In recent years, patients who are at high risk for developing Alzheimer's disease (AD) have become a focus of study. Several research groups have identified these patients, developed diagnostic criteria, and followed the patients longitudinally. These patients therefore constitute a clinical entity that is suitable for therapeutic interventions. In this article, we report our 5-year experience at the Mayo Clinic in characterizing a group of patients with mild cognitive impairment. These subjects were recruited from community-dwelling individuals who were receiving general medical care in the Department of Internal Medicine. They received the diagnosis of mild cognitive impairment if they met the following criteria: (a) complaint of defective memory, (b) normal activities of daily living, (c) normal general cognitive function, (d) abnormal memory function for age, and (e) absence of dementia. In following more than 75 of these patients, some of whom have been studied for as long as 5 years, it appears that approximately 10% to 15% of the subjects evolve to AD each year. We therefore evaluated the cognitive profiles of these patients at the time of their initial diagnosis in an attempt to predict who would remain stable and who would evolve to AD. Certain features of learning and memory performance indicated patients who were more likely to progress, but the strongest predictor was their apolipoprotein E status. The patients who possessed an ε4 allele were more likely to convert to AD at a more rapid rate then those who were not carriers. Our results and similar data from other study groups indicate that diagnostic criteria can be defined for patients who are likely to convert to AD; the natural history of these patients is becoming apparent, and variables that predict ultimate conversion can be defined. Consequently, patients with mild cognitive impairment constitute an important group for study, particularly from the aspect of therapeutic interventions.

These data suggest the following: (1) patients with mild cognitive impairment can be clinically defined, (2) many members of this group progress to Alzheimer's disease, and (3) APOE epsilon 4 allele status appears to be a strong predictor of clinical progression.

Despite recent advances in the molecular genetics of Alzheimer's disease (AD), several fundamental questions concerning risk of illness are unresolved, namely, if Mendelian factors account for the incidence of the disease, and if AD is an inevitable consequence of the aging process. This study was designed to address these issues and other aspects of familial aggregation of the disorder. A consecutive sample of 1,694 patients who met criteria for a diagnosis of probable or definite AD were ascertained in 13 centers participating in the Multi-Institutional Research in Alzheimer Genetic Epidemiology (MIRAGE) project. Lifetime risk and age at onset of AD among various strata of 12,971 first-degree relatives was estimated using survival analysis procedures. The lifetime risk of AD in first-degree relatives was 39.0% +/- 2.1% by age 96 years. Age-specific risk of AD declined after age 90 and the data set included 61 apparently unaffected persons who survived to age 96 without becoming demented. Female relatives had a higher risk of AD than male relatives at all ages. By age 80, children of conjugal AD couples had a cumulative risk of 54%, 1.5 times greater than the sum of the risks to children having affected mothers or fathers, and nearly 5 times greater than the risk to children having normal parents. Children of affected fathers had a cumulative risk that was 1.4 times the corresponding risk to children of affected mothers. Risk assessment in early-onset and late-onset families, using various strategies for determining the age cut-off, yielded contradictory results. These data suggest the following: (1) the lifetime risk among relatives does not support a simple autosomal dominant inheritance pattern of disease; (2) women are innately more susceptible to AD than men; (3) the proportion of hereditary cases may be higher in men than women; (4) distinction between early- onset and late-onset forms of AD has little meaning in the absence of a biological marker; (5) the risk of AD decreases after age 90; and (6) AD therefore may not be an inevitable concomitant of the aging process, a conclusion that has profound implications for basic and applied AD research. The age- and sex-specific lifetime risks derived from this study are sufficiently robust to be a reliable source of information for counseling relatives of AD patients.

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Background/Aims: To evaluate baseline characteristics and conversion to dementia in mild cognitive impairment (MCI) subtypes. Methods: We prospectively evaluated conversion to dementia in 106 patients with amnestic MCI (A-MCI) as defined by Petersen’s operationalized criteria on a paragraph recall task, amnestic-subthreshold MCI (AS-MCI) as defined by impairment on the ADAS-cog delayed word list recall with normal paragraph recall, nonamnestic MCI (NA-MCI) defined by a nonmemory domain, and in 27 patients with subjective memory loss who had no deficit on formal neuropsychological testing. Results: For all MCI subtypes, the 4-year conversion to dementia was 56% (14% annually) and to AD was 46% (11% annually). Conversion to AD in the A-MCI (56%) was similar to the rate in AS-MCI (50%). Conversion to AD in the A-MCI and AS-MCI combined was 56% (14% annually). Conversion to dementia in the NA-MCI was 52% (13% annually) and the majority converted to AD (62%). Conclusions: All MCI subtypes are at risk of converting to AD if the groups are carefully defined by an abnormal psychometric domain. All subtypes except subjective memory loss converted to AD at higher than expected rates. Both the A-MCI and AS-MCI subtypes had a similarly high rate of conversion to AD. The deficit on a word list recall task may develop before an abnormality on delayed paragraph recall is evident, at least in some subjects.