity available to all PMHNs is the ability to sharpen one’s skills to identify individuals who are at risk for genetic conditions such as early-onset AD, in particular, to make referrals to specialty genetics providers. The best tool for identifying individuals at risk for a genetic condition is a standard family history assessment. In the context of AD, a family history assessment could focus on determining the names, ages, presence or absence of AD, ages of symptom onset, and causes and ages of death for all family members across three generations. This family history data, placed in pedigree format, can assist providers in identifying whether the AD is isolated (a single case) or affecting multiple family members. If AD is affecting multiple family members, the pedigree will facilitate the identification of a recognizable Mendelian pattern of inheritance (e.g., autosomal dominant inheritance). The presence of early ages at onset of AD and multiple affected family members spanning multiple generations suggests a referral to specialty genetics providers. Finally, PMHNs can play important roles in providing ongoing supportive interventions to individuals who may be considering genetic testing or coping with genetic testing results, such as emotional support, evaluation and facilitation of coping skills, and monitoring for anxiety, depression, or both.
Genetic testing for AD is already clinically available for predictive purposes. The ability to provide improved and meaningful risk estimates to individuals based on the presence of one or multiple susceptibility gene alleles, although not feasible today, will likely be clinically available in the near future. PMH specialty providers can make important contributions to the development and implementation of genetic testing practices that are maximally beneficial for families experiencing AD and other complex adult onset disorders.
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