AD affects approximately 5 million people in the United States and more than 30 million people worldwide. A larger number of individuals have decreased levels of cognitive impairment (eg, minimal cognitive impairment), which frequently evolves into a full-blown dementia, thereby increasing the number of affected persons. The prevalence of AD is expected to substantially increase in this century because it preferentially affects the elderly, who constitute the fastest growing age group in many, especially industrialized, countries. Statistical projections indicate that the number of persons affected by the disorder in the United States will nearly triple by the year 2050.
AD is also a major public health problem from the economic perspective. In the United States, the cost of caring for patients with AD was more than $110 billion per year in the early 1990s, and the average yearly cost per patient is about $45,000. Because methods for assessing the economic effects of neurodegenerative disorders are still in their infancy, these figures must be interpreted as underestimates.
Many excellent treatises on AD have reviewed important aspects of the disorder in considerable detail. This article is intended to be a comprehensive but not necessarily exhaustive review of AD.
- Second to only certain cancers and cardiovascular disease, AD is frequently considered a leading cause of death in the United States.
Age: The prevalence of AD increases with age.
Medical Care: Therapeutic approaches to AD are based on developing theories of its pathogenesis and on the need to alleviate its cognitive and behavioral manifestations. The predominantly symptomatic approach preceded, by many decades, the more recent interventions based on our improving understanding of the pathogenesis and pathophysiology of AD.
To date, no interventions have been shown to convincingly prevent AD or slow its progression. Medical treatments for AD include psychotropic medications and behavioral interventions, cholinesterase inhibitors (ChEIs) and the avoidance of centrally acting anticholinergic medications, N-methyl-D-aspartate (NMDA) antagonists, and other and new therapeutic interventions.
- Psychotropic medications and behavioral interventions
- A variety of behavioral and pharmacologic interventions can temporarily alleviate clinical manifestations of AD, such as anxiety, agitation, depression, and psychotic behavior, which are best approached symptomatically. These interventions are useful in managing AD, though their effectiveness is often modest and temporary, and they do not prevent the eventual deterioration of the patient's condition.
- Behavioral interventions range from patient-centered approaches to caregiver training to help manage cognitive and behavioral manifestations of AD. These interventions are often combined with the more widely used pharmacologic interventions, such as anxiolytics for anxiety and agitation, neuroleptics for aberrant and/or socially disruptive behavior, and antidepressants or mood stabilizers for mood disorders and specific manifestations (eg, episodes of anger or rage).
- No specific agent or dose of individual agents is unanimously accepted for the wide array of clinical manifestations. At present, the US Food and Drug Administration (FDA) has not approved any agent for the treatment of AD. However, medications that many practitioners prefer are haloperidol, risperidone, olanzapine, and (more recently) quetiapine. The general recommendation is to use such agents as infrequently as possible and at the lowest doses possible to minimize adverse effects, particularly in frail, elderly patients.
- Particular concern has been raised about the potential for dopamine-depleting agents to aggravate the manifestations of dementia with cortical Lewy bodies (DCLB), also known as Lewy body dementia (LBD), because patients with DCLB may be extremely sensitive to these agents. Adverse reactions to conventional neuroleptics have fueled the search for new agents that alleviate disruptive behavior while minimizing the occurrence of extrapyramidal manifestations and worsening of motor and behavioral performance, which is frequently observed in DCLB. This is the basis for the recent trend to use new-generation agents to alleviate the behavioral manifestations of AD, with therapy usually extending into the more advanced stages of the disorder.
- Results of several studies indicate that anticonvulsants (eg, gabapentin) may have a role in the treatment of behavioral problems in patients with AD.
