An 80-Year-Old Man With Memory Loss

DR DELBANCO: Mr J is an 80-year-old retired teacher who has noticed memory loss for 7 years, which concerns both him and his family. For the past 2 years, he has received care from Dr B, a general internist practicing at the Beth Israel Deaconess Medical Center. Mr J has insurance through Medicare and supplemental commercial insurance. Mr J lives in his own home with his wife, who has a chronic, debilitating illness and is unable to walk; he serves as her principal caregiver. Three devoted children live nearby.

In addition to slowly progressive memory loss, Mr J has also complained of fatigue, and his family has worried about intermittent loss of interest and attention. Various physicians have felt he was depressed, but he has not shown a clear response to antidepressant medications, and in recent years, he has not taken them. He has not had any difficulties with activities of daily living, and until recent months, he has continued to manage the family's finances.

Mr J was an accomplished athlete until degenerative changes in his knee limited his mobility. He does not smoke and drinks 2 to 3 glasses of whiskey or wine daily. He notes that his mother had mild memory loss in her 80s, and one of his children has a long-standing affective disorder.

In 1989, 2 years after transurethral prostatectomy for prostatism, Mr J was found to have carcinoma of the prostate, staged as Gleason tumor grade 2 plus 3. Following radical prostatectomy, his prostate-specific antigen levels rose, and he completed a course of radiotherapy. Subsequently, tumor spread to the rectum and bladder, but he responded well to hormonal therapy, which was discontinued 9 months prior to the conference. His prostate-specific antigen levels have been negligible since, and currently he has no signs or symptoms of residual carcinoma.

Mr J recently had a cataract successfully removed and has hearing loss bilaterally helped considerably by hearing aids. Hyperlipidemia has been responsive to statins. His knee was recently replaced, affording improved mobility, and his occasional low back pain responds to anti-inflammatory agents. He has marked osteoporosis, noting 5 inches loss in height over the past 10 years. For this, he currently takes calcium supplements and alendronate sodium.

On physical examination when first referred to Dr B, Mr J appeared depressed. He had normal vital signs, bilateral hearing loss, a cataract in the right eye, and a swollen, tender knee with antalgic gait. Examination of the rectum revealed an irregular prostatic bed, with focal areas of induration.

On neurological examination, Mr J was fully oriented to person, place, and time, but exhibited poor short story recall. He had no difficulty with arithmetic. His early memory appeared good, but he had difficulty remembering names. Cranial nerve evaluation was unremarkable. He had signs of stocking and glove polyneuropathy, and the right great toe was upgoing in response to noxious stimulation. Tests for glucose intolerance were normal, as were the electrolytes, complete blood cell count, cyanocobalamin and folate levels, thyrotropin, rapid plasma reagin, and protein electrophoresis.

Dr B referred Mr J to a neurologist who confirmed the above findings and initiated neuropsychiatric testing, which revealed mild abnormalities of retention and recall without other cognitive deficits. The person performing the testing raised the question of "pseudodementia," consistent perhaps with depression. Magnetic resonance imaging of the head revealed a minor degree of focal atrophic change without vascular or ischemic abnormalities.

In the months before the conference, the patient's son noted some progression in the memory loss. In addition, the patient became disoriented to place while driving at night along an accustomed route, and this episode troubled the family. Two months prior to the conference, the patient's wife had a stroke. She is currently in a recuperative facility.

At present, the patient takes vitamin E, lovastatin, and alendronate. He and his family want to know if he has Alzheimer disease (AD) and if anything can be done to improve his memory or slow down the progression of his memory loss.

MR J: I find it hard to distinguish which problems are more important than others. But one that's been bothering me for about 5 years and is getting worse is my poor memory.

Frequently, I'm in a conversation and I try to think of, let's say, the name of a book. And I know the name of the book. I know it well. But at that moment, I can't bring it up. After the conversation is over, I go and look to see what the name of the book was, and I try to get some mnemonic devices that will keep me from forgetting it again, but I forget it again. I listened to classical music a lot. I used to be able to identify an awful lot of classical music. As soon as I hear it, I could think of what quartet it was of Beethoven's, or which piano concertos. And now, I recognize the works, but I can't name them.

