Alzheimer Disease; Causes, Symptoms, Diagnosis, Treatment









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Alzheimer disease (AD) is the most common causes of neurodegenerative disorder in elderly individuals. Clinically, patients initially present with short-term memory loss, subsequently followed by executive dysfunction, confusion, agitation, and behavioral disturbances.

Alzheimer’s disease (AD) also referred to simply as Alzheimer’s is a chronic neurodegenerative disease that usually starts slowly and worsens over time.[rx][rx] It is the cause of 60–70% of cases of dementia.[rx]rx] The most common early symptom is difficulty in remembering recent events (short-term memory loss).[rx] As the disease advances, symptoms can include problems with language, disorientation (including easily getting lost), mood swings, loss of motivation, not managing self-care, and behavioral issues.[rx]2rx] As a person’s condition declines, they often withdraw from family and society.[rx] Gradually, bodily functions are lost, ultimately leading to death.[rx]

Staging of Alzheimer Disease

Preclinical

  • Earliest pathological changes begin in the entorhinal cortex, followed by the hippocampus. In this stage, patients present with mild memory loss with no significant functional impairment in their daily activities. At this stage, it is classified as mild cognitive impairment.

Mild Alzheimer Disease 

  • Cognitive impairment starts at this stage as the disease progresses to the cerebral cortex. Along with memory loss, there is an inability to remember new information, forgetting things and appointments, repetitive questions and conversations, confusion, disorientation, personality changes, mood swings, loss of spontaneity, and impairment in reasoning and judgment.

Moderate Alzheimer Disease 

  • At this stage, the disease further spreads to areas of the cerebral cortex responsible for language, reasoning, and sensory processing. There is increasing memory loss and attention, and behavioral problems like wandering off and agitation begin to appear.
  • Patients at this stage have trouble recognizing own family and friends. They have apathy, social withdrawal, and loss of inhibition. They often make repetitive statements and have loss of impulse control. They also have difficulty with language, reading, and writing.

Severe Alzheimer Disease 

  • The disease progresses to involve the entire cortex at late stages. Patients at this stage of Alzheimer disease, cannot recognize their family and friends at all and are entirely dependent on others for daily activities. Along with other features, they also become incontinent of bladder and bowel and may have difficulty swallowing.

Stages of Alzheimer’s Disease[rx]

Effects of aging on memory but not AD
  • Forgetting things occasionally
  • Misplacing items sometimes
  • Minor short-term memory loss
  • Not remembering exact details
Early stage Alzheimer’s
  • Not remembering episodes of forgetfulness
  • Forgets names of family or friends
  • Changes may only be noticed by close friends or relatives
  • Some confusion in situations outside the familiar
  • forget about recent conversations or events
  • misplace items
  • forget the names of places and objects
  • have trouble thinking of the right word
  • ask questions repetitively
  • show poor judgment or find it harder to make decisions
  • become less flexible and more hesitant to try new things
Middle stage Alzheimer’s
  • Greater difficulty remembering recently learned information
  • Deepening confusion in many circumstances
  • Problems with sleep
  • Trouble determining their location
  • Forget about recent conversations or events
  • Misplace items
  • Forget the names of places and objects
  • Have trouble thinking of the right word
  • Ask questions repetitively
  • Show poor judgment or find it harder to make decisions
  • Become less flexible and more hesitant to try new things
  • Increasing confusion and disorientation – for example, getting lost, or wandering and not knowing what time of day it is
  • Obsessive, repetitive or impulsive behavior
  • Delusions (believing things that are untrue) or feeling paranoid and suspicious about carers or family members
  • Problems with speech or language (aphasia)
  • Disturbed sleep
  • Changes in mood, such as frequent mood swings, depression and feeling increasingly anxious, frustrated or agitated
  • Difficulty performing spatial tasks, such as judging distances
  • Seeing or hearing things that other people do not (hallucinations)

Late stage Alzheimer’s

  • Poor ability to think
  • Problems speaking
  • Repeats same conversations
  • More abusive, anxious, or paranoid
  • difficulty eating and swallowing (dysphagia)
  • difficulty changing position or moving around without assistance
  • weight loss – sometimes severe
  • unintentional passing of urine (urinary incontinence) or stools (bowel incontinence)
  • gradual loss of speech
  • significant problems with short- and long-term memory

