Treatment guidelines for Alzheimer-type dementia

  • Alzheimer's Disease
  • Biomarkers: Amyloid Plaque
  • Biomarkers: Neurofibrillary Tangles
  • Biomarkers: Brain Atrophy
  • Diagnostic Aids
  • Treatment and Prevention

Alzheimer disease

Treatment guidelines for Alzheimer-type dementia
Treatment guidelines for Alzheimer-type dementia

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At a glance

  • The diagnosis of Alzheimer disease (AD) is usually made from clinical observations and data from the patient history.
  • The average annual cost for the caregiver of an individual with AD is $34,000.
  • When behavioral treatments alone cannot control disabling psychopathology, medications may need to be added.
  • Treating behavioral and psychological symptoms of dementia can improve quality of life for patients and caregivers.
The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) defines dementia of the Alzheimer type as the development of multiple cognitive deficits manifested by both memory impairment and one or more cognitive disturbances.1 The deterioration of intellectual function and other cognitive skills leads to a decline in the ability to perform activities of daily living (ADLs).2 This decline occurs with a normal state of consciousness and in the absence of other acute or subacute disorders that may cause reversible cognitive deterioration, such as those seen in delirium or depression.3


Alzheimer disease (AD) is estimated to affect 6% to 10% of the U.S. population older than age 65 years.4 It has been estimated that the number of AD patients will reach 13.2 million by 2050, with a per-patient cost of approximately $91,000 over the course of the illness.5


AD is a primary neurodegenerative disorder. There are several competing theories that attempt to explain a singular cause of AD. The oldest of these is the cholinergic hypothesis, which proposes that AD is caused by reduced synthesis of the neurotransmitter acetylcholine.6 The cholinergic hypothesis has been criticized, largely because medications intended to treat acetylcholine deficiency have not yielded dramatic results.

In 1991, the amyloid hypothesis proposed that amyloid-beta deposits are the primary cause of AD.7 This theory was supported by research that revealed the location of the gene for the amyloid-beta precursor protein (APP) on chromosome 21. The hypothesis is made much more credible by the fact that people with trisomy 21, who thus have an extra gene copy, ubiquitously exhibit AD by aged 40 years.8

Apolipoprotein E (APOE3), a major genetic risk factor for AD, leads to excess amyloid buildup in the brain before symptomatology arises. Thus, amyloid-beta deposition precedes clinical AD.9 More evidence comes from the study of transgenic mice that express a mutant form of the human APP gene and develop fibrillar amyloid plaques and Alzheimer-like brain pathology with spatial learning deficits.10

In 2009, this theory was revamped, suggesting that a close relative of the beta-amyloid protein and not the beta amyloid specifically may be a major causative factor of the disease. The theory maintains that an amyloid-related mechanism that prunes neuronal connections in the brain in the fast-growth phase of early life may be triggered by aging-related processes in later life to cause the neuronal withering of AD.11

A 2004 study found no correlation between the deposition of amyloid plaques and neuron loss.11 This observation brought about more support for the tau hypothesis, which contends that tau protein abnormalities initiate the disease cascade.12 In this model, hyperphosphorylated tau begins to pair with other threads of tau. Ultimately, they form neurofibrillary tangles inside nerve-cell bodies.13 When this occurs, the microtubules disintegrate, causing the collapse of the neuron's transport system.14

The most recent literature posits a constellation of the aforementioned occurrences—including amyloid deposition, neurofibrillary tangles, synaptic losses, cholinergic dysfunction, selective neuronal injury, and neuronal death—and genetics as causative factors for the development of AD.15


The diagnosis of AD is usually made from clinical observations and collateral data from the patient history. Observations from relatives are often helpful as well. Diagnosis is based on the presence of characteristic neurologic and neuro­psychological features and the absence of other conditions. Advanced imaging with CT or MRI and single photon emission CT (SPECT) or positron emission tomography (PET) is used to help exclude other cerebral pathology or subtypes of dementia.16 Assessment of intellectual functioning, including memory testing, can further characterize the stage of the disease. Diagnosis can be confirmed with very high accuracy post-mortem when brain material is available and can be examined histologically.17