MR J'S SON: I think it goes a little beyond what he told you about the memory problem. It's generally at its worst when he's under great stress. A few days or so after my mother had the stroke, he forgot where she was and had to ask me. Another example is about a year ago, for maybe a couple of minutes, he was confused as to my sister's relationship to me. I asked him how she was related to me, and he said, "Isn't she your cousin?"

MR J: I don't remember that.

MR J'S SON: I remember it, Dad.

MR J: A few nights ago, I got lost. I was coming home in the evening, and there were a lot of lights where I was driving at that point. Suddenly, I couldn't remember which turn to take. I really felt like I was lost, although I knew sooner or later I'd find the right way to go. But I think earlier, I wouldn't have had that problem like that. I'd be interested to know if they thought I had Alzheimer's disease.

DR B: It's hard for me to know exactly what the troubles are. I was told at times that he'd forget that he needed to be somewhere at a certain time, or perhaps where he'd put something. But you hear this terribly often as patients get older. He was at odds somewhat with his family, and maybe remains that way, about exactly what the changes in memory meant. Occasionally he'd bring it up with me. I'd ask him about it, and he'd say, "It's a little difficult at times. I would forget to do something, and it seems to bug the family." On the other hand, I was getting calls, e-mails, and evidence of concern from his family that it was more than that and that they were really getting worried about him being able to function. I began to try to consider with him to what degree he perceived this as a problem and what we should do about it. I think I'm encouraged because there has not been much change in him over the past 2 years.

I want to know from Dr Larson whether I'm taking the right approach to this. Is there new knowledge in this area that means that I should accelerate or intensify an evaluation? Is there medicine to offer this patient that may hold off progression of whatever he has?

What are the epidemiology of memory loss and the national burden of illness of AD and other forms of dementia? Are there risk factors, such as age, sex, or family history? What is the typical course of such patients and the resulting burdens on the patient, family, and society? How should the clinician diagnose AD and distinguish it from other dementing illnesses? What are cost-efficient steps to take in its evaluation? What are the risks and benefits of treatment? Finally, does Mr J have AD, and how would you care for him?

DR LARSON: Memory failures are common, everyday occurrences. We accept them, albeit with disappointment, as students taking tests; we accept them, albeit with chagrin, in everyday social discourse. Memory failures are also the hallmark of dementia and, thus, may indicate pathologic neurodegeneration in the brain. The most common neurodegenerative process is now known, to lay persons and professionals alike, to be AD.

Dementia is a syndrome characterized by acquired, usually progressive, cognitive impairment, sufficient to cause functional impairment in usual social, occupational, and daily living activities. Almost 20 years ago, dementia was characterized as the "silent epidemic."¹ AD and Pick disease had long been recognized as well-known, but rare, causes of presenile dementia. However, dementia in the elderly was not well recognized by the medical profession or the public. The demographic shift to an older population, plus a general failure to recognize AD as increasingly common as people age, created the so-called silent epidemic of dementia. Over time, increasing recognition of the silent epidemic attracted public attention. Lay publications viewed the "discovery" of AD as newsworthy, and an important US government publication summarized its contents with the poignant title, Losing a Million Minds: Confronting the Tragedy of Alzheimer's Disease and Other Dementias.²

Alzheimer disease is the most common cause of dementia. Other relatively common causes include dementia associated with Parkinson disease, Lewy body disease, and dementias associated with alcoholism and cerebrovascular diseases. Although most persons in the early stages will be diagnosed as having a single disease causing dementia, so-called mixed causes are well known and relatively common as well. As dementia progresses and people age, the brain is at increased risk for other neurodegenerative processes. At least 1 neuropathologic series³ reported that, among older persons with relatively long-standing dementia, multiple neurodegenerative conditions, which might contribute to dementia, were more common at autopsy than those with a single cause of dementia. Overall, AD is the most common finding among elderly patients in North America, and probably worldwide, at all stages of dementia.

