By Gabrielle Strobel
Definition: What Is eFAD?
Early-onset familial Alzheimer disease (eFAD) is hereditary and marked by Alzheimer disease symptoms that appear at an unusually early age. Symptoms can start in a person's thirties, forties, and fifties (and very rarely in the late twenties). Generally, if you are diagnosed with eFAD, then one of your parents will also have had it if he or she lived long enough, and your siblings and your children may have a 50-50 chance of having inherited it. Very rarely, eFAD can make a first-time appearance in a family through a new genetic mutation.
Genetics researchers studied eFAD families to discover the three known genes that cause familial AD: amyloid precursor protein (APP), presenilin-1 (PS1), and presenilin-2 (PS2). Of these, PS1 mutations account for most eFAD, while APP and PS2 are more rare. Having a pathogenic mutation in one of these three genes virtually guarantees that one will develop early-onset Alzheimer disease. Tests can determine which gene is at fauly (see Diagnosis). There are also cases of eFAD that cannot be linked to one of these three genes. There may be additional genes waiting to be discovered, if only researchers could connect with more eFAD families.
Like the more common late-onset AD, eFAD is incurable. Over several years, the patient will lose memory and other mental functions, and become completely dependent on others. At this time, there is no treatment to slow down the disease. Ironically, eFAD patients often have been excluded from drug studies because of their young age, even though studies of these families have contributed to some of the most important findings about Alzheimer disease, including its very discovery (see "How Early-onset Dementia Led to a Historic Discovery") and, later, discovery of the genes causing it. By raising awareness of eFAD, we hope families will know they are not alone, and that researchers will do more to involve them in the search for treatments.
Prognosis: Is eFAD Different from LOAD?
Neurologists generally agree that eFAD and late-onset AD are essentially the same disease, apart from the differences in genetic cause and age of onset. eFAD progresses with the same overall sequence of symptoms and increasing impairments as LOAD. From the neurologist's perspective, two things stand out the most about eFAD, says Dennis Selkoe of Harvard Medical School. One is how pure the AD clinical syndrome develops in an otherwise healthy person (see Diagnosis), and the other is how high a burden the disease imposes on the spouse and children, who are often still young. These patients are active, working people who are in the midst of building a life for their families. Early-onset FAD is acutely tragic because the patient faces a relentless and progressive loss of brain function so prematurely, while he or she is still physically vigorous. As a result, eFAD is often accompanied by psychiatric complications such as depression and agitation.
While eFAD and LOAD are outwardly the same, the underlying process that leads to eFAD is distinct from that which results in LOAD. As a genetic disorder, eFAD clearly is the consequence of the malfunctioning of the mutated genes, whereas late-onset disease is more likely due to a gradual accumulation of age-related malfunctions. Some studies have noted that the pathologic hallmarks (protein deposits called plaques and tangles) are more severe in eFAD than LOAD, and may be concentrated in different regions. These differences in underlying mechanism suggest that treatments for eFAD may overlap with, but not always be identical to, treatments being developed for LOAD.
How Common Is Early-onset Familial Alzheimer Disease?
The medical literature estimates that between 1 and 5 percent of all Alzheimer cases are early-onset. This includes familial and sporadic forms, and translates into 50,000 to 250,000 people in the U.S. A report issued by the Alzheimer's Association in March 2007 puts the number of people with AD who are younger than 65 at around 200,000 (Alzheimer's Disease Facts and Figures [.pdf]), a large number than more visible neurodegenerative diseases such as ALS (Lou Gehrig disease) and Huntington disease.
When put to AD researchers, however, the simple question of how many people have eFAD generates a lengthy discussion. Why the uncertainty? For one thing, the answer depends on how one defines early-onset familial AD. For another, definitive data do not exist. The section below explains how scientists derive the numbers that are known to date, and why they have not yet been able to deliver precise counts. In short, the reasons boil down to the complexity of AD genetics, the difficulty of compiling family pedigrees, and misdiagnosis of AD in younger people for depression and other illnesses.
