An Overview of the Etiology, Diagnosis, and Treatment of Alzheimer Disease.

[Forsyth E, Ritzline PD. An overview of the etiology, diagnosis, and treatment of Alzheimer disease. Phys Ther. 1998;78:1325-1331.]

Etiology

In the past decade, tremendous strides have been made ill determining the multifactorial etiology of AD.[3] Known risk factors for AD include age and genetic factors.[1,5] Other possible risk factors are level of education, female sex, history of head injury, exposure to heavy metals and toxins, positive family history, and trisomy 21.[1,5,6] The characteristic neuropathologic findings of AD are senile or neuritic plaques, neurofibrillary tangles, loss of synaptic connections, and neuronal death in the cerebral cortex. [1,5-7]

The prevalence of AD doubles with each decade after 65 years of age.[5] The strongest support for a genetic basis of the disease comes from the fact that individuals with Down syndrome (trisomy 21) almost universally develop the neuropathologic symptoms of AD after age 40 years.[3] Three genes have been found to be associated with the development of the early-onset familial form of AD, and one gene is considered a risk factor for the more common late-onset form of AD]. [1,3,5,8,9] The 4 genetic loci already known as contributing to AD do not appear to account for all of the genetic risk of the disease. Most recently, chromosome 12 is suspected of having a susceptibility gene for AD.[10]

Most cases of AD occur in a sporadic, nongenetic fashion; only 5% to 10% of all cases of AD are familial.[6] Alzheimer disease is further divided into early-onset AD, a rare form of the disease with a mean age of onset below 65 years, or late-onset AD, with a mean age of onset at 65 years and older.[1] Therefore, the 4 subtypes of AD are early-onset familial, late-onset familial, early-onset sporadic, and late-onset sporadic.[1] The 3 autosomal dominant genes that account for all known cases of the early-onset familial form of AD are found on chromosomes 1, 14, and 21.[11] Strong genetic evidence exists for familial AD; however, whether these genes actually cause the disease or merely represent a susceptibility or risk factors for AD is unknown.[8]

Mutations within the gene on chromosome 21, which encodes for amyloid precursor protein (APP), the precursor of amyloid beta (A[Beta]) peptides, are associated with 2% to 3% of all cases of the early-onset familial form of AD. The presenilin 1 (PS1) gene located on chromosome 14 and the presenilin 2 (PS2) gene located on chromosome 1 are linked to 70% to 80% and 20% to 25% of the early-onset familial form of AD, respectively. The commonality between these 3 genes (ie, APP, PS1, and PS2) is that they alter APP processing, which leads to increased production of A[Beta]. The characteristic senile plaques of AD are formed from A[Beta] peptides that are derived from the proteolytic cleavage of APP.[1,3,5,8,9,11] Thus, according to the "amyloid cascade hypothesis," A[Beta] deposition is the initial critical event in the etiology and pathogenesis of AD; all other features of the disease follow (eg, neurofibrillary tangles, synapse and cell loss, dementia).[9]

Apolipoprotein E (apoE) is a serum lipoprotein involved in cholesterol metabolism that is encoded by a gene (APOE) on chromosome 19.[1] This is the only gene known to be associated with the more common late-onset forms of AD (familial and sporadic), accounting for 50% of the risk of AD.[1,3,5,8,10] Apolipoprotein E has 3 different forms: E2, E3, and E4. It is the inheritance of the E4 allele that confers the risk. Individuals who are homozygous for the E4 allele (E4/E4) are more likely to develop and have an earlier age of onset of AD than are those individuals with other genotypes of the APOE alleles.[5] Some carriers of the E4 allele, however, show no cognitive impairment,[5] and people without the E4 allele can develop AD.[1]

Beyond the known risk factors of age and genetics are several suspected risk factors for AD. Education is thought to be somehow protective against AD.[1,5] The prevalence of AD is greater in women, with the risk increasing during the postmenopausal period. This fact probably explains why women who take estrogen have a lower prevalence of AD compared with women who do not take estrogen.[5,7] The association of AD with coronary artery disease, low body weight, and hip fractures, all of which relate to low estrogen levels, further suggests that low estrogen levels play a role in AD.[3] Alzheimer's disease occurs earlier in individuals who have a history of head injury with loss of consciousness.[1,5,6,12] Exposure to heavy metals such as zinc and aluminum has also been explored as a possible risk factor for AD. Aluminum is known to accumulate in the brain with normal aging.[5,6] Individuals with a positive family history of AD are at higher risk for the disease.[1,5,6] This risk increases 4-fold for individuals having 1 or more first-degree relatives with dementia, and it increases 40 times if 2 or more first-degree relatives have AD.[5]

