In the earliest stages of the illness, the patient is concerned, but there are no social or employment problems and no evidence of memory deficit during a clinical interview. Progression to early dementia may be heralded by decreased performance in demanding work or social situations. Patients complain of poor concentration, more prominent memory loss, and confusion, and they may report that coworkers have noticed their relatively poor performance. Characteristically, there is an inability to learn and remember new information and difficulty in consolidating the information into memory (revealed by simple word retrieval testing or the use of a word list; see Chapter 169). Patients may present with visual-spatial deficits or difficulty with speech; they may report getting easily disoriented or lost when traveling to an unfamiliar location. Anxiety and/or depression may ensue as patients become aware of their symptoms; some begin to deny them. Changes in personality and judgment can cause problems with family and coworkers.

As the illness progresses, patients become unable to travel alone and are unable to handle their personal finances. Memory for recent events is drastically impaired, and patients display a decreased knowledge of current events. Complex tasks are impossible, but patients remain fairly well oriented to time and person and can travel to very familiar places, such as the corner drugstore. Many patients remain aware of their deficits and are capable of understanding what is happening to them. They instinctively withdraw from previously challenging situations and may even have trouble with the activities of daily living. Difficulty with speech and language is more pronounced. Denial may become pronounced. Anxiety and depression may increase, along with suspiciousness and agitation. The most difficult behavior at this stage is wandering and pacing (balance and gait are usually preserved); the patient may get lost.

Patients can no longer survive without some assistance. They are unable to recall major relevant aspects of their current lives or even the names of close friends and family members. Delusions and hallucinations are common. For example, the spouse may be accused of being an impostor, or patients may talk to imaginary persons or their own reflection in the mirror. Depression, agitation, aggression, and violent behavior may occur. Frequently, patients are disoriented to time or place. However, they generally remain able to eat and use the toilet without assistance, but they may have difficulty in properly choosing and putting on clothing.

In the final stages of the disease, patients become totally incapacitated and disoriented. They eventually forget their name and may not recognize their spouse. Incontinence is common, frequently with a loss of both bladder and bowel control. Personality and emotional changes are prominent, although these changes occasionally occur even in the earliest stages of disease (see prior discussion). Eventually, all verbal abilities are lost; motor skills further deteriorate, making gait and balance nearly impossible; and patients require total care. Total dependence on the caregiver ensues, leading to caregiver stress or “burnout” (see later discussion). Generalized cortical and focal neurologic signs and symptoms are frequently present. Death usually occurs from total debilitation or infection.

The course of AD from onset to death varies from 2 to 20 years. The average is about 8 to 10 years. Typically, the illness progresses at a fairly constant rate. If it has rapidly developed during the last year, it is likely to continue at that rate. A slowly progressive illness during the last 5 to 10 years suggests that the patient may survive for a number of years, especially if he or she is in otherwise good physical health. Other clinical features found to be independent predictors of more rapid progression to incapacity and death include hallucinations, paranoia, delusions, misidentification syndromes, extrapyramidal signs, and a low score on initial psychometric testing.

When examined in retrospective cohort study, simple lifestyle measures for elderly persons, such as regular modest exercise, are associated with significantly reduced risks of developing dementia, including AD. Walking at a slow pace for as little as 1.5 hours per week was associated with a 20% reduction in risk among elderly women in the Nurses’ Health Study. Subsequent prospective cohort study found a similar degree of benefit, which increased with increasing intensity and frequency of exercise (33% reduction in the most active group). In one of the few randomized trials of exercise in the elderly, a program of brisk walking for 21/2 hours per week was associated with improved cognitive function at 6 months, and residual benefit was noted 18 months later.

Similar degrees of reduced risk were found in cohort studies of elderly persons participating in cognitively stimulating leisure and social activities such as playing board games, playing musical instruments, or reading. Cognitive training exercises reportedly negated the expected amount of normal cognitive decline in an elderly population. These and other healthy lifestyle interventions need confirmation by prospective long-term study to better assess their precise contributions to prevention, but there seems little harm in implementing them while awaiting confirmatory data.

Persons consuming a diet high in fruits, vegetables, nuts, oily fish, and olive oil and low in animal fat and red meat—a Mediterranean-style diet—exhibit an independent reduction in risk of AD in retrospective and prospective cohort studies. The observed degree of reduction was as high as 40%. While these findings need confirmation, implementation of such a diet makes good sense, given its positive contributions to overall health, particularly cardiovascular health (see Chapters 18, 27, and 31).

Hypertension, hypercholesterolemia, smoking, and diabetes are major risk factors for vascular dementia, which often coexists with AD and makes for a worse prognosis. Even higher glucose levels (e.g., 115 mg/dL) in elderly people without diabetes have been associated with a significant increase in risk of dementia. Atherosclerotic risk factors also appear to increase the risk of progression to AD in persons with MCI. Consequently, there is interest in aggressive treatment of these atherosclerotic risk factors for prevention of AD. Studies are under way. In the meantime, maintaining good cardiovascular health makes good sense.

Homocysteine elevation, an independent atherosclerotic disease risk factor, is also associated with an increased risk of AD, but randomized trials of lowering homocysteine through the use of folate, B₁₂, and B₆ supplementation in older persons with an elevation in serum homocysteine have failed to show improved cognitive performance or the prevention of progression to AD. Supplements with high doses of these vitamins are popular and do lower homocysteine levels significantly, but not only do they not reduce cardiovascular risk in controlled trials, but in some studies increased rates of adverse vascular events were observed (see Chapters 18 and 27). Use is not recommended.