Diagnostic criteria

The National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) and the Alzheimer's Disease and Related Disorders Association (ADRDA) established and recently updated the most commonly used diagnostic criteria. These criteria require that the presence of cognitive impairment as well as a suspected dementia syndrome be confirmed by neuropsychological testing for a clinical diagnosis of possible or probable AD. A histopathologic confirmation, including a microscope examination of brain tissue, is required for a definitive diagnosis. Good statistical reliability and validity have been shown between the diagnostic criteria and definitive histopathologic confirmation.18 The eight cognitive domains most commonly impaired in AD are memory, language, perceptual skills, attention, constructive abilities, orientation, problem-solving, and functional abilities. These domains are equivalent to the NINCDS-ADRDA criteria as listed in the DSM-IV-TR.2

Diagnostic tools

Such neuropsychological screening tests as the Mini-Mental State Examination (MMSE) are widely used to evaluate the cognitive impairments needed to make an accurate diagnosis of AD. Except in cases of obvious cognitive impairment, neurologic examination in early AD will usually yield normal results. Psychological tests for depression are administered to patients, as depressive symptomatology may be concurrent with AD, an early sign, or even the cause of cognitive impairment. When available as a diagnostic tool, SPECT and PET neuroimaging are used to confirm a diagnosis of AD in conjunction with mental status examination results. In a person who already has dementia, SPECT appears to be superior to mental testing and medical history analysis in differentiating AD from other possible causes.19

Another objective marker of AD involves the analysis of cerebrospinal fluid for amyloid-beta or tau proteins.20 A new technique known as PiB PET has been developed for directly and clearly imaging beta-amyloid deposits in vivo using a tracer that binds selectively to the amyloid-beta deposits.21

Recent studies suggest that PiB PET is 86% accurate in predicting which people with mild cognitive impairment will develop AD within two years and 92% accurate in ruling out the likelihood of developing AD.22 Volumetric MRI, which can detect changes in the size of brain regions that atrophy during the progression of AD, also shows promise as a diagnostic method and may prove less expensive than other imaging techniques currently under study.23 Recent studies suggest that brain metabolite levels may be utilized as biomarkers for AD.24

Standard therapy

Rationale for the cholinergic approach. According to the cholinergic hypothesis, memory and cognitive disturbances result from reduced cholinergic transmission. This reduction in neuronal activity is a widely accepted feature of AD.25 Acetylcholinesterase (AChE) inhibitors are used to reduce the rate at which acetylcholine (ACh) is broken down, thereby increasing the concentration of ACh in the brain and fighting the loss of ACh caused by the death of cholinergic neurons.26

As of 2008, the cholinesterase inhibitors approved for the management of AD symptoms are donepezil (Aricept), galantamine (Razadyne), galantamine ER (Razadyne ER), and rivastigmine (Exelon). Donepezil is dosed at 5 or 10 mg at bedtime. Galantamine dose ranges from 8 to 12 mg b.i.d. The rivastigmine dosage range is 3 to 6 mg b.i.d.; a transdermal rivastigmine patch is available in 4.6 mg/day or 9.5 mg/day dosing.

There is evidence of the efficacy of these medications in mild-to-moderate AD27 and some evidence to support their use in the advanced stage. Only donepezil is approved for treatment of advanced AD dementia.28

The most commonly reported side effects are nausea and vomiting, both of which are linked to cholinergic excess. These side effects arise in approximately 10% to 20% of users and are mild to moderate in severity. Less common secondary effects include muscle cramps, bradycardia, anorexia, weight loss, and increased gastric acid production.29

In pivotal trials, each drug showed significant improvement on a cognitive measure compared with placebo. The differences that were noted related to dosing and time to reach effective dose.

Where to begin. The research strongly indicates the use of cholinesterase inhibitors as the gold standard of care for mild-to-severe AD. It is imperative that practitioners, patients, and relatives set realistic expectations of treatment. If there is no change or a slow change in the patient's cognitive/behavioral decline, the drug should be viewed as having a beneficial effect.

Take the following factors into account when choosing a cholinesterase inhibitor: (1) the dosing frequency and availability of a supervisor for medication administration; and (2) the number of weeks the drug will take to reach minimum therapeutic dose. Other deciding factors may be based on the patient's living situation and ability to deal with side effects. For example, if the patient is thin, donepezil will help him or her gain weight. If sleep disturbance is an issue, rivastigmine or galantamine may help the person sleep more soundly without the need for additional drugs.

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