Diagnosis

Dementia is "an impairment in cognitive function that is significant enough to interfere with the ability to conduct normal activities of daily living."[13(p42)] Alzheimer disease is the most common cause of dementia, accounting for 50% to 70% of cases.[13-15] Dementia can be categorized as either reversible or irreversible.[16] Some of the common causes of irreversible dementia include degenerative diseases (eg, AD, Parkinson disease, multiple sclerosis), infections (eg, neurosyphilis, acquired immunodeficiency syndrome), vascular disease (eg, multi-infarct dementia, stroke, anoxia), and other possible causes (eg, head trauma, normal-pressure hydrocephalus, alcoholic dementia).[16] Only 10% or less of the causes of dementia are reversible.[14] The following mnemonic may be beneficial to clinicians in identifying reversible causes of dementia:

D--drug use
E--emotional disorders (depression)
M--metabolic and endocrine disorders (dehydration,
   renal failure)
E--eye and ear disorders
N--nutritional disorders (vitamin [B.sub.12] deficiency) and
   normal-pressure hydrocephalus
T--tumor or trauma
I--infection (urinary tract infection, acute bronchitis)
A--atherosclerosis and alcoholism [13,16]

Early symptoms of AD are frequently mistaken by patients, caregivers, and physicians for the normal changes associated with aging.[16] Laboratory evaluation to rule out other possible causes of dementia generally includes a blood chemistry panel, liver and thyroid function tests, a serological test for neurosyphilis, and assessment of vitamin [B.sub.12] levels.[13,15,17] The National Institute of Neurological and Communicative Disorders and Stroke in conjunction with the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) have established valid clinical and research criteria, based on the use of conventional clinical, laboratory, and imaging techniques, for the diagnoses of definite, probable, and possible AD (Tab. 1).[14,15,18]

Table 1. National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) Criteria for the Diagnosis of Alzheimer Disease(a)

Criteria for the clinical diagnosis, of probable AD:

Dementia established by clinical examination and documented by the
  MMSE, BDS, or other similar examination, and confirmed by
  neuropsychologic tests
Deficits in 2 or more areas of cognition
Progressive worsening of memory and other cognitive functions
No disturbance of consciousness
Onset between ages 40 and 90 years, most often after age 65 years
Absence of systemic disorders or other brain diseases that could
  account for the progressive deficits in memory and cognition

The diagnosis of probable AD is supported by:

Progressive deterioration of specific cognitive functions such as
  language (aphasia), motor skills (apraxia), and perception
  (agnosia)
Impaired activities of daily living and altered patterns of behavior
Family history of similar disorders, particularly if
  neuropathologically confirmed

Laboratory results of:
  Normal lumbar puncture as evaluated by standard techniques
  Normal pattern or nonspecific EEG changes, such as increased
    slow-wave activity
  Evidence of cerebral atrophy on CT with progression documented by
    serial observation

Other clinical features consistent with probable AD, after
  exclusion of other causes of dementia:

  Plateaus in the course of progression of the illness
  Associated symptoms of depression; insomnia; incontinence;
    delusions; illusions; hallucinations; catastrophic verbal,
    emotional, or physical outburst; sexual disorders; and weight
    loss
  Other neurologic abnormalities in some patients, especially those
    with more advanced disease, including motor signs such as
    increased muscle tone, myoclonus, or gait disorder
  Seizures in advanced disease
  CT normal for age

Features that make the diagnosis of probable AD uncertain or
  unlikely:

  Sudden, apoplectic onset
  Focal neurologic findings such as hemiparesis, sensory loss,
    visual field deficits, and incoordination early in the course of
    the illness
  Seizures or gait disturbances at the onset of symptoms or very
    early in the course of the illness

Diagnosis of possible AD:

  May be made on the basis of the dementia syndrome; in the absence
    of other neurologic, psychiatric, or systemic disorders
    sufficient to cause dementia; and in the presence of variations
    in the onset, presentation, or clinical course
  May be made in the presence of a second systemic or brain disorder
    sufficient to produce dementia but not considered to be the
    cause of the dementia
  Should be used in research studies when a single, gradually
    progressive, severe cognitive deficit is identified in the
    absence of another identifiable cause

Criteria for diagnosis of definite AD:

  Clinical criteria for probable AD
  Histopathologic evidence obtained from biopsy or autopsy

Subtype classification for research purposes:

  Familial occurrence
  Onset before age 65 years
  Presence of trisomy-21
  Coexistence of other relevant conditions, such as PD

(a) Reprinted with permission[15] as adapted with permission from McKhann G, Drachman D, Folstein M, et al. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA work group under the auspices of the Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology. 1984;34: 939-944. AD = Alzheimer disease, MMSE = Mini-Mental State Examination, BDS = Blessed Dementia Scale, PD = Parkinson disease, EEG = electroencephalographic, CT = computed tomography.