- Cholinesterase inhibitors
- A strategy widely used to address the symptoms of AD is palliating the deficiency in cholinergic innervation to the cerebral cortex. Numerous lines of evidence indicate that the corticipetal cholinergic system is targeted relatively early and more or less selectively in AD. For over 2 decades, AD has been characterized by substantial loss of acetylcholine (ACh) in the cerebral cortex, progressive decline in cortical levels of choline acetyltransferase (biosynthetic enzyme necessary for the synthesis of ACh), and severe loss of neurons in the subcortical cholinergic nuclei that project to the cerebral neocortex (ie, basal nucleus of Meynert) and hippocampus (ie, medial septal nuclei).
- These observations have led to the theory that some of the clinical manifestations of AD are due to loss of the cholinergic innervation to the cerebral cortex. In turn, this theory led to development of an increasing number of compounds capable of palliating the cholinergic defect by interfering with the degradation of ACh by acetylcholinesterase (AChE), the synaptic, or specific, form of cholinesterase. More recent compounds include substances capable of blocking the nonsynaptic, or nonspecific, cholinesterases; these are frequently called butyrylcholinesterases (BuChEs).
- An often neglected aspect of palliation of cholinergic deficits is the avoidance of centrally acting anticholinergic medications. Patients not uncommonly receive both ChEIs and anticholinergic agents, which negate or at least counteracting the effects of the former. Therefore, a careful listing of the patient's medications is important to reduce the doses of, or ideally eliminate, all centrally acting anticholinergic agents.
- N-methyl-D-aspartate antagonists: A relatively new category of drugs, NMDA antagonists, is based on an entirely different mechanism of action. Memantine is the first NMDA antagonist approved in the United States. This agent is approved for treating the advanced stages of AD, in contrast with ChEIs, which are approved for only the early and intermediate stages. Of interest, memantine may also be helpful in other neurodegenerative conditions, such as Huntington disease, AIDS-related dementia, and vascular dementia.
- Antidepressants: The role of antidepressants in the treatment of mood disorders, and especially depression, cannot be overemphasized. Depression is observed in more than 30% of patients with AD, and it frequently begins before AD is clinically diagnosed. Therefore, palliation of this frequent comorbid condition can considerably improve their cognitive and noncognitive performance. Other mood modulators, such as valproic acid, can be helpful for the treatment of disruptive behaviors and outbursts of anger, which patients with moderately advanced or advanced stages of AD may have.
- Other and new therapeutic interventions: Other agents proposed for the treatment of AD and new drugs being developed are free-radical scavengers, and estrogen- or selective estrogen-receptor agonists, anti-inflammatories, and clioquinoline and other drugs.
- The proposal that oxidative stress causes AD and evidence suggesting that estrogen has a trophic effect on certain neuronal populations that is lost after menopause were the bases for previous recommendations to give high doses of tocopherol (1000 IU PO bid) to all patients and estrogen replacement therapy to postmenopausal women with AD. Federal and institutional policies do not mandate use of these agents; their common use reflects the widespread belief that they may be beneficial. Because findings show that estrogen supplementation may be associated with cognitive impairment and that high-dose tocopherol may cause adverse cardiovascular events, the entire body of evidence is being re-evaluated, and few (if any) now recommend these treatments. Results to date indicate that patients with clinical dementia do not benefit from estrogen replacement therapy.
- An additional treatment, the use of anti-inflammatory agents, is based on the postulation that inflammation is needed for many AD lesions, especially SPs, to develop and progress through the theoretical stages of increasing severity. This theory has received considerable support, and many studies purportedly show improvement or a lack of progression of the manifestations of AD over relatively short periods of anti-inflammatory therapy. No present recommendations require the use of anti-inflammatories in AD; results of large-scale trials still underway have not been published.
- New drugs under development include clioquinoline, an antibiotic that may help reduce brain amyloid deposition in patients with AD. Other, unrelated compounds under development and are also expected to reduce or eliminate cerebral amyloid deposition and possibly NFTs.
