Diagnosing Alzheimer’s Disease
There is no single test that proves a person has Alzheimer’s disease (AD). The process of diagnosing Alzheimer’s disease can be challenging because it is currently a diagnosis of exclusion, which means that one must exclude other neurological, psychiatric, or systemic disorders sufficient to cause dementia. After the clinical criteria for AD are met, the definitive test for AD is confirmation of the presence of neurofibrillary tangles by brain biopsy, which, if performed, is typically done at autopsy. Other than brain biopsy, a series of examinations are usually necessary to diagnose AD.
General Physical Examination and Medical History
The diagnosis of dementia begins with a thorough physical examination and complete medical history to evaluate overall health and identify any conditions that might affect the mind.
The doctor interviews the patient or family members to gather information about current and past illnesses. Knowledge of other family members’ medical conditions can be very helpful, especially if there is a family history of AD or related disorders.
Common questions the doctor might ask include:
- What kind of symptoms have you noticed?
- When did they begin and how often do they occur?
- Have they gotten worse?
- Is the patient taking any medications or supplements?
- What is the patient’s typical diet?
- Does the patient use alcohol?
The general physical examination typically consists of:
- Checking heart rate, blood pressure, and temperature
- Listening to the heart and lungs
- Collecting samples of blood and urine
Information from these tests can help identify other disorders that may cause symptoms similar to dementia including:
- Certain infections
- Kidney disease
- Heart or blood vessel disease
- Thyroid abnormalities
- Liver disease
- Lung disease
- Anemia, malnutrition or certain vitamin deficiencies
- Excess use of alcohol
- Medication side effects
The neurological examination tests the function of the brain and nervous system. During the neurological exam, the physician may test:
- Coordination and balance
- Muscle tone and strength
- Eye movement
Brain imaging can improve the accuracy of diagnosis and allow earlier diagnosis of AD and other dementias. There are two kinds of brain imaging: structural and functional.
- Structural imaging provides information about the brain anatomy and can detect loss of brain cells, tumors, strokes, certain brain infections, damage from head trauma, large blood clots, or abnormal fluid collections. Structural techniques include magnetic resonance imaging (MRI) and computed tomography (CT). MRI is typically part of the standard evaluation for AD, because AD is associated with brain cell damage and atrophy (shrinkage) in specific regions of the brain.
- Functional imaging reflects the metabolism or level of activity in different brain regions by showing how actively the cells use sugar or oxygen. Functional techniques include functional MRI (fMRI) and molecular neuroimaging, which include positron emission tomography (PET), and single photon emission computed tomography (SPECT). Medicare will pay for a PET scan to help distinguish Alzheimer’s from frontotemporal dementia.
FDG-PET is a type of PET imaging that measures glucose metabolism in the brain. In AD, there is decreased metabolism (or activity) in specific regions of the brain, which helps distinguish AD from frontotemporal dementia.
PIB-PET is a type of PET imaging that shows brain amyloid deposits. The brain of someone with AD usually demonstrates increased PIB binding (or higher levels of amyloid) compared to normal brains.
Combining imaging modalities, such as MRI, FDG-PET and PIB-PET, can help distinguish different types of dementias and improve early detection of Alzheimer’s disease.
A lumbar puncture is a procedure to sample cerebral spinal fluid (CSF), which is the fluid that surrounds the brain and spinal cord. CSF can be used to test for infections that can cause symptoms similar to AD, such as tuberculosis, syphilis, and fungal infections if there is clinical suspicion for such diseases. CSF can also be tested for levels of abnormal proteins that build up in certain types of dementia, including tau protein and amyloid beta (AB) peptides such as AB-42 in Alzheimer’s patients.
Mental Status Tests
Mental status testing helps the doctor identify whether the patient is oriented to date, time, and place, can remember words, follow instructions, do simple calculations, and is aware of having symptoms.
- Mini-cog – This test involves two tasks: (1) remembering three common objects, and (2) drawing a clock face representing a specific time.
- Mini-mental status exam (MMSE) – This common test involves a series of questions are designed to test a range of cognitive skills.
Examples of questions include:
- State the day, year, month, date, and season.
- Identify the location
- Repeat and remember the names of three objects
- Count backward from 100 by 7s or spell “world” backwards
- Copy a picture
- Follow a three-part instruction
The maximum MMSE score is 30 points. A score of 20 – 24 suggests mild dementia, 13 – 20 suggests moderate dementia, and less than 12 indicates severe dementia. On average, the MMSE score of a person with Alzheimer’s declines about 2 – 4 points each year.