The prevalence of AD increases dramatically with advancing age. Although AD is rare before age 65 years, the rate increases inexorably thereafter. In the United States, the age at diagnosis is almost certainly rising. In referral clinics, where patients tend to be younger, most are reported to be in their early 70s, whereas in community settings, the average age at diagnosis is in the late 70s. Since the most rapidly growing segment of the population is the oldest old, eventually persons older than 80 years will be the most prevalent age group with AD. Estimates of prevalence of dementia vary widely because of differences in research sampling strategies and diagnostic criteria. Representative prevalence rates are: 5% to 7% at age 75 to 80 years; 15% to 17% at age 80 to 85 years; approximately 35% at age 85 to 90 years; and 50% at age 90 to 95 years.^{4 - 6} One study reported a prevalence of 75% in those aged 95 years and older.⁶ At all ages, AD is reported to cause at least half and usually well over 70% of cases of dementia in the United States.

The combination of an aging population and highly variable methods of detection and diagnosis make it difficult to describe the national burden of AD and related dementias. Estimates vary widely, but there are probably 3 to 5 million persons with AD and related dementias in the United States. One inescapable conclusion is that AD is a major clinical and public health problem and will only increase in importance over the next 4 decades as more people live to advanced old age.⁶

The onset of AD is typically insidious, just as Mr J's cognitive decline has been. Some patients may be very aware of cognitive decline, but most are not. Family members can recognize abnormal deterioration in memory, difficulty learning new tasks, and a tendency to repeat oneself and dwell in the past. In the Honolulu Asian Aging Study, 21% of family informants failed to recognize a problem with memory in subjects subsequently found to be demented.⁷ In addition, in the community today, most older patients with dementia are not recognized as having dementia by their physicians.^{7 - 8} Thus, in the typical case, onset is insidious and persons are often not recognized as demented for long periods. Eventually, recognition may occur because of an apparent sudden crisis, such as getting lost, an accidental fall, discovery by neighbors or relatives of an unsafe, messy home environment, or acute confusion during illness or environmental stress. Careful questioning will usually demonstrate that cognitive impairment and dysfunction have been present for several years before the acute crisis. Cognitive screening tests are usually needed to detect dementia in its early stages, ideally before the advent of such crises.

Clinical features are best demonstrated by mental status examination, which usually reveals multiple areas of dysfunction. All patients will have memory impairment, along with language deficits (aphasia), apraxia, agnosia, visuospatial dysfunction, and/or impaired executive function, including errors in judgment. Detecting cognitive decline in persons who, at baseline, had extremely high or relatively low levels of cognitive function is a particular challenge. In my experience, sequential observation with repeated cognitive testing by an interested physician or more formal testing is the best way to make the diagnosis in these situations.

Mr J is difficult to diagnose as demented because his "score" on a screening test, like the Mini-Mental State Examination, likely remains in the normal range, although both patient and son note his declining cognitive abilities. The son also reports the typical signs of early dementia, including getting lost while driving. Highly educated persons can achieve Mini-Mental State Examination scores above the cutoff in mild stages of AD, with education being a well-known confounder of all cognitive screening tests.

The social setting will affect the presentation and course of the illness. Spouses may compensate for the patient's cognitive decline, resulting in relatively little apparent dysfunction. Or, as in this case, if the patient has complex tasks, responsibilities for another person, or unusually high self-expectation, rather mild impairment may cause "dis-ease" and dysfunction earlier in this progressive illness.

The general physical and neurologic examination is nonspecific. However, certain clinical features are noteworthy. For example, cognitive impairment, and especially memory loss, likely causes persons to underreport symptoms of acute and chronic disease.⁹ Therefore, undiagnosed and potentially treatable medical conditions are common in people with dementia.¹⁰ As the disease progresses, the primitive reflexes seen in newborns (or frontal lobe release signs) may reappear on neurologic examination, eg, grasp response and snout response. Extrapyramidal features, especially rigidity and gait disturbance, also may be evident as the disease progresses. Such patients are at higher risk for falls and a more rapidly deteriorating course.¹¹ These patients may also show pathologic findings of Parkinson disease, including Lewy bodies.