Symptoms of Alzheimer Disease

Memory loss is the key symptom of Alzheimer’s disease. An early sign of the disease is usually difficulty remembering recent events or conversations. As the disease progresses, memory impairments worsen and other symptoms develop. At first, a person with Alzheimer’s disease may be aware of having difficulty remembering things and organizing thoughts. A family member or friend may be more likely to notice how the symptoms worsen. Brain changes associated with Alzheimer’s disease lead to growing trouble with

Other symptoms may include

  • Persistent and frequent memory difficulties, especially of recent events
  • Vagueness in everyday conversation
  • The apparent loss of enthusiasm for previously enjoyed activities
  • Taking longer to do routine tasks
  • Forgetting well-known people or places
  • Inability to process questions and instructions
  • Deterioration of social skills
  • Emotional unpredictability
  • Persistent and frequent memory difficulties, especially of recent events
  • Vagueness in everyday conversation
  • The apparent loss of enthusiasm for previously enjoyed activities
  • Taking longer to do routine tasks
  • Forgetting well-known people or places
  • Inability to process questions and instructions
  • Deterioration of social skills
  • Emotional unpredictability

1. Reduced ability to take in and remember new information, which can lead, for example

  • Repetitive questions or conversations
  • Misplacing personal belongings
  • Forgetting events or appointments
  • Getting lost on a familiar route

2. Impairments to reasoning, complex tasking, and exercising judgment, for example

  • Poor understanding of safety risks
  • Inability to manage finances
  • Poor decision-making ability
  • Inability to plan complex or sequential activities

3. Impaired visuospatial abilities that are not, for example, due to eyesight problems. These could be

  • inability to recognize faces or common objects or to find objects in direct view
  • inability to use simple tools, for example, to orient clothing to the body

4. Impaired speaking, reading, and writing, for example

  • difficulty thinking of common words while speaking, hesitations
  • speech, spelling, and writing errors

5. Changes in personality and behavior, for example

  • out-of-character mood changes, including agitation, apathy, social withdrawal or a lack of interest, motivation, or initiative
  • loss of empathy
  • compulsive, obsessive, or socially unacceptable behavior

If the number and severity of symptoms confirm dementia, the following factors can then confirm Alzheimer’s.

  • a gradual onset, over months to years, rather than hours or days
  • a marked worsening of the individual’s normal level of cognition in particular areas
  • If symptoms begin or worsen over the course of hours or days, you should seek immediate medical attention, as this could indicate an acute illness.
  • Alzheimer’s is most likely when memory loss is a prominent symptom, especially in the area of learning and recalling new information.

Language problems can also be a key early symptom, for example, struggling to find the right words.

If visuospatial deficits are most prominent, these would include

  • inability to recognize objects and faces
  • difficulty comprehending separate parts of a scene at once
  • the difficulty with reading text, known as Alexia

Memory

Everyone has occasional memory lapses. It’s normal to lose track of where you put your keys or forget the name of an acquaintance. But the memory loss associated with Alzheimer’s disease persists and worsens, affecting the ability to function at work or at home.

People with Alzheimer’s may

  • Repeat statements and questions over and over
  • Forget conversations, appointments or events, and not remember them later
  • Routinely misplace possessions, often putting them in illogical locations
  • Get lost in familiar places
  • Eventually forget the names of family members and everyday objects
  • Have trouble finding the right words to identify objects, express thoughts or take part in conversations

Alzheimer’s disease causes difficulty concentrating and thinking, especially about abstract concepts such as numbers. Multitasking is especially difficult, and it may be challenging to manage finances, balance checkbooks and pay bills on time. These difficulties may progress to an inability to recognize and deal with numbers.

Making judgments and decisions

  • The ability to make reasonable decisions and judgments in everyday situations will decline. For example, a person may make poor or uncharacteristic choices in social interactions or wear clothes that are inappropriate for the weather. It may be more difficult to respond effectively to everyday problems, such as food burning on the stove or unexpected driving situations.

Planning and performing familiar tasks

  • Once-routine activities that require sequential steps, such as planning and cooking a meal or playing a favorite game, become a struggle as the disease progresses. Eventually, people with advanced Alzheimer’s may forget how to perform basic tasks such as dressing and bathing.