Important diagnostic tools include interviews of both the patient and a reliable informant to gather information on the patient's current condition, medical and family history, time and mode of onset of deterioration, and any symptoms suggestive of coexisting medical, neurologic, or psychiatric problems.[14,15,17] In addition to a comprehensive physical and neurologic examination, a screen of cognitive function, such as the Mini-Mental State Examination, should be administered.[13,14,17]

Cerebrospinal fluid (CSF) assays for tau proteins, which form the neurofibrillary tangles, and beta-amyloid peptides, which form the senile plaques, have also been developed.[19] The CSF examination, however, is primarily used for relatively young or other atypical patients.[15] Cerebrospinal fluid assays "cannot stand alone in diagnosis but potentially can improve the accuracy of clinical diagnosis to above the 85% range and may allow us to diagnose and initiate treatment sooner."[19(p199)]

The accuracy of imaging tools such as single photon emission computed tomography (SPECT), positron emission tomography (PET), computed tomography (CT), and magnetic resonance imaging (MRI) in the diagnosis of AD is controversial.[14,17,18,20] Some researchers[18,20] have reported the sensitivity and specificity of SPECT and CT to be too low to advocate the use of these tools independent of clinical evaluation in diagnosing AD. Due to the large overlap in information obtained from SPECT and CT, routine use of both tools is usually not justified.[20]

Although initially touted in the popular press, the use of tropicamide eyedrops for the diagnosis of AD is not reliable and study results have been conflicting.[21] The eyedrops reportedly caused pupil dilation in individuals with AD who are known to have acetylcholine deficiency because the iris sphincter is supersensitive to the cholinergic agent.[21]

A definite diagnosis of AD can only be made by biopsy or with specimens obtained at an autopsy; however, diagnostic accuracy during life is as high as 85% due to modern imaging and laboratory techniques and well-developed clinical criteria.[12-15,22] The gold standard for the diagnosis of AD continues to be the NINCDS-ADRDA criteria, which have a sensitivity of 80% to 100% and a specificity of 73% to 100%.[20]

Clinical Picture

Typically, 3 stages of AD are recognized.[23] Occasionally, a fourth stage is identified.[23] Each individual diagnosed with AD will exhibit certain symptoms, including loss of memory and intellectual ability. Generally, symptoms are more severe and an individual experiences a more rapid deterioration in cognitive and physical abilities with early-onset AD, as compared with late-onset AD.[24] Table 2 lists the signs and symptoms noted in each stage of AD.[24-26] Individuals, however, do not necessarily exhibit all of the signs and symptoms in each stage. Therefore, no 2 individuals will present the signs and symptoms of AD identically. Several problems exhibited by individuals with AD in the areas of activities of daily living (ADL), instrumental activities of daily living (IADL), behavior, and cognition are noted in Table 3.[24-26]

Table 2. Signs and Symptoms of the Four Stages of Alzheimer
Disease[24-26]

Stage 1                         Stage 2

Duration of 1-3 y               Duration of 2-10 y
Minimal patient awareness       Profound memory loss
  of the condition              Cognitive impairment-2 or
Mild anomia                       more of the following:
Personality changes                 Anomia
                                    Agnosia
Decreased problem solving           Apraxia
Decreased coping with               Aphasia
  difficult situations          Severe loss of judgment
Emotional lability              Erratic/bizarre behavior
No abstract thinking ability    Wanders aimlessly
Forgetful                       Violent outbursts
Loss of or poor short-term
  memory
Speech deficits
Social withdrawal

Stage 3                              Stage 4

Duration of 8-12 y                   Loss of all abilities
Severe impairment, all cognitive     Speech, motor coordination, all
functions                              memory lost
Physical impairment, generalized     Inability to recognize anyone
  muscular rigidity                  Loss of "self"
Incontinent
Inability to recognize family
  members
Inability to perform basic
  activities of daily living

