Early Onset Familial AD

Diagnosis of Early Onset Alzheimer Disease


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By Gabrielle Strobel

"The neurologist diagnosed conversion disorder (see Medline). I should not have believed that. We went to counseling sessions for a year but nothing happened."

Families with eFAD tell stories of being misdiagnosed because their doctors had ruled out the possibility of AD in people who are so young (see "A Diagnostic Odyssey"), or simply did not consider it seriously. "My brother's first symptoms were personality changes, weight gain, loss of physical coordination, and then short-term memory loss. We thought those signs would be enough for him to be diagnosed correctly given that his mother and uncle also had had early onset AD. But still it took nearly two years of neurological assessments before the doctors would give my brother his diagnosis," an unaffected sibling said. Ironically, AD specialists say that provided the doctor is attuned to AD occurring in younger people, diagnosing eFAD can actually be easier than diagnosing LOAD. Elderly patients are more likely to have other medical conditions that can cause dementia, making diagnosis trickier. For example, cardiovascular disease and diabetes are very common in older people, and can cause symptoms that overlap with AD. In younger patients, this is less likely to be the case. A main challenge in diagnosing eFAD is to distinguish it from other types of dementia that begin in middle age, for example, frontotemporal dementias such as Pick disease.

AD is defined by the presence of plaques and tangles in the brain. Strictly speaking, a clinical diagnosis can only be confirmed by examination of the brain tissue, typically by autopsy after death. In practice, however, physicians who are experienced with AD, particularly those at academic medical centers, can provide a clinical diagnosis of AD during life with an accuracy rate of 90 percent or better. This is not true everywhere. Some studies have documented that dementia is often overlooked in community care settings (Callahan et al., 1995Ganguli et al., 2004). "Some practicing physicians in the community may not have the experience, awareness, or time to detect AD, and hence many people with AD remain undiagnosed and untreated," says John Morris, an eminent AD clinician-researcher at Washington University's Alzheimer Disease Research Center in St. Louis, Missouri. "Proper diagnosis may be even more difficult for early onset AD, as some practicing physicians may not be aware that AD can develop in mid-life. The key to diagnosis is to find a physician who is interested and experienced in dementia." Morris recommends that families who are concerned about eFAD seek care at a university hospital with an AD research center or a specialized memory clinic. Families who live too far away from such a center may want to ask their local chapter of the Alzheimer Association for recommendations of physicians with a special interest in dementia.

What Are Early Signs?
Dementia is defined as the decline of cognitive functions including memory, as compared to the person's previous level of function. Dementia of the Alzheimer type is insidious in its onset, predictable in its downward progression, and irreversible (at least with treatments that are currently available). The first signs of eFAD are very similar to those of late-onset Alzheimer's. The sequence in which signs appear varies from person to person. Typical signs include the following:

Personality changes, such as brusqueness and insensitivity 
Frequent lapses of memory, especially of recent memories 
Forgetting appointments or the names of colleagues at work 
Unsettling moments of disorientation in previously familiar places 
Being unable to find the way home 
Becoming confused about familiar tasks such as handling money or placing a call 
Difficulty finding words 
Difficulty with voluntary movements, physical coordination 
Struggling to learn new things and adapting to changes at home or at work 
Losing interest in activities that were enjoyed previously 
Withdrawing from social contact; depression 
Mood swings, paranoia and fearfulness

Occasionally, a person's symptoms may also include insomnia, verbal or physical outbursts, sexual disorders, gait disorders, and weight loss. The Alzheimer's Association has a helpful list of 10 warning signs.

Spouses, relatives, or colleagues at work are often the first to notice that something is changing in a person who is developing AD. In other cases, the person him/herself may know early on that something is wrong (see first-person account of early stage eFAD). People who have already seen a parent and perhaps a sibling succumb to the disease are often extremely vigilant about any potential symptoms. Frequently, however, the affected person initially ignores or denies the presence of a problem. Many try to blame the symptoms on stress and overwork.

Diagnosis—What to Expect
To diagnose eFAD, the doctor follows the same guidelines as in LOAD. These are the following:

Examining for the presence of AD symptoms 
Ruling out other possible causes of dementia

In addition, the doctor will ask about a family history of early onset AD. Patients with eFAD often clearly remember having a parent with dementia, and that helps to diagnose eFAD at an earlier stage. Even if there is a family history, however, the neurologist or psychiatrist must still exclude other potential causes. This is important because even if people have an eFAD gene, this does not mean that all of their symptoms are due to the gene. They could still have hypothyroidism, vitamin B12 deficiency, or another underlying problem that is treatable. In certain cases, the doctor may offer genetic testing to confirm the diagnosis.

