Alzheimer’s disease (AD) is a tricky beast - mentally, emotionally, diagnostically, and in terms of its genetics.
A person at average risk has a 10-12% lifetime chance of developing AD, with early- onset Alzheimer's disease (EOAD) presenting before 60-65 years of age, though more often before 55 years of age, while late-onset Alzheimer’s disease (LOAD) presents after 60-65 years of age.
Both genetic and non-genetic factors, including sex, reduced mental and physical activity, high blood pressure, diabetes, high cholesterol, heart disease, tobacco use, obesity, and head trauma can impact the risk of developing AD.
A very small proportion of patients with EOAD carry variants in genes, specifically APP, PSEN1, and PSEN2, that can be regarded as the actual cause of their disease. People with variants in these genes are almost guaranteed to develop AD. The first-degree relatives of those who carry variants in those genes have a 50% chance to also carry the familial variant and therefore be at a significantly increased risk for EOAD.
Unfortunately, that information rarely makes the nightly news. More often, what does is the more nuanced APOE gene. There are different versions of the APOE gene; depending on the versions a person carries, the gene can impart a protective, neutral, or harmful effect on that person’s risk to develop AD.
APOE ε2 may provide some protection against the disease. If Alzheimer’s occurs in a person with this allele, it usually develops later in life than it would in someone with the APOE ε4 gene. Roughly 5% to 10% of people have this allele.
APOE ε3, the most common allele, is believed to have a neutral effect on the disease — neither decreasing nor increasing risk of Alzheimer’s.
APOE ε4 increases risk the for Alzheimer’s and is associated with an earlier age of disease onset in certain populations. About 15% to 25% of people have this allele, and 2% to 5% carry two copies.
People who carry two APOE4 copies, called APOE4 homozygotes, have been estimated to have a 60% chance of developing AD dementia by age 85. While APOE4 homozygotes account for only about 2% to 5% of the overall population, they make up a larger share of AD cases—an estimated 15%.
In a recent study of people primarily of European descent, most of those with two copies of APOE4:
began to develop the underlying abnormalities of Alzheimer’s disease as early as age 55
had AD brain changes from age 55 on in postmortem reports (compared with about half of those without APOE4)
had high levels of AD biomarkers starting at age 55
had abnormal levels of one AD biomarker, amyloid beta, in their cerebrospinal fluid by age 65
had detectable amyloid on brain imaging
began experiencing AD symptoms around 65 years of age, on average
experienced mild cognitive impairment diagnosis around age 72, on average
received a diagnosis of dementia around age 74
died around age 77
All these happened 7 to 10 years earlier than in people without APOE4.
In addition, the age of symptom onset was less variable and more predictable in those with two copies of APOE4 than in people without APOE4. In fact, the variability in age of symptom onset in homozygotes was comparable to that seen in other genetic forms of AD.
While other populations still need to be studied, the findings suggest a newly defined genetic form of Alzheimer’s disease, with implications for future research, diagnosis, and treatment.
That said, currently, genetic testing for LOAD is not recommended as the diagnostic yield is low and the overall result interpretation and risk assessment remain difficult, especially in light of the potential impact of non-genetic factors.
Imagine this scenario:
Patient A was diagnosed with Alzheimer’s at the age of 78.
Patient B, his son, is concerned about his chances of developing Alzheimer’s and would like to pursue testing. He is currently 40.
In this case, diagnostic genetic testing would not be recommended for either Patient A or Patient B given the late-onset in Patient A and that a genetic variant has not been identified in the family.
Now imagine this scenario:
Patient C was diagnosed with Alzheimer’s disease at the age of 51.
Patient D, his father, started presenting with signs of dementia at the age of 59 and died at the age of 63.
Patient E, who is Patient C’s brother, is concerned about his own recent manifestations of memory loss and would like to pursue testing. He is currently 48.
In this case, diagnostic genetic testing for Patient C is recommended given his clinical diagnosis of early-onset AD, especially in light of his family history of dementia. Identification of the molecular basis of disease in Patient C may help his brother, Patient E, confirm his own suspected diagnosis, determine which other relatives may be at risk, provide anticipatory guidance, and/or promote enrollment in clinical trials.
Still have questions? If you have a family history of Alzheimer’s disease and are considering genetic testing, talk with a genetic counselor to understand your risk and the benefits, limitations, and availability of testing.
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