Depression is also common with AD, affecting 30% to 60% of patients¹² at some time during the course of the illness. In the past, pseudodementia (or depression) was described as mimicking AD in the elderly. We now know that it is far more common for AD and depression to coexist. Isolated depression mimicking dementia and presenting as so-called pseudodementia is quite rare, and the term is now probably best avoided.¹²

The burden of AD is highly variable. Anxiety is common, and until recently, relatively underappreciated.¹³ Before diagnosis, there typically is an increase in visits to physicians in offices, clinics, or emergency departments. Once diagnosis is made, visits may actually become less frequent compared with similarly aged persons.¹⁴

The burden on families challenged to address safety and security issues, is considerable.¹⁵ Driving is often a source of conflict early in the disease. Patients with behavioral disturbances, wandering, and, especially, agitation likely present the greatest burden for families. Families may provide a substantial amount of voluntary care—frequently at great personal sacrifice. Spouses often become exhausted by the physical and emotional demands of caregiving.¹⁶ Depression in spouse caregivers is particularly common and probably affects a majority of them.^{17 - 18} Children may also experience clinically significant depression.¹⁹ Respite care and other community support services can be useful adjuncts to treatment to help the family cope with the disease.

The total societal burden of AD is difficult to quantify. General medical care costs (office visits, hospitalizations, and acute care services) are probably about equivalent for patients with AD compared with age-matched persons without AD.^{20 - 21} However, long-term care costs of AD are at least 10 times greater and such costs account for the majority of long-term care costs in the United States.²⁰ The increasing numbers of patients with AD in the United States and their attendant long-term care costs are, in my opinion, the reason why funding for long-term care costs will likely not be amenable to a public policy of federal funding. The costs of voluntary care by families and lost economic productivity are more difficult to estimate. For many families, providing care for a person with AD can be personally rewarding and a valuable experience, when persons willingly give back to a beloved spouse or parent. However, in other cases, family caregivers may need to give up their jobs, limit their social activities, and take time away from spouses or children to care for a demented parent. Thus, both opportunity and emotional costs can be great and are probably unmeasurable at a societal level. In Mr J's case, he has served as the caregiver for his wife and so the burden could become doubly hard for his family.

The most potent risk factor for AD is age.²² Family history is another well-known risk factor. Three autosomal dominant genes have been identified as causes of early onset AD-like illnesses. The apolipoprotein E4 allele increases the risk of late onset AD and explains some, but not all, of the familial clustering of AD. I would not suggest genetic testing for Mr J since it would not provide useful information for diagnosis or treatment.²³ Other risk factors include a history of head trauma, depression, low levels of education, deprivation during gestation and early childhood brain development, and exposure to known neurotoxins, possibly including organic solvents.²⁴ Of these risk factors, Mr J has only depression; whether that is related to his dementia onset is difficult to know. The concept of brain reserve (analogous to functional aerobic capacity and cardiac reserve) is an attractive unifying hypothesis regarding risk of AD²⁵ and suggests that genetic and environmental factors that maximize brain reserve and prevent neuronal loss or loss of neuronal connectivity will decrease the risk of AD and may delay onset of disease manifestations. Factors that limit development of brain reserve (deprivation in early life and lack of education) or promote brain cell loss (head trauma and neurotoxins) increase the likelihood of AD and may lead to earlier onset of dysfunction. If epidemiologic research reveals modifiable risk factors that could significantly delay onset of the disease (eg, by 5 years in 50% of persons), the prospects for reducing the public health burden are considerable, given the other competing causes of mortality in late old age.

The diagnosis of AD traditionally has been based on functionally significant cognitive impairment, a so-called typical clinical presentation, in the absence of another illness capable of causing cognitive impairment—a "rule-out" diagnosis. The 2 most widely used criteria in the United States are the National Institute of Neurological Disorders and Stroke–Alzheimer's Disease and Related Disorders Association (NINDS-ADRDA) criteria²⁶ and the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM IV) criteria. Both criteria are likely quite accurate, even though the operational definitions of what it takes to rule out alternative causes and comorbid conditions are not described.²⁷ Additionally, as patients age, the frequency of concomitant neuropathologic causes of dementia increases. The pathology of AD consists of neuritic plaques containing β-amyloid, neurofibrillary tangles, neuronal and synaptic loss, granulovacuolar degeneration, and Hirano bodies.

