Abstract
With the projected dramatic increase in the number of people who will be diagnosed with Alzheimer's disease (AD), interest
is growing in identifying and treating adults at high risk of developing the disorder. Recent research suggests that individuals
who will go on to receive a diagnosis of AD exhibit deficits in cognitive performance years beforehand. Those with mild cognitive
impairment (MCI), for example, have characteristic cognitive deficits, such as memory loss, and convert to a diagnosis of
AD at a faster rate than cognitively healthy controls. MCI has thus become a focus of research because it may help identify
high-risk individuals for whom prophylactic treatments designed to slow the progress toward AD can be prescribed. After describing
the diagnostic criteria and dementia outcomes associated with MCI, this article discusses several challenges to the study
of cognitive impairment before the diagnosis of AD.
Key words: preclinical Alzheimer's disease • mild cognitive impairment (MCI) • neuropsychological testing • family caregivers
Drugs discussed: donepezil
In 2000, approximately 4.5 million people in the United States were living with Alzheimer's disease (AD), and in 50 years
this number will almost triple to 13 million.1 Such a massive projected increase has led to considerable interest in discovering early markers of the disease so that individuals
who are at higher risk of developing AD in the near future can be identified. This effort is driven partly by the fact that
pharmacologic interventions may be most effective early in the disease course and by the hope that delaying the onset of AD
will reduce the substantial burden of the disease to patients and caregivers alike.2,3
The prodromal or preclinical period of AD is characterized by cognitive deficits that may allow the identification of individuals
who are at greatest risk of being diagnosed with the disorder in the near future—for example, those with mild cognitive impairment
(MCI). This article reviews the cognitive deficits in the preclinical period of AD in general, and in MCI as a specific instance.
(There are other varieties, such as cognitive impairment with no dementia.4 ) The article then examines the efficacy of current pharmacologic treatments in delaying the progression to AD and points
to some of the practical challenges involved in early identification of patients who are at high risk of developing it.
Cognitive deficits in preclinical AD
In considering cognitive impairment preceding the diagnosis of AD, the 2 major concerns are
- The presence and specificity of cognitive deficits as disease markers
- The time course and nature of longitudinal changes in cognitive performance.
To identify changes in cognition, studies in this area use formal neuropsychological testing that often takes 3 to 4 hours
and, ideally, is administered and interpreted by a neuropsychologist who specializes in memory disorders.
Episodic memory has traditionally been identified as the cognitive ability that may serve as the best marker of impending
dementia.5 It often involves remembering verbal or visual materials and can be measured by the ability to recall lists of words or
recognize faces immediately, as well as after a short delay. The potential importance of this cognitive domain as an early
marker of AD is supported by evidence indicating that brain structures critical for the successful retrieval of episodic memories
(eg, the hippocampus) are altered prior to a diagnosis of AD.6
In a meta-analysis that pooled information from 47 studies (for a total sample size of more than 10,000, including 1207 preclinical
AD cases), the results suggested that cognitive impairment in preclinical AD does not affect memory alone, but is more global.7 Although episodic memory was impaired among people who would eventually receive a dementia diagnosis, other cognitive domains
were similarly affected—for example, those related to executive functioning or the ability to plan and organize actions (eg,
balancing a checkbook, creating a meal), as well as the ability to respond rapidly to verbal and visual materials (eg, driving
a car). Moreover, these skills are directly relevant to performance of common instrumental activities of daily living (IADL),
and their loss may well signal the presence of a dementing condition.
Yet, the results of this study also suggest that the cognitive deficits preceding the diagnosis of AD may not differ qualitatively
from the loss of cognitive abilities that accompanies normal aging (as in the areas of fluid nonverbal intelligence, divided
attention, novel executive tasks, learning and recall of new information, spontaneous word finding, verbal fluency, complex
visuospatial skills, and reaction time).8 Persons who go on to be diagnosed with AD may show differences in the quantity of some skill but not a distinctive pattern
of impairment that would allow confident identification of an individual as being at higher risk of AD.
Results of the meta-analysis also provide information about the time frame of cognitive deficits in preclinical AD. The authors
reported that deficits were smaller among those who were evaluated more than 3 years before diagnosis but that the group differences
were still statistically significant.7 Other studies have observed cognitive differences between people who develop AD and those who do not as early as 20 years—and
even almost 60 years—prior to diagnosis.9,10 The Nun Study, for example, compared the grammatical complexity of stories written by women entering a convent at age 20
with their dementia status almost 60 years later.11 The results indicated that women who were diagnosed with dementia in late life showed low linguistic ability in young adulthood.