Surgical Care: No accepted surgical treatments exist for AD. One unconfirmed postulate was that omental transposition to the brain may be beneficial in AD, but most experts remain highly skeptical of this claim. Potential surgical treatments in the future may include the use of devices to infuse neurotrophic factors, such as growth factors, to palliate AD. Studies are also underway to evaluate a claim that ventriculoperitoneal shunting of CSF may be beneficial in AD.
Diet: No special dietary considerations exist for AD.
Activity:
- Both physical and mental activities are recommended for patients with AD. Many experts recommend mentally challenging activities, such as doing crossword puzzles and brainteasers, both to prevent deterioration and to slow its rate.
- The mental activities should be kept within a reasonable level of difficulty for the patient, they should preferably be interactive, and they should be designed to allow the patient to recognize and correct mistakes.
- Most important, these activities should be administered in a manner that does not cause excessive frustration and that ideally motivates the patient to engage in them frequently.
- Unfortunately, little standardization and rigorous testing has been done to validate this treatment modality.
Medication
The mainstay of therapy is the use of centrally acting cholinesterase inhibitors to palliate the depletion of ACh in the cerebral cortex and hippocampus. Because the clinical manifestations of AD are believed to be partly due to a loss of the cholinergic innervation to the cerebral cortex, compounds have been developed to palliate the cholinergic defect by interfering with the degradation of ACh by AChE, the synaptic (or specific) form of cholinesterase. Some of the more recently available compounds are substances that inhibit also the nonsynaptic (or nonspecific) cholinesterases, which are frequently called BuChE.
AChE inhibitors approved by the FDA for use in the early and intermediate stages of AD are tacrine (Cognex), donepezil (Aricept), rivastigmine (Exelon), and galantamine (galanthamine, Reminyl). Among these, only tacrine and rivastigmine also inhibit BuChE. This may be important for their therapeutic efficacy because BuChE levels increase during the course of AD and are present in some AD lesions, including senile plaques. At present, tacrine, is used seldom if at all because it has been superseded by the other 3. To date, the ChEIs is the only class of drugs that has been formally approved for use in AD.
An increasing number of clinical studies demonstrate that cholinesterase inhibition can have modest but detectable effects, such as improvement in cognitive performance, as measured by tools such as the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog). More recent evidence indicates that ChEIs may also alleviate the noncognitive manifestations of AD. For example, they can ameliorate behavioral manifestations, as assessed by using tools such as the Neuropsychiatric Inventory, and they may improve the performance of activities of daily living, as evaluated by using the Progressive Deterioration Scale.
In general, the benefits are temporary because ChEIs do not address the underlying cause of the degeneration of cholinergic neurons, which continues during the disease. Although the increasingly large family of ChEIs was originally expected to help in only the early and intermediate stages of AD, results indicate that (1) they improve cognitive performance in advanced stages; (2) they significantly improve behavioral manifestations (eg, wandering, agitation, socially inappropriate behavior associated with advanced stages); and (3) they help in patients with presumed vascular components added to dementia due to AD, as well as in patients with the DLB, which often co-occurs or overlaps with AD (Lewy body variant of AD).
Therefore, the modest benefits of ChEIs seem to extend beyond the low-level cognitive impairment in the early stages of AD. This phenomenon has not been fully explained. Interesting speculations, which remain to be tested experimentally, include the possibility that some of the newly recognized benefits in advanced behavioral and cognitive performance may be associated with the inhibition of BuChE, in addition to AChE, a characteristic of only some ChEIs currently in use.
The ChEIs share a common profile of adverse effects, the most frequent of which are nausea, vomiting, diarrhea, and dizziness. These are typically dose related and can be mitigated with slow uptitration to the desired maintenance dose. Use of drugs whose absorption peaks are blunted by food (eg, rivastigmine) can further mitigate adverse effects and improve the tolerability of ChEI treatment.