- Other tests for cognitive and functional assessment – These additional tests may also be utilized.
- Addenbrooke’s Cognitive Examination (ACE)
- Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE)
- Blessed Orientation-Memory Concentration Test
- Activities of Daily Living portion of Minimum Data Set (MDS)
- Barthel Index
- Functional Activities Questionnaire
Neuropsychological tests might also be performed to evaluate brain function and impairment. These tests examine intellectual function, academic achievement, executive functions, speed of cognitive processing, language processing, visuospatial processing, verbal learning and memory, visual learning and memory, sensory-perceptual functions, motivation, motor speed and strength, and assess personality.
It is important to evaluate for depression, which can sometimes present with symptoms similar to dementia.
EEG measures electrical brain activity. Although the EEG is not routinely used for the diagnosis for AD, it may be considered. In the early stages of AD, the EEG may be normal or only slightly abnormal. As the disease becomes more severe, the EEG may show slowed activity in the front parts of the brain (frontal lobe), which is important for cognition and personality. There may be an increase in abnormal frequencies (theta and delta) and a decrease in normal frequencies (alpha and beta), which may be associated with abnormal protein deposits and the level of cognitive impairment.
Because AD tends to run in families, family members of a someone with AD may want genetic testing for the disease. The one gene currently available for genetic testing is associated with an early onset form of AD (typically before age 60). Therefore genetic testing may only be appropriate for individuals with a family member who developed AD at an early age, or for confirming the diagnosis of AD in a person already exhibiting symptoms of AD at an early age.
Currently there are three known, autosomal dominant genetic syndromes that cause early onset AD. The mutations are found in the APP, PS1, or PS2 gene. This means that if a parent has a mutation in one of these genes, then the child has a 50% chance of inheriting the disease. Currently, genetic testing is only available for the PS1 gene. Testing for the other two genes is investigational at this time. These three genes only account for about half of the inheritable, early onset form of AD, which indicates that additional genes associated with inheritable forms of AD have yet to be identified. It is important to remember that most cases (approximately 95%) of AD are not associated with mutations in these three genes. Testing negative for one of these genetic mutations does not mean that you will not develop AD.
Genes that determine susceptibility to AD have been identified. Most of these genes are related to amyloid-beta deposition (APP; PS1; PS2; APOE; Cystatin-C; ubiquilin-1), oxidative stress (NOS2; NOS3), and inflammatory response (IL-1 alpha; IL-1 beta; IL-6; TNF-alpha). One of these genes, called APOE4, is associated with a higher risk of developing AD. Because having the gene only increases the risk but does not ensure development of the disease, the benefits of testing for this gene is controversial. It is currently only available to confirm the diagnosis of AD in those patients who already have dementia.
Genetic testing for AD remains a controversial issue, particularly because there is no way to prevent or cure the disease. Meeting with a genetic counselor can help determine whether one might benefit from genetic counseling. Additionally, discussing the risks and benefits with family members and a support network may facilitate the decision-making process.
At-Home Screening Test
A new test is available for detecting one of the potential, early signs of AD that can be performed at home. This test, called Early Alert, checks a person’s sense of smell or odor recognition. This test consists of twelve cards, each containing a specific odor, which the user must scratch and sniff and identify. If the user cannot correctly identify four or more of the odors, the manufacturer recommends that the user seek medical advice from a physician. The test should not be conducted if the user has congestion, sinusitis, or respiratory problems, because such conditions can alter one’s sense of smell.
Although this particular test has not been tested for efficacy, it was developed based on other studies that suggested that impaired odor recognition may be a useful tool for detecting early AD and mild cognitive impairment. More data are needed to determine whether a decline in a person’s sense of smell or odor recognition is related to Alzheimer’s disease. Because there are other causes of impaired odor recognition, and the relationship between declining odor recognition and Alzheimer’s disease is not clear, this test may be misinterpreted by the layperson. This test may be a useful addition to the available screening tools for AD and mild cognitive impairment.
More information about the Early Alert Alzheimer’s Home Screening Test can be found at this website: http://www.testsymptomsathome.com/FMG01.asp
Some researchers have proposed some possible factors that may predict which individuals might develop AD. These potential predictive factors include older age, sudden weight loss, being underweight, scores on a simplified version of a cognitive exam, the time it took to button a shirt, the time needed to walk 15 ft, and lack of alcohol consumption.
Blennow K, de Leon MJ, Zetterberg H. (2006). Alzheimer’s disease. Lancet. 368(9533):387-403.