Although these findings do not allow us to predict who will become demented in old age based on test scores in youth, they
suggest that AD is a disorder whose roots are put down many years before the disease manifests itself.
Cognitive deficits and clinical outcomes of MCI
Research indicates that cognitive deficits are present prior to the diagnosis of AD, but it has not provided specific clinical
criteria for identifying preclinical AD. MCI, however, which is conceptually related to preclinical AD, does have clinical
criteria that can be used to judge whether a person has MCI.12
In general, the criteria for MCI require cognitive complaints, preserved general cognitive functioning, intact ADL, and lack
of evidence for a diagnosis of dementia. Three types of MCI have been identified, however, each depending on the nature of
the cognitive impairment: MCI-amnestic; MCI-multiple domains slightly impaired; and MCI-single nonmemory domain impaired.13 Although patients with MCI-amnestic most often convert to a diagnosis of AD, those with MCI-multiple domains slightly impaired
may remain free of a dementia diagnosis or may convert to AD or vascular dementia. By contrast, those with MCI- single nonmemory
domain impaired may convert to frontotemporal dementia, Lewy body dementia, vascular dementia, primary progressive aphasia,
Parkinson's disease, or AD.
In terms of risk factors for AD, much of the interest in MCI has focused on the amnestic variant. The specific criteria for
MCI-amnestic include all of the following:
- A memory complaint, preferably confirmed by an informant
- Impaired memory functioning for age and education norms (as defined neuropsychologically)
- Preserved general cognitive functioning
- Intact ADL
- A diagnosis of dementia cannot be made.
People identified as MCI-amnestic progress to a clinical diagnosis of AD at an annual rate of 10% or 15%, whereas cognitively
healthy individuals do so at a rate of only 1% to 2% per year.13 With this higher-than-average rate of conversion to AD, MCI-amnestic has received significant attention as a potential therapeutic
target and as a way to better understand the transition from cognitive impairment to AD.
Controversies surrounding MCI
The concept of MCI has elicited great interest but not universal acceptance, since a number of studies have reported that
patients who meet criteria for MCI at one point may be classified as cognitively healthy at a subsequent measurement point.
This finding calls into question the theory that MCI only represents an intermediary stage in the development of AD.14 The fact that a person may meet criteria for MCI at one point but not at a later one may reflect extrinsic factors—such
as alcohol use, drug use, brain injury, and metabolic disturbances—that can produce decrements to cognitive abilities similar
to those seen in MCI. In addition, individuals with vascular damage may satisfy criteria for cognitive impairment, and these
patients are sometimes referred to as having vascular cognitive impairment.15,16
Some authors have argued that MCI and preclinical AD may simply represent early-stage AD.17 As such, MCI may simply reflect the insensitivity of the behavioral AD diagnosis rather than a separate and distinct stage
in the evolution of AD. Nonetheless, the idea that subtle cognitive deficits precede the clinical diagnosis of AD is intuitively
appealing and potentially helpful if it helps us identify those at greatest risk in order to intervene and slow the disease
course.
Pharmacologic approaches for delaying AD onset
In recent years, intensive research has focused on interventions that might prevent or delay clinical progression to AD.18,19 In a multisite trial examining the impact of donepezil on the progression from MCI to clinical AD, 769 participants with
MCI were randomized to treatment with vitamin E, 2000 IU/d; donepezil, 10 mg/d; or placebo, for 3 years.20 Progression to possible or probable AD was the primary clinical end point. During the 3-year follow-up, there were no statistically
significant differences in conversion rates to AD between placebo, vitamin E, and donepezil groups. However, in the first
12 months, patients who received donepezil progressed to AD at a slower rate than the placebo and vitamin E groups.
Donepezil has thus shown only a limited effectiveness in slowing disease progression. Perhaps people with MCI already have
significant impairment, and attempts to intervene should target patients with more subtle deficits. Future research should
focus on helping to identify the most effective pharmacologic therapies and the patients most likely to benefit from their
use.
