Most common cause of dementia; 10% of all persons over age 70 have significant memory loss, and in more than half the cause is AD. Cost is >$50,000 annually for a single pt with advanced AD.
Clinical Manifestations 
Cognitive changes follow a characteristic pattern beginning with memory impairment and spreading to language and visuospatial deficits, although 20% present with nonmemory complaints such as word-finding, organizational, or navigational difficulty. Memory loss is often not recognized initially, in part due to preservation of social graces until later phases; impaired activities of daily living (keeping track of finances, appointments) draw attention of friends/family. Once the memory loss becomes noticeable to the pt and spouse and falls 1.5 standard deviations below normal on standardized memory tests, the term mild cognitive impairment (MCI) is applied; roughly 50% will progress to AD over 4 years. Disorientation, poor judgment, poor concentration, aphasia, and apraxia are increasingly evident as the disease progresses. Pts may be frustrated or unaware of deficit. In end-stage AD, pts become rigid, mute, incontinent, and bedridden. Help may be needed with the simplest tasks, such as eating, dressing, and toilet function. Often, death results from malnutrition, secondary infections, pulmonary emboli, heart disease, or, most commonly, aspiration. Typical duration is 8-10 years, but the course can range from 1 to 25 years.
Pathogenesis
Risk factors for AD: old age, positive family history, and a history of head trauma with concussion. Pathology: neuritic plaques composed in part of Aβ amyloid, derived from amyloid precursor protein (APP); neurofibrillary tangles composed of abnormally phosphorylated tau protein. The apolipoprotein E (apoE) 
4 allele accelerates age of onset of AD and is associated with sporadic and late-onset familial cases. ApoE testing is not indicated as a predictive test. Rare genetic causes of AD are Down syndrome and mutations in APP, presenilin-1, and presenilin-2 genes; all increase production of Aβ amyloid. Genetic testing available for presenilin mutations; likely to be revealing only in early-age-of-onset familial AD.
Treatment: Alzheimer's Disease - AD cannot be cured, and no highly effective drug exists. The focus is on judicious use of cholinesterase inhibitor drugs; symptomatic management of behavioral problems; and building rapport with the pt, family members, and other caregivers.
- Donepezil, rivastigmine, galantamine, and memantine are approved by the FDA for treatment of AD. Due to hepatotoxicity, tacrine is no longer used. With the exception of memantine, their action is inhibition of cholinesterase, with a resulting increase in cerebral levels of acetylcholine. Memantine appears to act by blocking overexcited N-methyl-D-aspartate (NMDA) channels.
- - These compounds are only modestly effective and offer little or no benefit in the late stages of AD; they are associated with improved caregiver ratings of pts' functioning and with an apparent decreased rate of decline in cognitive test scores over periods of up to 3 years.
- - Donepezil (Aricept), target dose 10 mg/d PO, has the advantages of few side effects and single daily dosage.
- There is no role for hormone replacement therapy in prevention of AD in women, and no benefit has been found in the treatment of established AD with estrogen.
- Randomized trials of Ginkgo biloba have found it to be ineffective. Retrospective studies suggest that NSAIDs and statin medications may have a protective effect on dementia if used prior to the onset of the disease but do not benefit established AD.
- Other experimental approaches target amyloid either through diminishing its production or promoting clearance by passive immunization with monoclonal antibodies. New trials have targeted cognitively normal elderly who are amyloid positive with PET.
- Depression, common in early stages of AD, may respond to antidepressants or cholinesterase inhibitors. Selective serotonin reuptake inhibitors (SSRIs) are often used due to their low anticholinergic side effects. Management of behavioral problems in conjunction with family and caregivers is essential. Mild sedation may help insomnia.
- Control of agitation usually involves low doses of atypical antipsychotic medications, but recent trials have shown mild efficacy with significant side effects related to sleep and gait; in addition, all of the antipsychotics carry a black box warning in the elderly, increasing the risk of cardiovascular complications and death, and therefore should be used with caution.
- Notebooks and posted daily reminders can function as memory aids in early stages. Kitchens, bathrooms, and bedrooms need evaluation for safety. Pts must eventually stop driving. Caregiver burnout is common; nursing home placement may be necessary. Local and national support groups (Alzheimer's Disease and Related Disorders Association) are valuable resources.
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