AD is the most common cause of dementia in the U.S. population. Dementia currently affects approximately 4.5 million people in the United States and this number will grow to an estimated 10 million by 2050. As the most common etiology of dementia, it accounts for 70% or more of all
dementia diagnoses. Advancing age remains the single greatest risk factor for AD. Currently, it afflicts approximately 2% of the population between 65 and 70 years of age, and approximately 30% of the population older than 80 years. The incidence of new disease is approximately 3% per year in community-dwelling elderly with an average age of 75. Acquired impairment of short-term memory is its hallmark with at least one of the following four symptoms as well: aphasia, apraxia, agnosia, and executive dysfunction. Aphasia may be fluent or nonfluent. Patients may have difficulty coming up with the correct word when trying to name objects, often substituting words that describe an object (e.g., when asked to name a watch, the patient with AD might say “it’s a thing you use to tell time”). Apraxia is the inability to carry out motor tasks in the absence of motor weakness (e.g., a patient is no longer able to knit although there is no weakness of hands or arms because they cannot reproduce the necessary motion to create a stitch). Agnosia is the inability to recognize sensory information (visual, auditory, etc.); it may include getting lost in familiar surroundings or failing to recognize familiar people. Executive dysfunction is the inability to complete a sequence of tasks in proper order. An example of executive dysfunction might include losing the ability to balance a checkbook. On a more basic level, it might affect the ability to get dressed (i.e., inability to put clothes on in the proper sequence).

Other causes of dementia are less common. The absence of clinical diagnostic criteria that unequivocally separate one cause of dementia from another obfuscates efforts to pinpoint the prevalence of any specific cause of dementia. Vascular dementia (VD) is arguably the second most common cause of dementia. Two features help distinguish VD from AD, clinically. Although AD primarily affects the gray matter of the temporal lobes, VD tends to include multiple small infarcts in the deep white matter of the brain. In VD, this distribution of ischemia leads to marked slowing in patient response time to questions and is more likely to produce focal neurologic motor and sensory findings, including gait disorders. Sparing of the motor cortex makes motor findings, including gait disorders, much less common in early AD than in VD.

Since first described in 1961, diffuse Lewy body dementia (DLBD) has received increasing attention as a more common cause of degenerative dementia than previously recognized. Although Lewy bodies are the hallmark of Parkinson’s disease when found in the basal ganglia, particularly the substantia nigra, they may appear in cortical and subcortical areas as well. The astute clinician will suspect a diagnosis of DLBD when patients present with a triad of progressive but fluctuating cognitive decline, parkinsonism, and visual hallucinations (hallucinations are not typical early in the course of AD). Similarly, patients with a diagnosis of Parkinson’s disease may initially appear cognitively intact but over time, usually well after the motor signs of Parkinson’s disease have progressed, they develop progressive dementia. These latter patients have somewhat arbitrarily been diagnosed as having the “dementia of
Parkinson’s disease” to distinguish them from patients with DLBD who have the simultaneous onset of motor and cognitive dysfunction.

Frontotemporal dementias are a heterogeneous group of disorders that primarily affect the frontal and temporal areas of the brain. Most have nonspecific degenerative changes and not the Pick bodies that characterize Pick’s disease, the first of these disorders to be specifically recognized. These patients most often come to medical attention for behavioral and speech problems (both fluent and nonfluent) rather than primarily for memory loss.

Besides VD, the non-AD causes of dementia are relatively uncommon, each accounting for less than 5% of all dementia. Other etiologies are even more rare, such as Creutzfeldt-Jakob disease, a prion-related disease that may affect as few as one in a million people in the United States. Other rare primary degenerative neurologic diseases causing dementia would include Huntington’s chorea or progressive supranuclear palsy, each with its own relatively distinct set of clinical features.

Neurofibrillary tangles and neuritic plaques are postmortem findings pathognomonic for AD, and the diagnosis is certain only if the pathologist identifies a significant number of these lesions in the typical distribution (i.e., heavy concentrations in the hippocampus and surrounding areas of the temporal lobes). Ninety percent or more of patients with clinically diagnosed dementia of the Alzheimer’s type have the diagnosis confirmed at postmortem examination. Plaques and neurofibrillary tangles are also found in the brains of healthy elderly subjects, but in much smaller numbers than in the elderly patients with AD. Depletion of cholinergic neurons is another pathologic hallmark, and maintenance or supplementation of cholinergic function has been the focus of several treatments of AD.

