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Chapter 22

Alzheimer’s Disease

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Alzheimer’s Disease

Devastating illness Progressive memory loss Impaired thinking Neuropsychiatric symptoms Inability to perform routine tasks of daily living Alzheimer’s disease (AD) affects 4.5 million

Americans 4th leading cause of death – 100,000 deaths

per year

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Pathophysiology

Degeneration of neurons Early in hippocampus

• Memory Later in cerebral cortex

• Speech, perception, reasoning, and other higher functions

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Pathophysiology

Reduced cholinergic transmission Levels of acetylcholine (ACh) 90% below normal

• Important neurotransmitter• Critical to forming memories

Loss of cholinergic function not the whole story

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Pathophysiology

Beta-amyloid and neuritic plaques Form outside of neurons Spherical bodies composed of beta-amyloid core

Neurofibrillary tangles and tau Form inside neurons See Figure 22-1

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Fig. 22-1. Histologic changes in Alzheimer’s disease.

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Pathophysiology

Apolipoprotein E4 (apoE4) May also contribute to AD

Endoplasmic reticulum–associated binding protein Present in high concentrations in AD patients

Homocysteine Elevated plasma levels of homocysteine

associated with increased risk for AD

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Risk Factors Major risk factors

Advancing age Family history

Possible risk factors Female Head injury Low educational level Production of apoE4 High levels of homocysteine Low levels of folic acid Estrogen/progestin therapy Nicotine in cigarette smoke Sedentary lifestyle

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Symptoms

Memory loss Confusion Feeling disoriented Impaired judgment Personality changes Difficulty with self-care

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Symptoms

Behavior problems (wandering, pacing, agitation, screaming)

“Sundowning” Inability to recognize family members Inability to communicate

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Progressive Symptoms

Symptoms typically begin after age 65 years, but may appear as early as age 40 years.

Life expectancy from symptom onset may be 20 years or longer, but is usually 4 to 8 years.

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Diagnosis

NINCDS and ADRDA criteria based on patient’s age and clinical evaluation

Under the proposed new definition of AD, a patient must have episodic memory impairment plus at least one AD biomarker, as determined by MRI scan, PET neuroimaging, or CSF analysis. Note that overt dementia need not be present.

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Diagnosis

2007 international group of AD experts proposed new diagnostic criteria for AD.

Added technologies and tests that provide data for evaluation of characteristic changes of AD: MRI: atrophy of brain areas PET: altered patterns in the brain Cerebrospinal fluid analysis: presence of abnormal

proteins

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Drug Therapy

Goal of treatment is to improve symptoms and reverse cognitive decline.

Available drugs cannot do this. Five drugs are approved for AD dementia

(none are very effective).

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Drug Therapy

Neuronal receptor blocker Memantine

Cholinesterase inhibitors Donepezil Galantamine Rivastigmine Tacrine

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Drug Therapy

Treatment of AD with these drugs can yield improvement that is statistically significant but clinically marginal. Equivalent to taking a “weight loss drug” and

losing ½ pound after 6 months of therapy It is not recommended that all patients

receive these drugs because of the modest benefits.

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Drug Therapy

Cholinesterase inhibitors may delay or slow progression of disease, but will not stop it.

Drugs that block cholinergic receptors (first-generation antihistamines, TCAs, conventional antipsychotics) can reduce responses to cholinesterase inhibitors.

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Drug Therapy

Cholinesterase inhibitors Indicated for mild to moderate AD Prevent breakdown of ACh May help to slow progression of disease Only three are recommended for use and have

equivalent benefits:• Donepezil• Galantamine• Rivastigmine

Not recommended (causes liver damage):• Tacrine

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Drug Therapy

Cholinesterase inhibitors (cont’d) Adverse effects

• Cholinergic side effects• GI• Dizziness• Headache• Bronchoconstriction• Liver injury (tacrine)

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Drug Therapy

Memantine (Namenda, Namenda XR) First drug in a new class, the NMDA receptor

antagonists Indicated for moderate to severe AD Better tolerated than cholinesterase inhibitors Adverse effects

• Dizziness• Headache• Confusion• Constipation

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Fig. 22-2. Memantine mechanism of action.

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Other Treatments

Drugs for neuropsychiatric symptoms Symptoms experienced by 80% of AD patients Include agitation, aggression, delusions,

hallucinations Atypical antipsychotics SSRIs for depression (not AD symptoms)