Changes in personality and behavior

Brain changes that occur in Alzheimer’s disease can affect moods and behaviors. Problems may include the following:

  • Depression
  • Apathy
  • Social withdrawal
  • Mood swings
  • Distrust in others
  • Irritability and aggressiveness
  • Changes in sleeping habits
  • Wandering
  • Loss of inhibitions
  • Delusions, such as believing something has been stolen

Diagnosis of Alzheimer Disease

Imaging of brain structures include the following

  • A detailed medical history
  • A thorough physical and neurological examination
  • A test of intellectual function
  • Psychiatric assessment
  • A neuropsychological tests
  • Blood and urine tests
  • Lumbar puncture for cerebral spinal fluid tests
  • Magnetic resonance imaging (MRI) – MRI uses radio waves and a strong magnetic field to produce detailed images of the brain. MRI scans are used primarily to rule out other conditions. While they may show brain shrinkage, the information doesn’t currently add significant value to making a diagnosis.
  • Computerized tomography (CT) –  A CT scan, a specialized X-ray technology, produces cross-sectional images (slices) of your brain. It’s currently used chiefly to rule out tumors, strokes and head injuries.
  • Positron emission tomography (PET) scan –  PET scan images can help your doctor detect plaque buildup. Plaque is a protein substance related to Alzheimer’s symptoms.
  • Fluorodeoxyglucose (FDG) PET  –  scans show areas of the brain in which nutrients are poorly metabolized. Identifying patterns of degeneration — areas of low metabolism — can help distinguish between Alzheimer’s disease and other types of dementia.
  • Amyloid PET imaging – can measure the burden of amyloid deposits in the brain. This imaging is primarily used in research but may be used if a person has an unusual or very early onset of dementia symptoms.
  • Tau Pet imaging –  which measures the burden of neurofibrillary tangles in the brain, is only used in research.
  • Treatable forms of cognitive decline – including depression, chronic drug intoxication, chronic CNS infection, thyroid disease, vitamin deficiencies (especially B12 and thiamine), CNS angiitis, and normal-pressure hydrocephalus. CT and MRI can identify some of these other causes of dementia, including neoplasms, normal-pressure hydrocephalus, and cerebral vascular disease.
  • Other degenerative disorders associated with dementia – such as frontotemporal dementia (including frontotemporal dementia with parkinsonism-17; FTDP-17), Picks disease, Parkinson disease, diffuse Lewy body disease (LBD)

Features Suggestive of Diagnoses Other Than Alzheimer’s Disease.

Differential DiagnosisFeatures
  • Early marked behavioral disinhibition or apathy; early perseverative or compulsive behavior; hyperorality and dietary changes; executive function deficits but sparing of memory and visuospatial functions; prominent early aphasia (particularly loss of word and object knowledge, motor speech, and grammatical deficits).
  • Dementia with Lewy bodies (DLB)[
  • Fluctuating cognition; recurrent visual hallucinations, typically well-formed and detailed; spontaneous features of parkinsonism; REM sleep behavior disorder; severe neuroleptic sensitivity; deficits on tests of attention, executive function, visuospatial ability.
  • Vascular dementia (VD)
  • Onset of dementia within 3 months of recognized stroke; abrupt deterioration in cognitive function; fluctuating, stepwise progression of cognitive deficits; early presence of gait disturbance; early urinary symptoms not due to urologic disease; pseudobulbar palsy (dysphagia, dysarthria, emotional lability, inappropriate laughter or crying); depression, emotional incontinence, psychomotor retardation and abnormal executive function. (Note: Sudden onset of aphasia suggests a vascular etiology.)
  • Idiopathic normal pressure hydrocephalus (NPH)
  • Urinary incontinence not due to urologic conditions (

e.g., prostatism or chronic UTI); “glue-footed,” “magnetic” gait.

  • Any of these findings on imaging: (1) enlargement of the temporal horns of the lateral ventricles not entirely attributable to hippocampus atrophy; (2) callosal angle of 40° or more; (3) evidence of altered brain water content, including periventricular signal changes not attributable to microvascular ischemic changes or demyelination. (Note: NPH may also be secondary to traumatic brain injury and other insults.)

Abbreviations: REM, rapid eye movement; UTI, urinary tract infection.