Table 3. Problems Exhibited by Individuals With Alzheimer Disease in the Areas of Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL), Behavior, and Cognition[24-26]

ADL and IADL              Behavior                Cognition

Performs slowly           Denial of symptoms      Short-term memory
                                                   loss
Lacks initiation of       Restlessness and        Forgetting names,
 activities                anxiety                 appointments,
                                                   errands,
                                                   directions
Difficulty performing     Frustration             Loss of ability
 job                                               to recognize
                                                   family or close
                                                   friends
Difficulty managing
 finances                 Depression              Misplaces items
Difficulty performing     Irritability or         Repeats stories
 calculations              anger                   and questions
Forgetful when shopping   Isolation and social    Expressive or
                            withdrawal             receptive aphasia
Burns food, leaves
 stove or oven on         Apathy                  Vague speech
Forgets phone messages    Suspiciousness          Visual perception
                                                   deficits-glasses
                                                   will not correct
Difficulty finding
 familiar places          Aimless wandering       Impaired judgment
Poor self-care--wears     Disinhibition           Difficulty
 dirty clothes or the                             learningning new
 same clothes twice,                              materials or tasks
 wears clothes inside     Inappropriate sexual    Unable to
 out, forgets to bathe     behavior                compensate for
Difficulty completing                            declining abilities
 tasks                    Paranoia                Short attention
Difficulty finding or     Excessive verbal,        span
 operating bathroom        emotional, or          Decreased orienta-
 faucets                   physical outbursts      tion to place and
Difficulty with           Sleep disturbances       time
 peripheral vision        Hoarding of items       Uncoordinated or
                          Delusions                clumsy
                          Decreased stress        Misinterprets
                           tolerance               events or
                          Hallucinations           conversations
                          Refusal to stop
                           driving

Individuals in stage 1 of AD exhibit mild symptoms that are difficult to identify and that are often overlooked or ignored by others. As an individual progresses through the later stages of AD, the symptoms increase in frequency, duration, and severity, culminating with the person ultimately becoming totally dependent for self-care.[23,27]

Although the clinical picture may appear to be bleak, some functions are thought to be preserved until the last stage of AD, including long-term memory, motor skills, the ability to learn new procedures, and creative abilities.[26] These abilities may allow an individual to participate in athletic activities, play a musical instrument, perform crafts, or complete puzzles.[26]

Pharmacological Management

The first agent approved by the US Food and Drug Administration (FDA) for the treatment of AD was tacrine (Cognex).[5,17,19] Cholinergic neurons are destroyed in the cortical regions of brain of patients with AD.[28] Tacrine is a reversible, centrally acting acetylcholinesterase (ACHE) inhibitor that blocks the breakdown of acetylcholine.[28-30] The drug has been shown to improve cognitive function in patients with mild to moderate AD.[5,17,30] Limitations associated with the use of tacrine, however, include gastrointestinal side effects, hepatotoxicity, and the need to take it 4 times a day.[29-31] Another AChE inhibitor, donepezil (Aricept), recently approved by the FDA, appears to have few systemic side effects and requires being taken only 1 time a day.[17,19] Other AChE inhibitors and acetylcholine precursors are being investigated.[19]

Several other categories of drugs that have been investigated or that continue to be under investigation for the treatment of AD include anti-inflammatory medications, neurotrophic factors, estrogen, agents associated with protein processing, antioxidants, calcium channel blockers, and cholesterol-lowering drugs. Each of these categories of drugs will be discussed briefly.

Anti-inflammatory Medications

Proteins characteristic of the inflammatory process (eg, complement, inflammatory cytokines) are associated with amyloid plaques and neurofibrillary tangles.[19,30] The fact that inflammation may contribute to neurodegeneration has led to the investigation of anti-inflammatory substances, including nonsteroidal anti-inflammatory agents (NSAIDs) and glucocorticoids, for protection against AD.[5,19,28,30,32] A meta-analysis of epidemiological studies demonstrated a 50% to 75% reduction in AD development among persons taking NSAIDs.[28] A small group of patients with AD who were taking indomethacin showed no decline in cognitive function over a 6-month period in comparison with individuals receiving a placebo who showed a decline.[5]