Other conditions that may be clinically confused with AD are associated with different pathologic findings. A multifocal loss of brain tissue secondary to ischemia is seen in the setting of multiinfarct dementia. Degeneration of the dopaminergic cells in the substantia nigra and Lewy bodies are found in patients with Parkinson’s disease. Sometimes pathologists find cortical and subcortical neuronal loss associated with Lewy bodies outside the traditional distribution of these lesions in Parkinson’s disease. This entity is now identified as DLBD and may represent the second most common cause of neurodegenerative dementia after AD.

The evidence for a hereditary predisposition of AD has led to genetic research that has identified several chromosomal abnormalities that increase the risk for developing AD. Researchers have identified defective genes in chromosomes 1, 14, and 21 that are linked to autosomal dominant inheritance patterns of AD in a small number of families. Afflicted patients in these families often have earlier onset of dementia, between 35 and 65 years of age, which is considerably earlier than the usual onset in patients with late-life AD typically
beginning in the eighth decade or later. Late-life onset of AD occurs more often in patients who have the Apolipoprotein (Apo) E4 allele on chromosome 19. Three ApoE alleles have been described, namely ApoE2, ApoE3, and ApoE4. Although ApoE4 appears to increase the risk for development of late-onset AD, ApoE3 is the most commonly inherited allele and appears to confer neither a greater nor lesser risk of developing AD. ApoE2 is very rare (approximately 1% of the population) and may confer a slightly lower risk of AD. Not all individuals with an ApoE4 allele will develop AD and, conversely, AD occurs among many people who are homozygous for ApoE3. Therefore, genetic testing, with the exception of an autosomal dominant pattern inheritance of the disease, does not reliably predict an individual’s risk of developing AD. Advancing age remains the single greatest risk for developing AD. The absence of consistent correlation between the presence or absence of currently known genetic markers and the risk of AD, and the absence of interventions that clearly delay or prevent the development of AD (see following text) suggest that genetic testing currently has little clinical utility.

Numerous studies have shown that physicians overlook more than 50% of patients who have cognitive impairment. This is most often due to the clinician’s failure to do formal mental status testing that would objectively identify these deficits. The Folstein Mini–Mental Status Examination (MMSE) and similar brief mental status tests (e.g., the Pfeiffer and the Blessed Dementia Scales) are quick, reliable screening tools to assess cognitive function and may estimate the severity of mental status impairment. The MMSE measures orientation, memory, and attention as well as the status of written and spoken language and visuospatial skills. With a sensitivity of 87% and specificity of 82%, the MMSE results are reproducible when the test is administered either by a health care professional or by someone trained to administer the test. One of the best single-item screening tests is clock drawing. The inability to draw familiar, relatively simple objects may reflect apraxia, often an early sign of dementia. The examiner asks the patient to draw a clock face, fill in the numbers, and then draw the hour and minute hands indicating a time, such as “10 minutes past 2.” Studies suggest that this simple test has a sensitivity and specificity similar to more elaborate screening tools like the MMSE.

Efforts to halt or at least delay the progression of cognitive decline in patients suspected of having AD is extremely challenging. First, the clinician must rule out potential reversible factors that may hasten a patient’s deterioration. Depression is a common complication of AD. Left unrecognized, depression may lead to a loss of interest, and decrease in ability to concentrate and function in patients with AD. Treatment of depression can “reverse” some of the additional decline in intellectual function that occurs when depression is left untreated. Second, medication side effects can give the appearance of progression of AD. A large number of medications, including anticonvulsants, muscle
relaxers, analgesics, and others, may be implicated. Psychoactive medications, particularly those with anticholinergic side effects such as tricyclic antidepressants, are notorious for causing reversible increased confusion and cognitive decline in patients with underlying dementia. The experienced physician will work methodically to reduce or eliminate medications that may exacerbate cognitive losses of patients with AD, recognizing that medications are the single most common cause of reversible cognitive impairment. In addition to reducing medications that may exacerbate cognitive decline, clinicians should rule out abnormalities such as B₁₂ deficiency, hypothyroidism, hypo- or hyperglycemia, hyponatremia, or other metabolic problems that may also hasten cognitive impairment. Finally, structural abnormalities such as subdural hematomas, normal pressure hydrocephalus, or brain tumors occasionally lead to reversible deterioration in memory and related intellectual function. The presence of focal neurologic signs and/or the presence of a gait disorder are not consistent with a diagnosis of AD and may trigger a request for a brain imaging study to rule out one of the three structural central nervous system problems noted in the preceding text that may present opportunities for intervention to reverse cognitive losses.