Treatment of Alzheimer Disease

  • Although cardiovascular risk factors, such as hypercholesterolemia, hypertension, diabetes, and smoking, are associated with a higher risk of onset and course of AD,[rx][rx] statins, which are cholesterol-lowering drugs, have not been effective in preventing or improving the course of the disease.[rx][rx][rx]
  • Long-term usage of non-steroidal anti-inflammatory drugs (NSAIDs) was thought in 2007 to be associated with a reduced likelihood of developing AD.[rx] Evidence also suggested the notion that NSAIDs could reduce inflammation related to amyloid plaques, but trials were suspended due to high adverse events.[rx] No prevention trial has been completed.[rx] They do not appear to be useful as a treatment, but as of 2011 were thought to be candidates as presymptomatic preventatives.[rx]Hormone replacement therapy in menopause, although previously used, may increase the risk of dementia.[rx]

According to the Alzheimer’s Association, the following are important elements of dementia care

  • effective management of any conditions occurring alongside the Alzheimer’s
  • activities and day-care programs
  • involvement of support groups and services

FDA-Approved Medications for Alzheimer’s Disease.

Medication
(Brand Name)
MechanismFrequencyHow SuppliedDosage/Comments
  • Donepezil (Aricept)
AChEIDaily (half-life > 24 hours)Tablets: 5 and 10 mg regular and orally disintegrating tablets. Now available in 23 mg for moderate to severe disease.Start at 5 mg. Target is 10 mg, although 5 mg also effective. 23 mg only should be used in moderate to severe disease. (This may have more frequent GI side effects).
  • Galantamine (Razadyne)
AChEI; also allosterically modulates the nicotinic receptorBID, tablets and liquid. ER once a day formulation.Tablets: BID, 4, 8, 12 mg. Oral solution: 4 mg/mL. ER: QD 8, 16, 24 mg.Start at 4 mg BID. Gradually increase to target of 8–12 mg BID. Adequate dose 16–24 mg.
  • Rivastigmine (Exelon)
AChEI; also inhibits BChEBID capsules or liquid, or a daily patch.Capsules: 1.5, 3, 4.5, and 6 mg. Oral solution: 2 mg/mL. Patch: 4.6 mg/24 hours and 9.5 mg/24 hoursStart at 1.5 mg BID. Target is 6 mg BID. Very gradually increase to minimize side effects. Patch: 1 month on the 4.6-mg patch, then increase to 9.5 mg. Oral formulations have more GI side effects than a patch. Need to get to 6–12 mg daily for effect.
  • Tacrine (Cognex)
AChEIQIDCapsules: 10, 20, 30, 40 mgNot used because of dosing and tolerability issues. 30% GI side effects, 30% hepatocellular damage.
  • Memantine (Namenda)
NMDA antagonistBIDTablets: 5, 10 mg. Only approved for moderate to severe disease.Start at 5 mg QD; titrate to 10 mg BID over 4 weeks (titration blister package available). Only indicated for moderate to severe disease.

Abbreviations: AChEI, acetylcholinesterase inhibitor; BChE, butyl-cholinesterase; BID, 2 times a day; ER, extended release; FDA, US Food and Drug Administration; GI, gastrointestinal; NMDA, N-methyl-d-aspartic acid; QD, every day; QID, 4 times a day.

Drug Therapy

  • No disease-modifying drugs are available for Alzheimer’s disease, but some options may reduce the symptoms and help improve quality of life.

Cholinesterase inhibitors that are approved for symptomatic relief in the U.S. include

  • Donepezil (Aricept)
  • Rivastigmine (Exelon)
  • Tacrine (Cognex)
  • A different kind of drug, memantine (Namenda), an NMDA receptor antagonist, may also be used, alone or in combination with a cholinesterase inhibitor.

Lifestyle

  • People who engage in intellectual activities such as reading, playing board games, completing crossword puzzles, playing musical instruments or regular social interaction show a reduced risk for Alzheimer’s disease.[rx]
  • This is compatible with the cognitive reserve theory, which states that some life experiences result in more efficient neural functioning providing the individual a cognitive reserve that delays the onset of dementia manifestations.[rx]
  • Education delays the onset of AD syndrome without changing the duration of the disease.[rx] Learning a second language even later in life seems to delay getting Alzheimer disease.[rx]
  • Physical activity is also associated with a reduced risk of AD.[rx] Physical exercise is associated with a decreased rate of dementia.[rx] Physical exercise is also effective in reducing symptom severity in those with Alzheimer’s.[rx]