Preclinical AD and MCI: Practical challenges
Figure 1 Hypothetical course of cognitive decline for persons who will or will not be diagnosed with Alzheimer's disease
|
Although the literature on cognitive deficits in preclinical AD and MCI suggests a way to identify high-risk patients, its
practical application is more challenging. A fundamental problem is the substantial variability among humans in all cognitive
functions, which leads to significant overlap in performance between those whose skills are normally low and those who were
once "smarter" but are losing ground and will later prove to have AD. This is most clinically relevant in individuals who
begin with extraordinary cognitive ability but may decline dramatically from their initial levels while still remaining in
the normal range of performance on cognitive tests. Current criteria for an AD diagnosis stress specificity at the price of
low sensitivity to early decline.
Some of the associated diagnostic challenges are portrayed graphically in Figure 1. Although the patterns of cognitive performance
for normal aging and AD are hypothetical, they represent current understanding of the preclinical and early stages of AD.
The initial differences among persons who will or will not be diagnosed with AD are represented by mean group differences
but also by overlapping error bars that represent the substantial heterogeneity of functioning that makes the prospective
identification of AD patients so challenging.7 Subsequent declines follow almost parallel courses, reflecting evidence suggesting that the magnitude of the cognitive deficits
remains relatively stable until shortly before clinical diagnosis.21,22 In addition to the pattern of normal aging, 2 groups who will go on to receive a dementia diagnosis are shown in the figure,
one representing individuals with lower lifelong cognitive functioning and one representing those who are initially more able.
These groups receive the dementia diagnosis at different ages, with the initially more able group showing delays in diagnosis.
However, some evidence suggests that the magnitude of decline subsequent to the diagnosis of AD is accelerated for persons
who were initially higher functioning.23 This pattern may reflect the fact that the superior cognitive skills of the initially more able group can compensate for
the brain changes associated with AD, but once these reserves are lost, this group reveals rapid cognitive declines.
The best available clinical method for early detection of AD involves repeat neuropsychological testing. The initial testing
can suggest developing deficits, often meeting criteria for MCI, which often worsen noticeably over relatively short periods
(1-2 years). Medical and neurologic evaluation at the time of initial testing is valuable for detecting potentially treatable
and reversible causes of cognitive loss. However, until effective treatment that alters disease progression is available,
there is little reason, other than patient request, to perform repeat neuropsychological testing for the early identification
of AD.
Another practical challenge for the clinician is the impact of an MCI diagnosis on the patient and family. Caregiving for
a person with AD is well known to be stressful and disruptive for the patient and the caregivers.24,25 However, much less is known about the impact of a diagnosis of MCI on the family unit. In a study that examined the spouses
of 27 patients who were recently diagnosed with MCI, the results indicated that although the spouses were not as distressed
as typical dementia caregivers, they were already exhibiting elevated caregiver burden, as well as symptoms of depression
and anxiety.26 As a result, supportive services for caregivers of persons with MCI may be required.
Conclusions and future directions
For many years before a diagnosis of AD, patients exhibit a variety of cognitive deficits. This fact suggests that we may
be able to identify persons who are at high risk of developing AD and intervene to slow the disease course. However, it is
also clear that our ability to prospectively identify such patients, as well as to slow the course of AD, is still a work
in progress. Future research should attempt to find specific early disease markers. Progress may be enhanced by a multidisciplinary
approach, whereby information from cognitive tests is supplemented by genetic, biological, and radiologic markers of impending
AD. A better understanding of the early pathophysiologic and symptomatic changes of AD will aid in discovering new treatments
to postpone or mitigate the effects of the disease.
Series Editor Judith A. Neugroschl, MD, is Assistant Professor of Psychiatry, Mount Sinai School of Medicine, New York, NY.
Dr Small is Associate Professor, School of Aging Studies, University of South Florida, Tampa; and a coinvestigator at the Florida
Alzheimer's Disease Research Center, Tampa.
Ms Gagnon is a student at the School of Aging Studies, University of South Florida, Tampa.
Dr Robinson is Chief of Geriatrics and Director, Memory Disorders Clinic, Sarasota Memorial Hospital, Sarasota, Fla.
Disclosures: Dr Small, Ms Gagnon, and Dr Robinson disclose that they have no financial relationship with any manufacturer in this area
of medicine. Preparation of the article was supported by NIH Research Grant #R03 AG-024082 from the National Institute on
Aging to Dr Small.
References
1. Hebert LE, Scherr PA, Bienias JL, et al. Alzheimer disease in the US population: prevalence estimates using the 2000 Census.
Arch Neurol. 2003;60:1119-1122.
2. DeKosky ST. Early intervention is key to successful management of Alzheimer disease. Alzheimer Dis Assoc Dis. 2003;17(suppl):S99-S104.