For practical and research purposes, doctors and scientists need defined populations for study and the numbers change based on the definitions. The definition would seem to rest on two criteria:
- Age of onset: early versus late
- Heritability: familial versus sporadic
By these criteria, Alzheimer disease can be sliced into four subcategories:
||Early-onset AD (EOAD)
||Late-onset AD (LOAD)
||Early-onset familial (eFAD)
In reality, however, Alzheimer disease exists in a continuum, a mix of gradations across these definitions. Also, each subtype of AD is not a pure form unto itself. For example, a family is categorized as either early-onset or late-onset AD, but new research shows that about a quarter of families with LOAD also have a relative who develops EOAD (Brickell et al., 2006).
A diagnosis of AD in the thirties, forties, and fifties clearly is considered EOAD and past 75 it is LOAD, but there is no consensus on exactly where to place the cutoff. Formal diagnostic texts put it at age 65; but some investigators prefer 60 and use that age in their research. Most large epidemiological studies don't assess eFAD separately with the standard tools of prevalence (percentage of the population who have a disease at any given time) and incidence (percentage of people who get it every year) because those numbers are very low, and large epidemiology studies of dementia rarely capture people below 65. Because population-based epidemiology numbers are few and far between, scientists instead work with estimates generated from patient counts in clinical settings, and that is where the 1 to 5 percent figure comes from. The wide range stems from local differences, such as different referral patterns and levels of specialization.
Some epidemiologists note that 5 percent of all AD (i.e., around 250,000 U.S. cases) might overstate the true number of eFAD cases because a larger fraction of old people than young people who develop AD may not be diagnosed, and therefore not counted in the statistics. Losing one's mental abilities at 50 is such a dramatic event that people eventually find their way to a neurological clinic and get counted, more so than when it happens in one's eighties. On the other hand, some neurologists hesitate to diagnose AD in people under 60, driving numbers of early-onset cases down. And the number of early-onset cases among the tens of millions of people in the U.S. who have no health insurance is unknown, especially in remote rural areas where health care services are sparse and access is a problem. Given these uncertainties, researchers generally accept 2 to 3 percent of all AD (i.e., roughly 100,000 U.S. cases) as a conservative estimate.
The second criterion for measuring forms of AD—familial versus sporadic—also is more complicated than it appears at first sight. The term familial implies that at least two generations of a family have AD. Familial AD can occur with early onset and late onset, but the precise number is unclear. That is because familial AD is not always caused by the clear-cut inheritance of a single gene, but may cluster in families by way of a more murky genetic pattern, where several unlucky genes may add up in their effects on the body to drive down AD's age of onset. This form is more difficult to identify, and so the numbers of affected families are not accurately counted.
Scientists do not fully understand the relative contributions of genetics and the environment to AD, but they believe that there is a spectrum. The later the onset of AD, the more aging and environmental factors are thought to dominate and the smaller a person's genetic predisposition appears to be. The earlier the age of onset, the more likely AD is to be driven by a deterministic, powerful mutation in a single gene that gets passed on through generations. This kind of AD inheritance is like that of quintessential genetic diseases, such as hemophilia, or classic traits of textbook genetics, such as the color of Gregor Mendel's garden peas. The familial mutations reported in the scientific literature (see AD/FTD mutation database and Alzforum mutations list) are of this kind. The middle of the gene-environment spectrum is much more hazy, and it is the subject of intense research. Many candidate genes are being scrutinized, but none are clearly understood. Scientists do not yet know how the genes interact with one another or with environmental factors to create a burden of AD risk in a given person. Overall, epidemiologists estimate the heritability of AD in this middle category to be approximately 80 percent.
Autosomal-dominant forms of eFAD result from mutations in one of three genes. They are APP on chromosome 21, presenilin-1 on chromosome 14, and presenilin-2 on chromosome 1. Of these, presenilin-1 is by far the most common cause of eFAD. Another gene, ApoE, is known to increase the likelihood that a person will develop AD when it comes in the form known as ApoE4. However, it does not cause autosomal-dominant disease like the three genes described above. Rather, ApoE4 is a risk factor. It is important to be aware of the difference between a deterministic mutation and a genetic risk factor. Very few carriers of known pathogenic APP or presenilin mutations live past middle age without developing AD, whereas many people who carry two ApoE4 copies do. In other words, a finding of a pathogenic APP or presenilin mutation constitutes a genetic diagnosis. A finding of two ApoE4 alleles does not; it simply means that the person's odds of developing AD are increased by about 12- to 15-fold. Scientists think that ApoE4 lowers the age of onset by about a decade from when that person would have otherwise developed AD. (People without ApoE4 tend to die of other causes before they are old enough to get AD.) In a given family with an APP or presenilin-2 (but not presenilin-1) mutation, carriers who also have inherited an ApoE4 gene tend to get sick at a younger age than their relatives who have the more neutral ApoE3 or the somewhat protective ApoE2 version alongside the APP or presenilin mutation.