Diet

  • Conclusions on dietary components have at times been difficult to ascertain as results have differed between population-based studies and randomized controlled trials.[rx] There is limited evidence that light to moderate use of alcohol, particularly red wine, is associated with lower risk of AD.[rx]
  •  There is tentative evidence that caffeine may be protective.[rx] A number of foods high in flavonoids such as cocoa, red wine, and tea may decrease the risk of AD.[rx][rx]
  • Reviews on the use of vitamins and minerals have not found enough consistent evidence to recommend them. This includes vitamin A,[rx][rx] C,[rx][rx] the alpha-tocopherol form of vitamin E,[rx]selenium,[rx] zinc,[rx][rx] and folic acid with or without vitamin B12.[rx]
  • Evidence from one randomized controlled trial indicated that the alpha-tocopherol form of vitamin E may slow cognitive decline, this evidence was judged to be “moderate” in quality.[rx] Trials examining folic acid (B9) and other B vitamins failed to show any significant association with cognitive decline.[rx]
  • Omega-3 fatty acid supplements from plants and fish, and dietary docosahexaenoic acid (DHA) do not appear to benefit people with mild to moderate Alzheimer’s disease.[rx][rx]
  • Curcumin as of 2010 had not shown benefit in people even though there is tentative evidence in animals.[rx] There was inconsistent and unconvincing evidence that ginkgo has any positive effect on cognitive impairment and dementia.[rx] As of 2008, there was no concrete evidence that cannabinoids are effective in improving the symptoms of AD or dementia;[rx] however, some research into endocannabinoids looked promising.[rx]

Management

There is no cure for Alzheimer’s disease; available treatments offer relatively small symptomatic benefit but remain palliative in nature. Current treatments can be divided into pharmaceutical, psychosocial and caregiving.

Medications

Three-dimensional molecular model of donepezil, an acetylcholinesterase inhibitor used in the treatment of AD symptoms
The molecular structure of memantine, a medication approved for advanced AD symptoms
  • Five medications are currently used to treat the cognitive problems of AD: four are acetylcholinesterase inhibitors (tacrine, rivastigmine, galantamine, and donepezil) and the other (memantine) is an NMDA receptor antagonist. The benefit from their use is small.[6][167][168] No medication has been clearly shown to delay or halt the progression of the disease.
  • Reduction in the activity of the cholinergic neurons is a well-known feature of Alzheimer’s disease. Acetylcholinesterase inhibitors are employed to reduce the rate at which acetylcholine (ACh) is broken down, thereby increasing the concentration of ACh in the brain and combating the loss of ACh caused by the death of cholinergic neurons.[170] There is evidence for the efficacy of these medications in mild to moderate Alzheimer’s disease,[rx][rx][rx] and some evidence for their use in the advanced stage.[rx]
  • The use of these drugs in mild cognitive impairment has not shown any effect in a delay of the onset of AD.[rx] The most common side effects are nausea and vomiting, both of which are linked to cholinergic excess. These side effects arise in approximately 10–20% of users, are mild to moderate in severity and can be managed by slowly adjusting medication doses.[rx]
  • Less common secondary effects include muscle cramps, decreased heart rate (bradycardia), decreased appetite and weight, and increased gastric acid production.[rx]
  • Glutamate is an excitatory neurotransmitter of the nervous system, although excessive amounts in the brain can lead to cell death through a process called excitotoxicity which consists of the overstimulation of glutamate receptors. Excitotoxicity occurs not only in Alzheimer’s disease but also in other neurological diseases such as Parkinson’s disease and multiple sclerosis.[rx]
  • Memantine is a noncompetitive NMDA receptor antagonist first used as an anti-influenza agent. It acts on the glutamatergic system by blocking NMDA receptors and inhibiting their overstimulation by glutamate.[rx][rx] Memantine has been shown to have a small benefit in the treatment of Alzheimer’s disease.[rx]Reported adverse events with memantine are infrequent and mild, including hallucinations, confusion, dizziness, headache, and fatigue.[rx] The combination of memantine and donepezil has been shown to be “of statistically significant but clinically marginal effectiveness”.[rx]
  • Atypical antipsychotics are modestly useful in reducing aggression and psychosis in people with Alzheimer’s disease, but their advantages are offset by serious adverse effects, such as stroke, movement difficulties or cognitive decline.[rx] When used in the long-term, they have been shown to associate with increased mortality.[rx] Stopping antipsychotic use in this group of people appears to be safe.[rx]

Alternative Medicine

Various herbal remedies, vitamins and other supplements are widely promoted as preparations that may support cognitive health or prevent or delay Alzheimer’s. Clinical trials have produced mixed results with little evidence to support them as effective treatments.