Vascular dementia, often called multi-infarct dementia, is characterized by strokes; sudden deterioration and a step-wise course, including recovery after acute decline; and focal neurologic findings consistent with cerebrovascular accidents. Periventricular lucencies on computed tomography (CT) scan and unidentified bright objects (hyperlucencies) on magnetic resonance imaging (MRI) do not constitute specific evidence for multi-infarct dementia. Evidence of discrete strokes on CT or MRI supports the diagnosis of vascular dementia. Pure vascular dementia in the elderly is probably unusual, with mixed vascular dementia and AD more common.³

Dementia associated with Parkinson disease and the more recently appreciated Lewy body disease are other relatively common causes of dementia in the elderly.³ The typical case of dementia due to Parkinson disease occurs in a person with well-established Parkinson disease (≥5-10 years) who then develops cognitive impairment.^{28 - 29} However, dementia and the typical features of Parkinson disease can also develop simultaneously. Lewy body disease has gained attention recently as a cause of dementia in the elderly.³⁰ While these patients also have insidious onset of dementia, they are distinguished from typical AD cases by variations in severity, rigidity and gait disturbance, visual hallucinations, and atypical (extrapyramidal) reactions to neuroleptics. At autopsy, patients with Parkinson disease and Lewy body disease causing dementia will frequently have pathologic findings of AD as well. Less common causes of dementia include progressive supernuclear palsy, alcohol-related encephalopathy including Wernicke disease, and metabolic encephalopathies. In patients with unexplained focal findings, atypical presentations, including incontinence, seizures, or severe headache early in the course of dementia, the so-called surgically treatable causes—normal pressure hydrocephalus, subdural hematoma, and brain tumor—should be considered, but these typically do not present as isolated dementia.³¹ Metabolic encephalopathies can cause dementia-like illness or can contribute to delirium superimposed on underlying dementia. Confusion and cognitive impairment due to adverse drug reactions are probably the most common cause of reversible cognitive impairment in this context.³² Other relatively frequently reported causes of impairment due to metabolic encephalopathy are hypothyroidism, hyperthyroidism in the elderly, hypercalcemia, hyponatremia, and hypoglycemia. Vitamin B₁₂ deficiency can also cause diffuse cognitive dysfunction,^{6 ,33} as well as the peripheral neuropathy, subacute combined degeneration.

Diagnostic evaluation of a person with suspected or actual dementia is usually quite valuable. It provides patients and families with an accurate diagnosis that will explain confusing symptoms and behaviors. Unexpected findings are common. A plan for subsequent follow-up and treatment can be initiated after evaluation.

History and physical examination, including neurologic and mental status examination, provide the greatest diagnostic yield and will allow diagnosis of the common causes of dementia, plus detection of previously undiagnosed, but treatable, comorbid illnesses, like adverse drug reactions, depression, congestive heart failure, chronic obstructive lung disease, and symptomatic osteoarthritis.⁵ Laboratory tests of particular value include thyroid function tests (TSH), complete blood cell count (CBC) and chemistry screens (serum creatinine, sodium, glucose and calcium), and vitamin B₁₂ levels (Table 1).³⁴ Many clinicians also routinely include an erythrocyte sedimentation rate (ESR), VDRL or fluorescent treponemal antibody (FTA), and serum folate in the so-called dementia workup, although the value of these tests is not well documented. Selected use of chest radiography (for suspected aspiration or heart failure), urine cultures (for patients with incontinence and suspected urinary tract infection), and similar frequently ordered tests are often needed and may be even more valuable in this population, since historical details are often unavailable or not reliable in demented patients.^{3 ,33} Neuroimaging with CT or MRI is standard in most US communities,³⁴ although the yield is low.^{31 ,33} An evidence-based practice standard on the workup of dementia, like that of the Canadian Consensus Development group,³⁵ recommends that neuroimaging be used selectively, on the basis of specific clinical findings to diagnose or rule out causes of dementia other than the nonfocal neurodegenerative diseases, like AD, Parkinson disease or Lewy body disease, which are not diagnosed by neuroimaging. Research is ongoing to define the role of functional neuroimaging (for example, single photon emission CT) in the diagnosis of Lewy body disease, AD, and Huntington disease.³⁶