Neurotrophic Factors

Neurotrophic factors, which are necessary for neuronal survival and development, may be insufficient in individuals with AD.[5,28,30] Nerve growth factor (NGF), one of several neurotrophic factors studied, has been shown to enhance survival of cholinergic neurons in the basal forebrain and to demonstrate cognitive benefits in experimental animal models.[30] These substances, however, do not cross the blood-brain barrier, creating a challenge for devising a safe way to administer these drugs.[5,28,30] The best option, which has demonstrated cognitive benefits in aged animals, may be the use of an oral agent, such as AIT-082, that crosses the blood-brain barrier and stimulates the production of NGF.[30]

Estrogen

Estrogen exhibits both neuroprotective and neurotrophic effects on cholinergic neurons.[5,19,28,30] Studies have shown estrogen to be protective against the development of AD and to actually improve cognitive and affective function in some women with probable AD.[29] In addition to the known benefits of estrogen in preventing heart disease, osteoporosis, and stroke, the data supporting the use of estrogen in the prevention and treatment of AD is encouraging.[29] The risk of breast and endometrial cancer with estrogen therapy, however, must be considered on an individual basis.[29]

Protein Processing Agents

Medications that would help prevent the deposition of amyloid plaques and the accumulation of tau proteins, which form the neurofibrillary tangles, would target the characteristic lesions of AD.[28,30]

Antioxidants

Free radicals, which are by-products of oxygen metabolism, are molecules with an unpaired electron in their outer shell.[5,28,30] This reactive oxygen species might be responsible for the neuronal degeneration associated with aging and AD.[28,30] Potential therapeutic agents include the enzymes superoxide dismutase and catalase, the antioxidants vitamins E and C, idebenone, and the selective monoamine oxidase-B inhibitor selegiline (Deprenyl)[5,17,28,30] In a study conducted by the Alzheimer's Disease Cooperative Study Consortium,[28,30] vitamin E and selegiline were given alone and in combination to individuals with moderate AD over a 2-year period. Results of the study are pending.[28,30]

Calcium Channel Blockers

Aging is associated with an increase in calcium channels in neurons.[29] Calcium channel blockers work to prevent the calcium influx into nerve cells that leads to their death.[5,28,30] In a study of young rats versus old rats, the calcium ion channel density was found to be 3 times greater in the older rats, which demonstrated poorer performance with learning tasks.[28] Furthermore, in some studies, the calcium channel blocker nimodipine slowed the decline of cognitive function in AD-type dementia.[30]

Treatment Strategies

Generally, the primary care physician, who is responsible for directing the care, as well as preventing and treating comorbid medical conditions of persons with AD, works in conjunction with professional and nonprofessional health care providers and the family.[16,33] All persons involved should recognize that treatment and care will be long term and that not all individuals with AD will be institutionalized.[16,33] The overall medical goals should be to maximize the person's abilities, rehabilitate lost functions when possible, ensure the safety of the individual, and educate and support family members.[16]

Psychosocial Implications

Many areas such as AD education, legal and financial planning (eg, durable power of attorney, living wills and trusts), support groups, and nursing home placement should be discussed with individuals who have AD when they are able to participate to some degree in those discussions.[33,34] The most difficult treatment decision for families is often when to place someone in a nursing home.[13]

The stress of caring for someone with AD is extreme and often produces anxiety and depression among caregivers, which can lead to the use and abuse of psychotropic medications.[16] These medications may impair a caregiver's cognitive function, resulting in possible harm to the person for whom care is being provided.[16] Family education, counseling, and formal and informal support groups are imperative for the emotional and physical well-being of caregivers.[33]

Conclusion

As life expectancy continues to increase, AD will become an even greater concern to our society. Research is helping to unravel the complex nature of the etiology of this disease. Great strides have been made in the diagnosis of AD and in the treatment of individuals with AD. The role of physical therapy in the diagnosis of AD and in the treatment of people with AD has not been evaluated with clinical research. In view of the needs of individuals with AD, however, physical therapists could be integral members of the health care team involved in treating individuals with AD. The unique skills that physical therapists possess may help to prevent loss of functional abilities, delay institutionalization, and enhance the overall quality of life for these individuals.

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E Forsyth, PhD, PT, is Assistant Professor, Krannert School of Physical Therapy, University of Indianapolis, 1400 E Hanna Ave, Indianapolis, IN 46227 (USA) ([e-mail]). Address all correspondence to Dr Forsyth.

PD Ritzline, PT, is Director, Physical Therapist Assistant Program, and Assistant Professor, Krannert School of Physical Therapy, University of Indianapolis.