Some of the treatments that have been studied recently include:

  • Omega-3 fatty acids – Omega-3 fatty acids in fish or from supplements may lower the risk of developing dementia, but clinical studies have shown no benefit for treating Alzheimer’s disease symptoms.
  • Curcumin – This herb comes from turmeric and has anti-inflammatory and antioxidant properties that might affect chemical processes in the brain. So far, clinical trials have found no benefit for treating Alzheimer’s disease.
  • Ginkgo –  Ginkgo is a plant extract containing several medicinal properties. A large study funded by the National Institutes of Health found no effect in preventing or delaying Alzheimer r’s disease.
  • Vitamin E – Although vitamin E isn’t effective for preventing Alzheimer’s, taking 2,000 international units daily may help delay the progression in people who already have the disease. However, study results have been mixed, with only some showing this benefit. Further research into the safety of 2,000 international units daily of Vitamin E in a dementia population will be needed before it can be routinely recommended.
  • Supplements promoted for cognitive health – can interact with medications you’re taking for Alzheimer’s disease or other health conditions. Work closely with your health care team to create a safe treatment plan with any prescriptions, over-the-counter medications or dietary supplements.

Lifestyle and Home Remedies

Healthy lifestyle choices promote good overall health and may play a role in maintaining cognitive health.

Exercise

  • Regular exercise is an important part of a treatment plan. Activities such as a daily walk can help improve mood and maintain the health of joints, muscles and the heart. Exercise can also promote restful sleep and prevent constipation.
  • People with Alzheimer’s who develop trouble walking may still be able to use a stationary bike or participate in chair exercises. You may find exercise programs geared to older adults on TV or on DVDs.

Nutrition

  • People with Alzheimer’s may forget to eat, lose interest in preparing meals or not eat a healthy combination of foods. They may also forget to drink enough, leading to dehydration and constipation.

Offer the following

  • Healthy options – Buy healthy food options that the person with Alzheimer’s disease likes and can eat.
  • Water and other healthy beverages – Try to ensure that a person with Alzheimer’s drinks several glasses of liquids every day. Avoid beverages with caffeine, which can increase restlessness, interfere with sleep and trigger a frequent need to urinate.
  • High-calorie, healthy shakes, and smoothies  – You can supplement milkshakes with protein powders or make smoothies featuring favorite ingredients. This may be particularly important when eating becomes more difficult.

Estrogen Replacement Therapy

  • Considerable evidence has emerged regarding the role of estrogen on brain development, neuron survival, regeneration, and plasticity. It appears to exert its effect in the brain by enhancing transcription and mediation of nongenomic events.
  • It has been suggested that the abrupt decline of estrogen production in postmenopausal women increases the risk for these women developing AD; men, in contrast, have an intrinsic supply of estrogen by aromatizing testosterone in the brain. There is increasing evidence that estrogen replacement therapy (ERT) in postmenopausal women may have a role in delaying AD by improving cognitive function and reducing the risk for both cognitive impairment and AD, as shown in several open-labeled clinical trials and at least one double-blind placebo-controlled trial, although a recent major double-blind controlled study found no effect of estrogen in patients who already had AD., In one of the latter studies, estrogen failed to improve cognitive or functional outcomes after 1 year of use, but there was a time-limited benefit (2 months) on the MMSE, similar to previous reports.
  • The selective estrogen receptor modulators are another interesting class of compounds currently being tested in AD. These act as estrogen agonists in some tissues and antagonists in other tissues (raloxifene, tamoxifen, droloxifene, and timeline).