Treatment of a patient with AD begins with diagnosis, assessment, and commitment to educate patients and family and answer the many questions they typically have at diagnosis. It is also important to establish a plan for follow-up at the time of diagnosis and not leave an impression that after diagnosis there is not much to offer. I believe that it is important to explicitly address concerns regarding safety and security, including driving, and set up a plan for ongoing support in the home, possibly including respite care. For patients like Mr J who have become lost while driving, I generally recommend a formal test of driving skills at a local driving school with special interest in dementia or a driving evaluation at a rehabilitation medicine facility with a brain injury recovery program. Advance directives are possible early in the course of AD when the patient's preferences can still be communicated.³⁷

I believe an exercise program, usually consisting of walking, is valuable for as long as the patient is able to do this. For individuals like Mr J, I recommend daily brisk walks for 20 to 60 minutes, as tolerated, accompanied by a cognitively intact companion. There are likely immediate benefits, but most importantly, while physical decline, frailty, and falls are to be expected, these are not inevitable and can be attenuated. Our clinical trial of this type of walking program demonstrates improved physical function, which persisted at 2-year follow-up (E.B.L., unpublished data). Strategies to minimize behavioral disturbance are also valuable, and, if effective, do not carry the risk of adverse effects common with psychotropic and sedating drugs, especially during the treatment of agitation.

Recent studies have suggested that various medications may favorably affect the course of AD (Table 1).^{38 - 40} The most widely studied drugs in the United States are the cholinesterase inhibitors, especially donepezil hydrochloride.³⁹ Donepezil can lead to improved cognition and functional ability in a small minority of patients. It also attenuates the rate of decline in longitudinal cohort studies. It does not cure or reverse cognitive impairment, and thus, many patients and families may be disappointed by a lack of dramatic benefit. Estrogen replacement may lower the risk of AD in women, but it is unlikely to have benefit as treatment.^{41 - 42} Nonsteroidal anti-inflammatory drugs have been proposed as another candidate that could reduce the risk of AD.⁴¹ Relatively high doses of vitamin E (2000 IU/d) were found to slow the rate of decline in 1 study, which also demonstrated a similar effect for selegiline hydrochloride.⁴² Ginkgo biloba (10 mg/d) was effective in a study of patients with diverse types of dementia.⁴³ Other therapeutic agents are in development, undergoing clinical trials, or being reviewed by the Food and Drug Administration for possible licensing and marketing. The good news is that there are therapeutic options today to slow the progression of the disease, and, in some cases, moderately improve function.^{44 - 45} The disappointing news is that the treatments are not as effective as most patients and their families would like and do not prevent ongoing decline. Many patients and families will decide to forgo such treatment after therapeutic trials.

In individual cases, treating comorbid conditions may produce greater benefit than so-called cognitive enhancing treatments. For example, treatment of depression with antidepressants or behavioral therapy usually results in remission of depressive symptoms and is generally well tolerated.⁴⁶ Other common conditions that, when treated, can result in functionally meaningful improvement include congestive heart failure, symptomatic urinary tract infection, hypothyroidism, and the general array of chronic and acute medical illnesses seen in the elderly.¹⁰

Returning to Mr J, his history contains many features commonly found in AD. He has had unexplained weight loss, he feels his memory is worse, and his son specifically complained 2 years ago about his father's failing memory. The son now states that Mr J's cognitive impairment is even worse—to the point where he has had trouble finding his way when driving. Several evaluations of cognitive function demonstrate mild deficits in memory, knowledge of everyday events, and executive function, as demonstrated by his difficulty grasping the meaning of proverbs. He strikes many observers as depressed, and he is certainly burdened, indeed, overwhelmed, by his devotion to and care for his ailing wife. On the other hand, he performed extremely well in a screening examination designed to detect dementia. I suspect he would have performed at a higher level 2 or 3 years ago. His diagnostic evaluation reveals no other illnesses that might cause cognitive impairment.