3. Brookmeyer R, Gray S, Kawas CH. Projections of Alzheimer's disease in the United States and the public health impact of
delaying disease onset. Am J Public Health. 1998;88:1337-1342.
4. Tuokko H, Frerichs RJ. Cognitive impairment with no dementia (CIND): longitudinal studies, the findings, and the issues.
Clin Neuropsychologist. 2000;14:504-525.
5. Small BJ, Herlitz A, Bckman L. Memory and cognitive functioning in preclinical Alzheimer's disease. In: Morris RG, Becker
JT, eds. The Cognitive Neuropsychology of Alzheimer's Disease. 2nd ed. New York, NY: Oxford University Press; 2004:63-77.
6. Braak H, Braak E. Staging of Alzheimer disease-related neurofibrillary tangles. Neurobiol Aging. 1995;16:271-284.
7. Bckman L, Jones S, Berger A-K, et al. Cognitive impairment in preclinical Alzheimer's disease: a meta-analysis. Neuropsychol. 2005;19:520-531.
8. Craft S, Cholerton B, Reger M. Aging and cognition: what is normal? In: Hazzard WR, Blass JB, Ouslander JG, et al, eds.
Principles of Geriatric Medicine and Gerontology. 5th ed. New York, NY: McGraw-Hill; 2003:1355-1372.
9. La Rue A, Jarvik LF. Cognitive function and prediction of dementia in old age. Int J Aging Hum Development. 1987;25:75-89.
10. Whalley LJ, Starr JM, Athawes R, et al. Childhood mental ability and dementia. Neurology. 2000;55:1455-1459.
11. Snowdon DA, Kemper SJ, Mortimer JA, et al. Linguistic ability in early life and cognitive function and Alzheimer's disease
in late life: findings from the Nun Study. JAMA. 1996;275:528-532.
12. Petersen RC, Smith GE, Waring SC, et al. Mild cognitive impairment: clinical characteristics and outcomes. Arch Neurol. 1999;56:303-308.
13. Petersen RC, Doody R, Kurz A, et al. Current concepts in mild cognitive impairment. Arch Neurol. 2001;58:1985-1992.
14. Larrieu S, Letenneur L, Orgogozo JM, et al. Incidence and outcome of mild cognitive impairment in a population-based prospective
cohort. Neurology. 2002;59:1594-1599.
15. Pedelty L, Nyenhuis DL. Vascular cognitive impairment. Curr Treat Options Cardiovasc Med. 2006;8:243-250.
16. Rockwood K, Black SE, Song X, et al. Clinical and radiographic subtypes of vascular cognitive impairment in a clinic-based
cohort study. J Neurol Sci. 2006;240:7-14.
17. Morris JC, Price JL. Pathologic correlates of nondemented aging, mild cognitive impairment, and early-stage Alzheimer's
disease. J Mol Neurosci. 2001;17:101-118.
18. Cummings JL. Alzheimer's disease. N Engl J Med. 2004;351:56-67.
19. de la Torre J, Aliev G, Perry G, et al. Drug therapy in AD. N Engl J Med. 2004;351:1911-1913.
20. Petersen RC, Thomas RG, Grundman M, et al. Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med. 2005;325:2379-2388.
21. Amieva H, Jacqmin-Gadda H, Orgogozo JM, et al. The 9 year cognitive decline before dementia of the Alzheimer type: a prospective
population-based study. Brain. 2005;128:1093-1101.
22. Small BJ, Fratiglioni L, Viitanen M, et al. The course of cognitive impairment in preclinical Alzheimer disease: three-
and 6-year follow-up of a population-based sample. Arch Neurol. 2000;57:839-844.
23. Andel R, Vigen C, Mack WJ, et al. The effect of education and occupational complexity on rate of cognitive decline in
Alzheimer's disease. J Int Neuropsychol Soc. 2006;12:147-152.
24. Zarit SH, Todd P, Zarit J. Subjective burden of husbands and wives as caregivers: a longitudinal study. Gerontologist. 1986;32:665-672.
25. Haley WE, Levine EG, Brown SL, et al. Psychological, social, and health consequences of caring for a relative with senile
dementia. JAGS. 1987;35:405-411.
26. Garand L, Dew MA, Eazor LR, et al. Caregiving burden and psychiatric morbidity in spouses with mild cognitive impairment.
Int J Ger Psych. 2005;20:512-522.