Anti-Inflammatory Agents

  • The hypothesis that anti-inflammatory therapy can slow the progression of AD has gained support from some retrospective epidemiologic studies. There are very few prospective double-blind clinical trials of nonsteroidal anti-inflammatory drugs (NSAIDS) in AD.
  • Nonrandomized studies with NSAIDs (indomethacin, ibuprofen, diclofenac, naproxen), steroids (low-dose prednisone), and other anti-inflammatory agents (hydroxychloroquine, colchicine) showed promising results in modulating the course of the disease. Unfortunately, these studies included small sample sizes. Recent studies have not replicated the previous positive results.
  • A 16-month, double-blind, placebo-controlled, low-dose study in 138 patients with AD receiving prednisone showed that there was no slowing of the rate of cognitive decline compared with placebo. Although some previous high-dose prednisone studies showed improvement, the use of high-dose steroids over a long period of time can cause substantial health problems.
  • Another class of anti-inflammatory agents is that of the cyclooxygenase-2 (COX-2) inhibitors (celecoxib, rofecoxib). By being more specific for the brain than the currently available NSAIDs, they are now favored in clinical trial use for patients with AD. A major double-blind placebo-controlled trial comparing rofecoxib with naproxen and placebo has now been completed and the results were negative.

Antioxidant agents, selegiline and vitamin E

  • Current theories suggest that an increase in the free-radical formation may occur in AD and have a direct toxic effect. The brain may be vulnerable to the damaging effects of oxidative stress because of an abundance of catecholamines and a relatively low concentration of antioxidative enzymes (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase). Furthermore, Aβ has been implicated in increased free-radical formation.
  • Vitamin E in doses of 1000 IU orally twice daily and selegiline (a monoamine oxidase B inhibitor) in doses of 5 to 10 mg orally every morning, seem to minimize free-radical damage by acting as free-radical scavengers. A recent major double-blind study comparing the effect of selegiline alone, vitamin E alone, selegiline and vitamin E with placebo in patient’s with AD showed that both delayed nursing home placement and the loss of activities of daily living. However, neither selegiline nor vitamin E improved cognition compared with placebo. There was no additive effect in combining vitamin E with selegiline.

Treatment of Behavioral Disturbance

  • A wide range of dementia-associated behavioral disturbances afflicts the majority of patients with AD, with depression and psychosis being the most commonly studied from the point of view of treatment. Depression in patients with AD should be treated aggressively, with careful monitoring of cognitive function. With limited clinical trial data, the treatment of depression in AD remains empirical and consists in starting an antidepressant at a low dose and increasing it slowly.
  • Sufficient dosage and duration of treatment are needed for clinical response in depressed patients without dementia. The depressed elderly may take up to 6 weeks to respond to antidepressant medication and patients with AD should be expected to take as long.
  • Reversible monoamine oxidase inhibitors like brofaromine and moclobemide appear to be also effective in patients with depression and dementia, without the severe potential side effects of the classic monoamine oxidase inhibitors (phenelzine, tranylcypromine).
  • Use of tricyclic antidepressants –  is limited to nortriptyline and desipramine since they have fewer anticholinergic properties than their parent compounds amitriptyline and imipramine. They were both studied in double-blind, placebo-controlled trials and were effective in treating depression in AD patients.
  • All newer antidepressants -including fluoxetine, sertraline, paroxetine, fluvoxamine citalopram,nefazodone, bupropion, mirtazapine, and venlafaxine appear to have beneficial effects in depression in AD patients, although only fluoxetine, paroxetine, and fluvoxamine were studied in double-blind, placebo-controlled trials. At the present time, the selective serotonin reuptake inhibitors (SSRIs) are the standard of care for the treatment of depression in patients with AD.
  • Depression in these patients can very often be complicated by psychosis and behavioral disturbances, which can also be an independent feature of the disease. The incidence of psychosis in patients with AD is 25% to 50%. Multiple treatments have been proposed, but very few controlled trials are available. Treatment of psychosis in patients with AD should rely on atypical antipsychotics such as risperidoneand olanzapine, which have been used in double-blind placebo-controlled trials.
  • Risperidone was studied in a large (625 patients) double-blind, placebo-controlled study evaluating the efficacy and safety of an atypical antipsychotic in the treatment of psychosis and behavioral symptoms in patients with AD. This trial showed that 1 mg of risperidone per day significantly improved psychosis without the emergence of the side effects associated with typical antipsychotics.
  • Another recent double-blind, placebo-controlled study compared the effects of risperidone with those of haloperidol and placebo in patients with AD, and showed equal efficacy of risperidone with haloperidol (similar 1-mg dose of each of the compounds), but with significantly fewer extrapyramidal side effects with the atypical agent.

References

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