1. Chapter 22 Alzheimer’s Disease

2. 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

3. Pathophysiology • Degeneration of neurons • Early in hippocampus • Memory • Later in cerebral cortex • Speech, perception, reasoning, and other higher functions

4. 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

5. 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

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

7. 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

8. 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

9. Symptoms • Memory loss • Confusion • Feeling disoriented • Impaired judgment • Personality changes • Difficulty with self-care

10. Symptoms • Behavior problems (wandering, pacing, agitation, screaming) • “Sundowning” • Inability to recognize family members • Inability to communicate

11. 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.

12. 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.

13. 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

14. 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).

15. Drug Therapy • Neuronal receptor blocker • Memantine • Cholinesterase inhibitors • Donepezil • Galantamine • Rivastigmine • Tacrine

16. 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.

17. 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.

18. 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

19. Drug Therapy • Cholinesterase inhibitors (cont’d) • Adverse effects • Cholinergic side effects • GI • Dizziness • Headache • Bronchoconstriction • Liver injury (tacrine)

20. 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

21. Fig. 22-2. Memantine mechanism of action.

22. 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)