There are several aspects we have to take care of when analyzing the epidemiologic facts.

A.HOW MANY PERSONS HAVE ALZHEIMER’S DISEASE? AGE AS A MAJOR DETERMINANT

Can the prevalence of Alzheimer’s disease be measured? The diagnostic criteria for dementia that were introduced by the American Psychiatric Association in 1980 as the DSM-III criteria required that there be loss of intellectual abilities of sufficient severity to interfere with social or occupational functioning as well as impairment of memory and at least one other area of cognition in an individual who is alert and awake. In clinical experience, many individuals begin symptomotology with cognitive deficit in just one area, often but not always memory, and do not reach the point at which this deficit interferes with life activities for some period of time, thus making the diagnosis quite conservative. The impact of these conservative diagnostic criteria on community studies may be considerable since elderly persons with impairment of only memory or who are still functioning well despite mild cognitive changes in two areas of cognition would not be counted as demented even if in the early stage of Alzheimer’s disease. Thus, the figures for Evans and associates for the prevalence of dementia in East Boston were almost double those obtained in the Shanghai study of dementia described below. These differences may be real differences between communities, but may also reflect of the impact of DSM-III criteria which were used in the Shanghai study whereas, in the East Boston study, the requirement for demonstration of functional impairment was not used.

Despite these problems there is universal agreement between studies that when one plots the log of age-specific prevalence of dementia against a linear plot of age in years a straight line can be obtained over the range of ages between 65 and 85 years, indicating that dementia doubles every 4.9 to 5.1 years.

B.CASE–CONTROL AND LONGITUDINAL STUDIES IDENTIFY OTHER RISK FACTORS

With the conservative but accurate DSM-III and McKhann et al. diagnostic criteria for dementia and Alzheimer’s disease, it became feasible to select individuals with probable Alzheimer’s disease with a high degree of accuracy and compare them to age- and gender-matched controls to identify other risk factors. A number of such case–control studies have been carried out during the last decade. Family history, of course, has been known as a risk factor for Alzheimer’s disease for decades and certainly have been confirmed in case–control studies, particularly in those dealing with subjects with onset before the age of 75. Another risk factor demonstrated to be a relatively strong risk factor in a collaborative reanalysis of 12 case studies by EURODEM was head injury associated with a loss of consciousness or a brief hospitalization.60 Additional risk factors of interest reported by the EURODEM analysis include a history of severe depression, a history of Down’s syndrome in a relative, a history of Parkinson’s disease in a first-degree relative, and perhaps a history of advanced maternal age.

Another provocative finding, obtained in one longitudinal study that included cardiovascular as well as neurological workups on a yearly basis, the Bronx Aging Study, is that myocardial infarct is a risk factor in elderly women. This finding takes on added interest in view of the finding that the Apolipoprotein E4 allele is a risk factor for both heart disease and Alzheimer’s disease. This finding has yet to be confirmed in other studies. However, Sparks et al. have reported a very significant increase in plaques in neocortex in medical examiner cases of elderly individuals who had a 75% stenosis of a coronary vessel compared to those who did not have heart disease.

C.LACK OF EDUCATIONAL ATTAINMENT AS A RISK FACTOR FOR ALZHEIMER’S DISEASE AND OTHER PROGRESSIVE DEMENTIAS

In 1988, Mortimer considered two sets of risk factors for Alzheimer’s disease: social variables, such as education and occupation, and individual psychological characteristics including intelligence, personality, and stress. He argued that “… psychosocial factors act primarily to reduce the margin of intellectual reserve to a level where a more modest level of brain pathology results in a diagnosable dementia.” He predicted that as a consequence these psychosocial risk factors would have their strongest association in late onset at a time when the aging process has reduced the normal brain reserve.

We had the opportunity to confirm these predictions. In 1987, Drs. David Salmon, Igor Grant, and Robert Katzman at UCSD were invited to participate in a survey of the prevalence of dementing disorders in a randomly selected population of 5055 elderly who lived in the Jin-An district in Shanghai, China,63 which was carried out by Mingyuan Zhang and colleagues at the Shanghai Institute of Mental Health in collaboration with Drs. William Liu, Paul Levy, and Elena Yu at the University of Illinois in Chicago. An unexpected finding was that 27.2% of the cohort had never been to school, i.e., had no education whatsoever; 36.7% had received elementary education, many only 1 to 2 years; and 36.1% had middle school educations or higher, with doctoral degrees, thus constituting a very wide spread in the educational spectrum in this community. During the first phase it was quickly apparent that those without formal education would obtain quite low scores on the Chinese version of the Mini-Mental State Examination that we had used, so following the recommendations of Kittner and associates64 we used education-specific cut-off scores on this examination in selecting subjects for a more intensive clinical evaluation. It was interesting that the deficits in those with no education extended beyond reading or calculation; approximately 90% of those without formal education were unable to copy the overlapping pentagons figure on the Mini-Mental State Examination. Individuals who had never held a brush or pencil early in life were not able to learn to use these tools.

In the second phase of this survey, an intensive clinical examination based on DSM-III and NINCDS–ADRDA criteria was carried out on subjects who were below the education-specific cutoff scores on the Chinese version of the Mini-Mental Status Examination plus 5% of the remaining subjects from phase 1. The work-up included a major illness history, physical examination, neurological examination, psychiatric interview, depression scales, and neuropsychological tests. Functional change was measured by dementia symptom lists, the Pfeffer functional scale and the Instrumental Activities of Daily Living and Activities of Daily Living scales. Clinical diagnoses made by the examining physicians were subsequently reviewed by experienced neurologists and psychiatrists. There was a very dramatic effect of education on the prevalence of dementia and of Alzheimer’s disease, particularly among the women. For example, among 75- to 84-year-old women, the prevalence of dementia was 3.9% in those with middle school or more education, 12.6% in those with elementary school, and 18% in those with no education. Even though we used education-specific cut-off points, we were concerned that the known relationship of mental status test to education might have confounded the diagnostic process. We therefore carried out a further analysis of the data using computer algorithms to determine the diagnosis. Reanalysis of data using computer diagnoses based only on impairment of instrumental activities of daily living and dementia symptoms reported by informant shows an almost identical effect of low education. Moreover, the finding in this analysis and in the original analysis that the noneducated individuals under the age of 75 seldom have an increased risk of dementia whereas this risk is present over the age of 75 again suggests that the education effect in this cohort is real and is consistent with the Mortimer prediction.

A similar effect of education was observed in studies of the prevalence of dementia carried out in France, Sweden, Italy, Finland, and Israel as well as in studies of incident cases of dementia carried out in North Manhattan. An exception has been the Framingham study which did not show an education effect. Additional supportive evidence in regard to the education effect is found in studies of longevity without functional impairment in an order of Catholic sisters as well as from studies of incident cases of cognitive impairment in the EPESE studies (White). With regard to the strength of the education effect, this must be determined in a multivariate analysis taking age into account because age is such a powerful determinant, and lack of education is much more common in older individuals. With such multivariate analysis in the Shanghai study, the relative risk for those with middle school education vs. noneducation was 2.04 and in the Bordeaux study it was 1.94.

Still, it must be remembered that while education is a risk factor, that Alzheimer’s disease is a democratic disease. Individuals in any occupation or of any intellectual ability may be afflicted. An example is George Beadle, a Nobel laureate who was, in large part, personally responsible for opening up the area of biochemical genetics and who also served as the President of the University of Chicago for 7 years, who died in the 1980s at age 86 of Alzheimer’s disease. However, in many community studies, lack of education is an important risk factor.