Some families with early-onset AD know which genetic mutation is responsible for their disease, but more do not. The three known AD genes together explain only half of all early-onset AD. Frequently, neurologists at referral centers will see people with early-onset AD who have no family history; those are called sporadic cases. Of these, some people, upon genetic testing, turn out to have a previously identified mutation in one of the three dominant genes. Others prove to have a different mutation in one of the three genes. More often, however, geneticists cannot pin down a cause, so the story of that person's, or family's disease awaits the discovery of new AD genes.
Another frequent situation is that affected patients or their caregivers can tell their doctor fragments of a family history but not enough detail for a geneticist to puzzle out if the disease is truly familial in origin, much less which gene could be at fault. Typically, the caregiver of a young person with AD may know of one parent who had it but died, plus perhaps stories about some relatives back in the family's country of origin. Incomplete family information is one reason why, despite the large number of individual early-onset AD cases, geneticists have been able only in relatively few instances to piece together the multi-generational pedigrees that form the basis for identifying disease genes.
After a thorough clinical evaluation to establish the presence of clinical AD (see Diagnosis), the first thing a knowledgeable clinician will try to do when AD looks familial is to establish the patient's family tree to trace the pattern of inheritance. In some cases, families are so motivated to better understand their disease that they undertake the genealogy themselves, said Nick Fox of the Dementia Research Center at London's University College. In other instances, delicate family dynamics can stymie the gene sleuth. A U.S. physician described a case where a patient with obvious early-onset AD had two healthy parents and looked entirely different from his siblings. "I suspected non-paternity, but could not pursue the possible familial source of this patient's AD," the physician said. "If the family did not know of the non-paternity, they wouldn't want to find out at that stage in life through me."
Another reason why eFAD numbers are vague is that neurologists and psychiatrists may hesitate to diagnose AD in young or middle-aged people. Some are insufficiently aware of eFAD, while others hold off on diagnosing it exactly because it is considered very rare. In effect, eFAD gets passed off for something else and proper diagnosis is delayed until the patient is older, said Thomas Bird of the University of Washington, Seattle. Frequently that something else is depression (for a personal account, see interview). Yet other doctors are misled by variations in how eFAD presents (see Diagnosis). Confusingly, familial AD sometimes shows up in one family member in his/her thirties and in another in the sixties, although in a majority of families disease begins in the forties and early fifties. In rare instances, disease can show up in different guises in different members of a single family. For example, in one case a family member exhibited weakness and gradual paralysis of the legs and only minor dementia, while another had pure AD. Such variations probably are the result of secondary genes that somehow modify the effect of the original AD mutation to push onset back or forward, or to create a different combination of symptoms.
All told, researchers in the field suspect that an additional one to three genes causing eFAD remain to be found, plus several more that influence the age at which AD strikes. Knowing more genes may eventually help scientists get a better grasp on defining eFAD, but to be able to pinpoint them, scientists need more families willing to participate in research. To date, the available collections of families with AD willing to participate in research have been large enough only to identify genes that either have strong effects or that occur relatively frequently. For genes that affect one's AD risk weakly, and for less common genes, larger samples of patients and healthy relatives will be needed.
To date, families with eFAD have been viewed as exceedingly rare exceptions, too rare to include in clinical studies and drug trials. In one sense, this makes eFAD the ultimate orphan disease; it lacks the visibility, funding, and advocacy groups associated with diseases such as Huntington disease and ALS, even though the numbers affected by early-onset AD are comparable or greater.
NEXT: How Early-onset Dementia Led to a Historic Discovery