Diagnosis—The Standard Process
Here are some typical steps you can expect during the diagnostic exams:

Medical history, including separate interviews with an informant/relative and the patient 
Clinical examination, including the following:

  • Neurologic examination, i.e., a check on sensory and motor systems (cranial nerves, reflexes, gait, coordination, etc.) and brief assessment of mental status (orientation, attention, recent recall, calculation, naming, understanding, reading, writing, drawing, etc.)
  • Psychiatric assessments of mood, apathy, delusions and hallucinations, anxiety, etc.

A series of neuropsychological tests 

Laboratory assessments of blood and perhaps cerebrospinal fluid 

Possibly brain imaging (CT, MRI, PET) 

Possibly EEG

Detecting memory deficits is central to properly distinguishing AD from other progressive dementias that can strike in mid-life, for example, frontotemporal dementia or vascular cognitive impairment. These other diseases cause numerous problems with cognition, but memory is not affected as prominently as in AD. The doctor will then try to determine if the deficits have become worse, and if they have led to trouble functioning in daily life. The neurologic examination, blood tests, and imaging studies are aimed at ruling out a host of other potential causes for the symptoms. They include dementia associated with Parkinson's, Huntington's or Creutzfeldt-Jakob diseases, frontotemporal dementias, vascular cognitive impairment, depression, bipolar disorder, drug abuse, thyroid disease, anemia, bacterial or viral infections of the central nervous system, hematoma, trauma, hydrocephalus, brain tumors. AD is probably not the cause when the person has seizures or is not fully conscious.

In general, AD is unlikely when symptoms appear suddenly, within hours or days, rather than over the course of weeks and months. The exception to this rule is when a new medical condition unmasks a dementia that the patient had previously compensated for, but this is less common in younger patients than in the elderly. "With early onset AD, frequently a problem at work becomes the event that brings the patient in," said Reisa Sperling, an AD neurologist-researcher at Brigham and Women's Hospital in Boston, Massachusetts.

Once the doctor suspects AD, (s)he will likely ask the patient to take a variety of tests of memory, visual perception, and thinking. It is important to note that the performance on those tests varies depending on the person's educational background, level of mental activity at work, and age. In addition, AD gets steadily worse over time, so the tests must be repeated after 6-12 months to see if there has been a decline. Highly intelligent people at an early stage of AD can score higher than a healthy person of average intelligence, which makes their diagnosis initially more difficult. Yet over time their scores will fall, whereas a healthy person's scores will improve, if anything, thanks to the training effect of taking the same test twice. Neuropsychological tests are never the sole basis for a diagnosis of AD but instead support the clinical impression. They are most valuable for defining the precise pattern of a person's cognitive impairment and for measuring change over time, particularly in the setting of clinical trials of drugs or other treatments.

Body fluids, collected in a blood draw and sometimes a spinal tap, are sent to a laboratory for tests to rule out other diseases, such as measurement of iron levels to rule out anemia or the common iron overload disease hemochromatosis, or of chronic infections such as cryptococcal meningitis or syphilis.

The process of AD diagnosis differs somewhat from center to center, but in general neurologists follow guidelines adapted from two widely used sets of criteria. One is the so-called NINCDS/ADRDA criteria developed by a joint working group of scientists from the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Association (McKhann et al., 1984). The other is the criteria in the psychiatrist's diagnostic bible, the current edition of the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM-IV, text revised in 2000). Both are broadly similar. Outside of the U.S. and Canada, the World Health Organization's International Classification of Diseases (ICD 10th revision, 1992), finds wide application. The DSM-IV and the ICD still maintain a formal separation between EOAD and LOAD in their nomenclature, although for practical purposes the diagnosis is the same. A recent reappraisal of the current diagnostic criteria is underway as part of the process to prepare the DSM-V (Reisberg, 2006).

Diagnosis—The Cutting Edge
The diagnostic criteria in the NINCDS/ADRDA or DSM-IV guidelines are fairly stringent. Their goal is to avoid the mislabeling of patients as having AD when in fact they might suffer from something else. As a consequence, these criteria are not sensitive for the earliest stages of AD. Better methods for earlier diagnosis are now being developed at AD research centers, because researchers agree that once better AD therapies are available, they will probably be most effective if administered during the earliest, even preclinical, stages of disease. Some of these methods are described in this section.