The dilemma for the clinician in Mr J's case is common for clinicians confronted by a patient with an extremely high premorbid level of function. Family and friends (and, occasionally, the patient) will report decline when traditional screening tests and bedside mental status questions do not reveal typical findings of dementia. If Mr J has AD (which I think is 80%-90% likely), the key to establishing the diagnosis is the demonstration of significant and persistent decline over time in the absence of a cause other than AD. Confirmation of Mr J's diagnosis will likely become apparent in the next year or 2. Follow-up is particularly important in such cases to avoid false-positive diagnoses and mislabeling patients. I recently saw a very similar patient who had normal cognitive function in 1996 but demonstrated significant decline 2 years later when confronted by end-of-life care for her spouse. In the midst of this family crisis, she was diagnosed as meeting all criteria for AD. However, 1 year later, after resolution of the crisis and resumption of normal activities, she tested in the completely normal range and was fully functional. Thus, we abandoned the diagnosis of AD. This may occur with Mr J as well, but it would be unusual.

At this point in Mr J's illness, careful follow-up and observation will be an important part of his treatment. He may experience improved sense of well-being based on resolution of stress related to caregiving burdens. Treatment of depression may be helpful. The best diagnostic test will be time: how Mr J functions over time in everyday activities and on measures of cognitive performance. Such serial observations can be made by interested primary care physicians and from reports of the patient and his family. I suspect that Mr J already has an advance directive, but if he does not, this would be worth addressing to assess preferences at a time when his judgment and ability to express himself are so well preserved. This would also allow his physician to address safety and security issues and preferences and attitudes about future living situations, including long-term care if that ever becomes an issue.

Although Mr J may be typical of the challenges we have diagnosing high performing individuals in the early stages of AD, a far more typical problem is underappreciation and failure to detect dementia. Most patients with dementia do not complain of memory loss or even volunteer symptoms of cognitive impairment unless specifically questioned. Many will appear normal in casual conversations and during a general office visit with their physician. All recent community-based studies have found that the majority of AD cases in the community are not known as such by their physicians.⁷ Although we do not know the consequences of a delayed diagnosis of AD, there is ample evidence that elderly patients with cognitive impairment are at high risk for accidents, delirium, hip fractures, and other potential disasters.^{47 - 48} I believe physicians should incorporate brief, cognitive screening strategies in visits with older patients who have problems that may suggest dementia, especially with persons aged 80 years and older.⁵¹

MR J: When I'm under pressure, I tend to fear that I'm not going to remember something. For example, I was worried that I might be asked to say something about my doctor here, and I couldn't remember his last name for maybe 20 seconds, and then it came to me.

MR J'S SON: One thing is, my dad hasn't had a decent night's sleep, probably in the last 5 years. The irony of my mother's stroke earlier this month is that, with her in the hospital, he's sleeping fairly normally. Even before the stroke, she was quite disabled, and she was always asking him to do this and that. He quit working several years ago because he's been a full-time caregiver. It seems possible to me that the reason a little bit of memory is coming back is that he's getting a decent night's sleep and is not constantly being ordered around during the day.

A PHYSICIAN: Do societies with a shorter life expectancy, for reasons of not having the advantages of Western medicine, for example, have dementia onset at an earlier age? Is this linked in some way to a larger sociologic and anthropologic phenomenon?