When patients with AD have no evidence of reversible contributors to their cognitive decline, therapies aimed at halting or reversing disease progression have been only modestly successful to date. Recognizing that cholinergic neuronal loss is a predominant pathologic finding in AD, investigators have focused on finding ways to enhance cerebral cholinergic activity. This effort led to the development of cholinesterase inhibitors that block the breakdown of acetylcholine in the brains of patients with AD. The U.S. Food and Drug Administration (FDA) has approved a total of five medications for the treatment of AD, four of which are cholinesterase inhibitors. The first of the cholinesterase inhibitors, namely tacrine (Cognex), is no longer used because it must be taken on an empty stomach four times a day and has been associated with gastrointestinal and hepatic toxicity. Donepezil (Aricept) was the second agent approved and can be taken once a day, usually at bedtime and has minimal gastrointestinal toxicity and no reported hepatotoxicity. The FDA also approved galantamine (Razadyne) and rivastigmine (Exelon) which are prescribed twice a day and may cause slightly more gastrointestinal upset but also have no apparent hepatotoxicity. More than 9,000 patients have now participated in randomized controlled trials of cholinesterase inhibitors lasting up to 1 year. All were pharmaceutical company sponsored and had strict criteria for participation that some experts suggest would have excluded 90% of patients with dementia. All of these studies showed modest slowing of progression on scales that measured cognitive function, behavior, and global function. This effect is equivalent to preventing progression of AD for a few months. In a modestly successful attempt to study longer-term effects of cholinesterase inhibitors in a more inclusive group of demented patients over several years, a group of British investigators reported their results in 2004 for a study entitled “AD 2000.” At the end of this 3-year study, they found no differences in clinically significant outcomes such as
caregiver report of the patients’ function, caregiver burnout, nursing home placement, or hospitalization. The study did demonstrate a persistent slowing of decline in cognitive tests that was equivalent to delaying disease progression for 3 months. The absence of a clinically significant benefit was disappointing. Memantine (Namenda) is the only other medication currently FDA approved for treatment of AD. This drug is a partial antagonist of the N-methyl D-aspartate (NMDA) receptor in the brain, an important mediator of glutamate activity. Experimental evidence suggested that excessive activity of the NMDA receptor may be associated with progression of AD and suppression of NMDA activity might slow the progression of the disease. In studies of approximately 1,000 patients, memantine has a similar effect as the cholinesterase inhibitors in slowing the deterioration of patient performance on several scales in studies lasting up to 1 year. Like the cholinesterase inhibitors, memantine has minimal toxicity but has not been subjected to long-term randomized trials to determine its effectiveness in slowing the clinical deterioration of AD.

Epidemiologic and small intervention studies have suggested that medications including estrogen, nonsteroidal antiinflammatory agents such as ibuprofen, vitamin E, selegiline (a monoamine oxidase inhibitor), ginkgo biloba, and others may slow the progression of AD. Unfortunately, none of these agents have proved effective to date in long-term, randomized studies. Therefore, none of these medications has received FDA approval in the prevention or treatment of AD.

In summary, no currently available medications for the treatment of AD have significant clinical impact on the prevention or progression of this disease. Improvement in cognition and function is most likely to occur when the clinician reduces or discontinues medication that can interfere with cognitive function, recognizes and treats depression, and corrects overlooked medical conditions (e.g., congestive heart failure, emphysema) or metabolic abnormalities (e.g., hyponatremia, hypoglycemia).