It may be reasonable to perform serial trials of different individual ChEIs when effectiveness of 1 medication decreases or if adverse effects are not tolerable. A new agent in this class should be tapered up when one switches among ChEIs, with the understanding that cognition and/or behavior may temporarily worsen during this period. No current evidence supports the use of more than 1 ChEI at a time. Another important clinical caveat is that, once a ChEI is started, it should be continued indefinitely. Stopping the medication may precipitate an acute, and possibly severe, cognitive and behavioral decline that may not be resolved by restarting the ChEI. The cause for this potentially catastrophic decline is not known.
| Drug Name | Rivastigmine (Exelon) -- Centrally acting AChE and BuChE inhibitor. |
|---|---|
| Adult Dose | 1.5 mg PO bid for 1 mo, 3 mg PO bid for 1 mo, 4.5 mg PO for 1 mo, then 6 mg PO bid thereafter |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity |
| Interactions | None reported; metabolized by cholinesterases (no significant hepatic metabolism) |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Administer with large meals to minimize adverse effects; titrate up slowly |
| Drug Name | Donepezil (Aricept) -- Centrally acting AchE but not BuChE inhibitor |
|---|---|
| Adult Dose | 5 mg PO qd for 3-4 wk, the 10 mg PO qd |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity; sick sinus syndrome, other supraventricular cardiac conduction abnormalities; peptic ulcer disease; bladder outflow obstruction |
| Interactions | Increases effects of succinylcholine, ChEIs, or cholinergic agonists; may increase fluvoxamine levels |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Caution in patients with seizures, asthma, sick sinus syndrome, or other supraventricular conduction abnormalities |
| Drug Name | Galantamine (Reminyl) -- Enhances central cholinergic function; likely to inhibit AChE. |
|---|---|
| Adult Dose | 16-24 mg PO qd bid |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity |
| Interactions | Can interfere with effect of anticholinergics; synergistic effect if given with other ChEIs, succinylcholine, or other neuromuscular blocking agents |
| Pregnancy | B - Usually safe but benefits must outweigh the risks. |
| Precautions | Most frequent adverse events are nausea, vomiting, diarrhea, anorexia, and weight loss; dose titration needed in patients with hepatic and/or renal dysfunction; can cause bladder outflow obstruction; prescribe with care in patients with lung disease; could potentiate tendency for seizures |
| Drug Name | Memantine (Namenda, Axura) -- NMDA antagonist indicated for all stages of AD. NMDA-receptor overstimulation in CNS by glutamate (excitatory amino acid) may contribute to symptoms; no evidence confirms glutamatergic deficit in AD. |
|---|---|
| Adult Dose | 5 mg PO qd, gradually titrate to 20-mg/d target dose as follows (allow >1 wk between increases): 5 mg PO bid, 5 mg PO q am, 10 mg PO q pm, 10 mg PO bid |
| Pediatric Dose | Not indicated |
| Contraindications | Documented hypersensitivity |
| Interactions | Coadministration with drugs causing alkaline urine (eg, sodium bicarbonate, carbonic anhydrase inhibitors) may decrease clearance by 80%, leading to accumulation and toxicity; coadministration with other NMDA antagonists (eg, amantadine, ketamine, dextromethorphan) may increase toxicity; concurrent use with another drug eliminated via renal tubular secretion (eg, hydrochlorothiazide, triamterene, cimetidine, ranitidine, quinidine, nicotine) may alter plasma levels of both |
| Pregnancy | B - Usually safe but benefits must outweigh the risks. |
| Precautions | Common adverse effects are dizziness (7%), headache (6%), and constipation (5%); predominantly excreted renally, no data support use in severe renal impairment |
| Drug Name | Tocopherol (Vitamin E) -- Nutritional supplement with antioxidant properties |
|---|---|
| Adult Dose | 1000 IU PO bid |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity |
| Interactions | Increases hypoprothrombinemic response to oral anticoagulants |
| Pregnancy | X - Contraindicated in pregnancy |
| Precautions | May cause fatigue, headaches, and blurred vision |
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