The hypothesis that “oxidative stress” from free-radical formation might damage neurons has been given much play in the lay media, spurred by commercial interests promoting the use of vitamins and other supplements. The hypothesis derives support from epidemiologic data and small, randomized trials revealing an association between the dietary intake of fruits and vegetables (i.e., foods rich in the so-called antioxidants) and a reduction in the risk of developing AD noted earlier. However, randomized, controlled trials of supplement preparations containing the so-called antioxidant vitamins (e.g., C, E, β-carotene, flavonoids), even at high doses, have consistently failed to show any protective effect and do not support their use. The notion that such use is harmless and therefore worth a try is contradicted by studies showing potential risk of adverse effects with high doses of some vitamins (e.g., E, β-carotene, and the combination B₆/B₁₂/folate—see discussion of homocysteine and Chapters 18, 27). The best nutritional advice is to adopt a well-balanced diet as described earlier and to consider vitamin supplements only in the presence of documented deficiency. Moderate alcohol intake (<2 oz/d) has not been shown to be harmful (but red wine offers no special advantage despite enophilic enthusiasm for its purported health benefits).

Fish-oil supplements containing omega-3 fatty acids are very popular for their purported contribution to cardiovascular health (which remains to be fully established—see Chapters 18, 27, and 31). Their use in prevention of dementia is the subject of ongoing study, stimulated in part by epidemiologic data suggesting an inverse association between omega-3 fatty acid consumption and risk of AD, the high concentration of docosahexaenoic acid (one of the two major omega-3 fatty acids in fish oil) in brain synapses, and reduced levels in persons with AD. Pending results of such studies, the best advice seems to be that of the American Heart Association, which recommends two servings per week of an oily fish (e.g., salmon, herring, sardines, anchovies, trout), a more palatable and more nutritious approach than consuming fish-oil tablets every day. One might want to take into consideration the high mercury content of some oily fish (e.g., shark, tuna, sword fish) in making fish choices.

Randomized, placebo-controlled trials of Ginkgo biloba, nonsteroidal anti-inflammatory drugs, estrogens, antioxidants, and statins have produced either negative results or inconsistent findings that do not provide a sufficient scientific basis to warrant their use for primary prevention. Often the initial rationale for use was a preliminary finding from an epidemiologic study or a small prospective trial of inadequate design. For example, early epidemiologic data suggested some protection against the development of AD in postmenopausal women using hormone replacement therapy (HRT), but more definitive data from the Women’s Health Initiative Memory Study failed to confirm the initial findings and even suggested an increase in risk of dementia (including AD).

The avoidance of known toxins that can cause brain injury is important for prevention of any type of dementia. Of particular concern are aniline dyes, heavy metals, and perhaps very high levels of dietary mercury (see Chapter 169). There is no evidence that the avoidance of aluminum-containing preparations (e.g., antacids) is of any benefit, although concerns were raised when aluminum deposition was noted in the central nervous system of patients with AD.

Epidemiologic evidence from community-based study finds a relationship between use of anticholinergic drugs and cognitive decline in the elderly. Discontinuing such drugs was associated with a decreased risk of decline.

Tasks include communication of the diagnosis, estimation of prognosis, and extensive patient and family education and
support; treatment options remain limited in the absence of disease-modifying therapy, but with its advent will come intensive interest in early treatment at this stage of illness.

Communicating an accurate diagnosis and prognosis without instilling unnecessary fear and potential harm can be a challenge. Since progression to AD is not inevitable, some recommend that in communicating the diagnosis, clinicians avoid terms that mention Alzheimer disease (such as “early Alzheimer disease,” “prodromal Alzheimer disease,” or “mild cognitive impairment of the Alzheimer type”). Nonetheless, addressing the obvious concern about progression to AD is essential. One can help put things into perspective by noting that average risk of progression to AD in community-based populations is about 5% to 10% per year, substantially lower than that seen in reports from specialty clinics. Moreover, one can mention that a substantial fraction of patients (up to one quarter) revert to normal cognitive function over the course of 6 months, perhaps because depression or medication was actually the source of the problem and not AD. Patients and families may ask about newly developed tests for early detection for AD, given the amount of attention paid to them in the media. Noting that at present these tests have no impact on treatment and are intended mainly for research purposes can alleviate demand for unnecessary testing and the risk of a false-positive diagnosis.

Persons presenting with more severe deficits have the greatest risk of progressing to AD probably because they are closest to it. The risk assessment can be adjusted based on the patient’s clinical presentation (i.e., mild symptoms imply lesser risk of progression). A number of instruments providing structured measures of cognitive function correlate with risk and can be incorporated into clinical practice. The application of testing modalities that focus directly on AD pathophysiology (e.g., genetic testing, MRI imaging of the hippocampus, detection of tau protein and beta-amyloid peptides in the CSF, PET imaging of synaptic transmission and brain amyloid), though drawing much media attention, will remain confined to research settings until standardization of measurement, ranges of normal and abnormal, correlations with clinical outcomes, and impact on clinical care can be established.

The healthy lifestyle measures noted earlier in discussion of primary prevention and the application of a cognitive rehabilitation program (i.e., computer-assisted training and use of mnemonics, and association strategies) can produce a transient improvement in cognitive function in persons with MCI; they are probably worth recommending, but neither these measures nor early application of drugs used to improve cognition in AD appears capable of altering the natural history of the disease in persons with MCI. The only MIC persons with reversible disease are probably those who have depression or another
non-Alzheimer pathophysiology responsible for their cognitive decline. One oft-quoted early study suggested a disease-slowing benefit with use of the cholinesterase inhibitor donepezil during MIC in carriers of the APOE ε 4 allele; a delaying effect was noted at 12 months but was no longer evident at 36 months. Subsequent randomized, placebo-controlled trials and metaanalyses of cholinesterase inhibitors have shown no effect on disease progression.