If you had a genetic predisposition or mutation that would lead to Alzheimer disease (AD), frontotemporal dementia (FTD), or Lewy body dementia (LBD), would you want to know? If there was a test that could show that you were developing changes known to be associated with one of the neurodegenerative dementias, would you opt for the test or not? These questions are not just theoretical; they are a reality. They are the questions that more of us are increasingly going to encounter, and will have to answer, for ourselves and discuss with our patients.
Genetic Factors in Dementia: What We Know
The Human Genome Project opened the door to an explosion of scientific inquiry that has directly led to unraveling the underlying genetic contribution to many diseases.1 Beyond a better understanding of the causes of specific diseases, the hope is that this knowledge will lead to better ways to prevent and improve treatments. In the past 2 decades, we have learned much about the genetic mutations that lead to some relatively rare forms of AD; identified one genetic risk factor for late-onset AD, the e-4 allele of apolipoprotein (ApoE-4); and our understanding of the genetics of less common dementias, such as LBD and FTD, continues to increase.2
But biology is not always destiny. The genetic code each human has is remarkably similar (99.9%) to all other humans but with variations that lead—sometimes directly and sometimes indirectly—to susceptibility and, in some cases, directly to disease. As we learned in basic biology, there is the genotype (ie, the genetic material, gene, or set of genes) that is responsible for a specific trait inherited directly from one’s biologic parents. Then there is the phenotype, the visible expression of that genetic material in a physical characteristic and based on the genetic material one inherits and the influence of one’s environment.
For a long time, dating back to the mid 20th century, there has been recognition that genetics play a role in AD and other dementias.3 A strong hereditary component has been evident in AD through the identification of a number of families where the disease could be traced through generations. These relatively rare families were the early indications that genetic factors may play a role in the pathogenesis of AD, and perhaps other dementias (FTD, LBD) and related disorders, such as Parkinson disease.3
Genetic factors are now recognized to play an important role in most age-related dementias. While other factors, including aging itself, contribute to dementia, the role of specific disease-causing genes and genetic factors in the most common age-related dementias has received increased attention in recent years. Current thinking is that there is a spectrum of genetic involvement in neurodegenerative dementias.4 At one end, the “pure” genetic forms (eg, Huntington disease, early onset autosomal-dominant AD) are thought to be modestly influenced by environmental factors (such as degree of physical activity). At the other end, acquired disorders (eg, the chronic traumatic encephalopathy described in football players and boxers) is likely to be influenced by genetic factors. Typical AD, whether early or senile-onset, appears to fall in the middle of this genes/environment continuum.4
Most age-related neurodegenerative diseases, including virtually all dementias, are now known to be due to protein conformational disorders. The underlying pathology involves abnormal accumulation and deposition of specific proteins within the brain, often within specific neuropathological structures. We can now test for these proteins through cerebrospinal fluid (CSF) analysis and visualize their accumulation with positron emission tomography scans utilizing specific tracers. But should we? And what is one to do with the information? It is a pandora’s box that is slowly being pried open.
Apoe testing is available clinically and commercially to anyone who orders it. ApoE4 status, together with imaging and CSF biomarkers, can be used to increase the probability of correctly diagnosing AD or predicting progression from mild cognitive impairment to AD.5 Since there is no change in clinical practice tied directly to Apoe genetic information, and some potential harm if this information becomes part of person’s medical record, ApoE allele testing is not currently recommended or used in clinical practice. The National Institutes of Health only recommends genetic testing of ApoE status as part of clinical trials.5 When testing is done in this context, the information is usually not shared with the individual, which raises ethical questions about disclosure of medically relevant information to research participants. A recent study showed that well-informed individuals are generally well-equipped to handle this piece of genetic information.6
The discovery of AD disease genes has spurred the development of biomarkers that can be used to make diagnostic and prognostic predictions.7 Biomarker studies have led to a new understanding that AD, and probably the other neurodegenerative dementias, is a disease process that extends over decades, beginning silently long before clinical symptoms appear. Growing evidence indicates that biomarkers can help us identify evidence of disease well before a person shows cognitive symptoms. This is analogous to identification of atheroma buildup in coronary arteries before the development of angina or microcalcifications on a mammogram before presence of a discrete mass. In these disease states, however, there are proven interventions and treatments; with AD and other neurodegenerative dementias, we do not have these tools—yet.
Considerations and Conclusion
So, should we do the tests? Would you want to know? And what do we do with the information? When a patient or family asks, “is it hereditary?” my response is “Yes, and no. It’s just like all medical conditions.” When they say, “I want to be tested,” that requires a much longer conversation, which I expect will be needed for growing numbers of individuals in the near future, necessitating a referral to or consultation with a genetics counselor. And when someone says that they want to know if they could be developing AD, I ask “why” and “what would you do differently?”
1. National Human Genome Research Institute. An Overview of the Human Genome Project, What was the Human Genome Project? genome.gov website. https://www.genome.gov/12011238/an-overview-of-the-human-genome-project/. Updated May 11, 2016. Accessed March 22, 2019.
2. National Institute on Aging. Advances in Alzheimer’s Disease & Related Dementias Research. nia.nih.gov ebsite. ttps://www.nia.nih.gov/about/advances-alzheimers-disease-related-dementias-research. Accessed March 22, 2019.
3. Blacker D, Tanzi RE. The genetics of Alzheimer disease: current status and future prospects. Arch Neurol. 1998;55(3):294-296.
4. Paulson HL, Igo I. Genetics of dementia. Semin Neurol. 201;31(5):449-460. doi:10.1055/
5. Genetics Home Reference, National Library of Medicine, National Institutes of Health. Can a direct-to-consumer genetic test tell me whether I will develop Alzheimer disease? https://ghr.nlm.nih.gov/primer/dtcgenetictesting/dtcalzheimer. Published March 19, 2019. Accessed March 22, 2019.
6. Green RC, Roberts JS, Cupples LA, et al; REVEAL Study Group. N Engl J Med. 2009; 361(3):245-254.
7. Vemuri P, Wiste HJ, Weigand SD, et al; Alzheimer’s Disease Neuroimaging Initiative. Serial MRI and CSF biomarkers in normal aging, MCI, and AD. Neurology. 2010;75(2):143-151.