Breitner JC. (1996). APOE genotyping and Alzheimer’s disease. Lancet. 347(9009):1184-5.
Devanand DP, Pelton GH, Zamora D, et al. (2005). Predictive utility of apolipoprotein E genotype for Alzheimer disease in outpatients with mild cognitive impairment. Arch Neurol. 62(6):975-80.
Djordjevic J, Jones-Gotman M, De Sousa K, Chertkow H. Olfaction in patients with mild cognitive impairment and Alzheimer’s disease. Neurobiol Aging. 2008;29:693-706.
Dubois B, Feldman HH, Jacova C, Dekosky ST, Barberger-Gateau P, Cummings J, Delacourte A, Galasko D, Gauthier S, Jicha G, Meguro K, O’brien J, Pasquier F, Robert P, Rossor M, Salloway S, Stern Y, Visser PJ, Scheltens P. (2007). Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDS-ADRDA criteria. Lancet Neurol. 6(8):734-46.
Duff K, McCaffrey RJ, Solomon GS. The Pocket Smell Test: successfully discriminating probable Alzheimer’s dementia from vascular dementia and major depression. J Neuropsychiatry Clin Neurosci. 2002;14:197-201.
Higuera D, Harmon A, Honeywell M, Emanuel F. At-home test for Alzheimer’s disease. US Pharm. 2008;33:49-50.
Holston EC, Schutte DL. (2004). The clinical utility of genetic information in the care of persons with Alzheimer’s disease. Medsurg Nurs.13(6):415-9.
Lendon CL, Ashall F, Goate AM. (Mar). Exploring the etiology of Alzheimer disease using molecular genetics. JAMA. 277(10):825-31.
Mayeux R, Saunders AM, Shea S, Mirra S, Evans D, Roses AD, Hyman BT, Crain B, Tang MX, Phelps CH. (1998) Utility of the Apolipoprotein E Genotype in the diagnosis of Alzheimer’s disease. N Engl J Med. 338(8):506-11. Erratum in: N Engl J Med 1998;338(18):1325.
McConnell LM, Koenig BA, Greely HT, Raffin TA. (2007). Genetic testing and Alzheimer’s disease: Has the time come? Recommendations of the Stanford program in genomics, ethics and society. Nature Medicine. (4):757-759.
Pentzek M, Grass-Kapanke B, Ihl R. Odor identification in Alzheimer’s disease and depression. Aging Clin Exp Res. 2007;19:255-258.
Peters JM, Hummel T, Kratzsch T, et al. Olfactory function in mild cognitive impairment and Alzheimer’s disease: an investigation using psychophysical and electrophysiological techniques. Am J Psychiatry 2003 Nov;160(11):1995-2002.
Nee LE. N. (2007). Genetic counseling and presenilin-1 Alzheimer’s disease: “Research Family” members share some thoughts. Am J Alzheimers Dis Other Demen. 222(2):99-102.
Post SG, Whitehouse PJ, Binstock RH, et al. (1997). The clinical introduction of genetic testing for Alzheimer disease. An ethical perspective. JAMA. 277:832-836. (Summary) Statement of a consensus group supported by the National Human Genome Research Institute and the National Institutes of Health.
Schutte DL. (2006). Alzheimer disease and genetics: anticipating the questions. Am J Nurs. 106(12):40-7.
Serretti A, Olgiati P, De Ronchi D. (2007). Genetics of Alzheimer’s disease. A rapidly evolving field. J Alzheimers Dis.12(1):73-92.
Small GW, Rabins PV, Barry PP, et al. (1997). Diagnosis and treatment of Alzheimer disease and related disorders. Consensus statement of the American Association for geriatric Psychiatry, the Alzheimer’s Association, and the American Geriatrics Society. JAMA. 278(16):1363-71.
Steele, CD. (2000). The genetics of Alzheimer disease. Nurs Clin North Am. 35(3):687-94.
Waldemar G, Dubois B, Emre M, Georges J, McKeith IG, Rossor M, Scheltens P, Tariska P, Winblad B; (2007). EFNS. Recommendations for the diagnosis and management of Alzheimer’s disease and other disorders associated with dementia: EFNS guideline. Eur J Neurol. 14(1):e1-26.Higuera D, Harmon A, Honeywell M, Emanuel F. At-home test for Alzheimer’s disease. US Pharm. 2008;33:49-50.
Wilson RS, Schneider JA, Arnold SE, et al. Olfactory identification and incidence of mild cognitive impairment in older age. Arch Gen Psychiatry. 2007;64:802-808.