DR LARSON: It's hard to prove that because it's so difficult to tease out socioeconomic, especially educational, effects on screening tests. For example, we've done work in a very rural community in Taiwan where the typical patient with dementia is younger than in our US study.⁵⁰ The median education is less than 1 year. It's a very agrarian group. But there aren't nearly as many people living into their 80s. Therefore, you have to be careful about how you compare groups. In general, worldwide, we're now learning that a lot of chronic diseases have increased risk associated with exposures and environmental disturbances in childhood and in utero. I'm now convinced from our own data⁵¹ that you can show increased risk for AD based on the adequacy of the environment around the time a person was born. For example, if you're the sixth child, as opposed to the first child, in a family where resources are limited, your risk of AD in late life is greater.

A PHYSICIAN: One problem in this population is driving and complications from driving. As physicians, we have a responsibility to the patient, to the family, and to society. How do you handle this with people? Taking away driving takes away their independence, but also is an issue of safety. What are our legal responsibilities with this population?

DR LARSON: State laws differ with regard to driving, so you need to know your state law in terms of legal obligations. In my practice, when a family says the person needs to stop driving, I try to be helpful. I affirm their observations, because they're mostly always right. If there is a question, I've developed a relationship with a driving school that specializes in evaluating older persons. They'll do a risk evaluation of a person, which simply gives the family and the person some objective information on competencies. You can also go to the state authorities and ask that the person be reexamined by the state. There may be some litigation risks to a person's estate, depending on the outcome of the evaluation. In practice, I tend to recommend the private sector first.

A PHYSICIAN: Given the insidious onset of the disease, and my understanding that once it's fully progressed no intervention is particularly helpful, could you give us more guidance about when to institute therapy?

DR LARSON: I believe that at any phase in the disease you really can be helpful as the patient's physician. You shouldn't have the attitude that there's only one time to intervene. People with advanced disease have responded to donepezil, for example, whereas most research has been done in early disease. Based on the neurochemistry and neuropathology of the brain, there's no reason to think of anybody as hopelessly unresponsive, except perhaps at the most advanced, preterminal phase of the disease. What I will do is look at what patients value, what functions they'd like to retain, and work with them in any way I can think of to help them regain or retain those functions. If the troubles are with falling and gait instability, you should address that, because people with this disease are probably at 4-to-5 times increased risk for falling and hip fractures. The mortality rate after a hip fracture is probably over 50% in the following 3 to 6 months. If that happens early in a disease, you probably have excessive morbidity or disability because of the disease. Therefore, I think of interventions as being constant and dynamic, where you're looking for what can you do to help the patient along the trajectory of the disease.

A PHYSICIAN: Mr J and his son have quite eloquently described how caregiver stress is contributing to his illness. What do physicians need to know about resources for patients to relieve some of this caregiver stress?

DR LARSON: Most communities have local self-help groups affiliated with the Alzheimer's Association (http://www.alz.org/). Such groups are extremely effective. One randomized trial of the use of education and self-help groups showed that nursing home placement was postponed by an average of 1 year. Respite care services are also available. A knowledgeable social worker with experience in geriatrics will know about community resources.

A PHYSICIAN: You mentioned that neuroimaging without specific indications is usually of no value. Yet we do it because patients and families want it. You imply that the same might be said about the new medicines. How do you approach these dilemmas?

DR LARSON: In this condition, there's tremendous heterogeneity; you cannot use a one-size-fits-all approach. The knee-jerk, big casino workup is not the way to take care of these patients. Use your clinical sense. If you have specific questions that need to be answered with a CT or MRI scan, do it. If the family and the patient are saying to you, "I'm not going to be satisfied that you've done a good job without a CT scan," you're not going to be able to avoid it. On the other hand, if no question remains in your mind about the differential diagnosis, there's no need to do this. When it comes to treatments, you want to look at the evidence base and assess what's of value to the patient. Evidence suggests that donepezil has an effect for some patients on the course of the disease. The effect in the single case is what is critical. When I start a drug like this I say, what are the functions we want to target for improvement? Let's measure them at baseline and again 1 or 3 months after taking the medication and see if it's worth it. The cost may be $3 or $4 per day to take the pill. If you see no benefit, how many of us want to spend our savings doing that? I'm not willing to rob people of the opportunity to do something in the face of this devastating disease. But treatment is a case-by-case decision.