Increasingly, major Alzheimer research centers measure cerebrospinal fluid (CSF) levels of the Aβ42 peptide and of phosphorylated forms of the protein tau. This is largely done for research purposes, but also occasionally to support the diagnosis of AD versus other diseases. In research settings, these markers are proving to be quite good at predicting AD at its earliest stages. At present, however, no fluid-based test can diagnose AD on its own.

While the diagnosis continues to be largely based on symptoms, a growing number of centers use various types of brain imaging to support the diagnostic workup. A magnetic resonance imaging (MRI) or a computerized tomography (CT) scan looks at physical damage or changes in the brain. Such a scan can rule out tumors, hydrocephalus, strokes, or other problems with the brain vasculature. Both methods can measure whether certain brain areas are shrinking and whether the fluid-filled ventricles are expanding (which would also indicate a shrinkage of brain matter). Further, MRI and CT can help the doctor decide if damage to the brain's white matter might contribute the patient's symptoms. Such imaging can support the diagnosis of AD, but is not used by itself to diagnose AD.

Positron emission tomography (PET) is another brain imaging method that involves injecting a radioactive marker to detect certain brain changes. PET is used only in a few major centers with AD research programs. PET can detect how much oxygen or glucose (a sugar) different brain areas are using. People with AD will have a drop in oxygen or glucose use in parts of the brain involved in memory. In a small number of research centers, PET is being used together with a chemical called PIB, which sticks to amyloid deposits, one of the main pathological lesions in the brains of AD patients. PIB-PET imaging can detect amyloid in the brain of a living patient, and thus might be used for early diagnosis. However, the relationship of PIB binding and preclinical symptoms is still being worked out. These procedures, like the overall diagnostic process, do not differ significantly between eFAD and LOAD. None of them constitutes a stand-alone diagnostic.

At the end of the day, AD is a disease of brain function, and the doctor's observations of the patient's symptoms remain all-important. A big challenge is to detect AD at its earliest stage, when the changes are very subtle—too subtle, in fact, to be detected by the standard tests. (See "Pushing the Envelope on Early Diagnosis").

For people who are still in their thirties, forties, and fifties, obtaining a correct diagnosis for the cause of their cognitive impairments can be challenging. If there is a strong family history of dementia, a positive diagnosis of early onset Alzheimer disease raises a second, formidable question: Is the cause genetic? Is this, in fact, eFAD? Our next section addresses genetic testing and the complicated questions that this raises. For additional information on diagnosis, see our ARF Diagnosis page.

Further reading:
Knopman DS, DeKosky ST, Cummings JL, Chui H, Corey-Bloom J, Relkin N, Small GW, Miller B, Stevens JC. Practice parameter: diagnosis of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2001 May 8;56(9):1143-53. Abstract

Morris JC. The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology. 1993 Nov 1;43(11):2412-4. Abstract

Hughes CP, Berg L, Danziger WL, Coben LA, Martin RL. A new clinical scale for the staging of dementia. Br J Psychiatry. 1982 Jun 1;140():566-72. Abstract

Reisberg B, Ferris SH, de Leon MJ, Crook T. The Global Deterioration Scale for assessment of primary degenerative dementia. Am J Psychiatry. 1982 Sep 1;139(9):1136-9. Abstract

Reisberg B, Ferris SH. Brief Cognitive Rating Scale (BCRS). Psychopharmacol Bull. 1988 Jan 1;24(4):629-36. Abstract

Sclan SG, Reisberg B. Functional assessment staging (FAST) in Alzheimer's disease: reliability, validity, and ordinality. Int Psychogeriatr. 1992 Jan 1;4 Suppl 1():55-69. Abstract

Galasko D, Hansen LA, Katzman R, Wiederholt W, Masliah E, Terry R, Hill LR, Lessin P, Thal LJ. Clinical-neuropathological correlations in Alzheimer's disease and related dementias. Arch Neurol. 1994 Sep 1;51(9):888-95. Abstract

Alzheimer Association, AD Staging

Where to Turn If You Suspect Mid-life Dementia?
If you see worrisome signs of what could be dementia in a loved one or yourself, you may want to see a specialist soon. Because Alzheimer disease is so strongly associated with advanced age, not all community-based physicians will spot the disease in a much younger person. Consider seeking a referral to a tertiary care center. Typically, this will be an academic medical center with a specialty memory clinic, or a federally funded AD research center. There, you are most likely to receive an up-to-date diagnosis and care. These centers offer opportunities to participate in research, if you wish to do so, and may have access to experimental procedures that are not yet broadly available.

Later this spring, this website will publish a list of clinics with expertise in eFAD. Alternatively, your local Alzheimer Association chapter may be able to recommend a physician.