One of the reasons for the difference in risk of pathologically and clinically defined AD associated with APOE-ε4 may be that a substantial proportion of individuals satisfying neuropathological criteria for AD at autopsy do not become demented before death. As shown in , this percentage can be quite large, suggesting that there are likely to be risk factors that modify the clinical expression of the pathology of AD. Two of these factors are attained education and the size of the fully developed brain. Numerous studies have found low educational attainment to be a risk factor for prevalent18-30
dementia, although a few studies have failed to confirm this association.42-44
The effect of lower education on the expression and detection of AD is likely multifactorial, related to lower IQ, poorer test-taking ability, and less mental exercise.
Prospective Studies of Nondemented Elderly: Percent Meeting Neuropathological Criteria for Alzheimer's Disease (AD)
Smaller brain size attained in childhood,45
estimated from scans46-48
or from head circumference,49-51
has been associated with increased prevalence,48,51
earlier onset of symptoms,47
and increased severity of cognitive deficit46,49,51
in AD as well as with lower scores on cognitive screening tests in a community sample of nondemented older adults.50
However, negative studies have been published in which total intracranial volume, a measure of maximum attained brain size, was found not to be associated with the presence of AD in studies of clinically derived cases and cognitively normal community volunteers.53,54
shows findings from a large study of older persons who were screened with a mental status exam called the Cognitive Abilities Screening Instrument or CASI.49,55
Head circumferences above 55 cm had little effect, but smaller circumferences were associated with lower scores on this screening test. When individuals with probable AD were examined separately from those without this illness, it was found that the entire effect of head circumference on mental status was attributable to individuals with probable AD. Patients with probable AD who had smaller head circumferences had lower scores on the global mental status test, whereas head circumference had no effect on global cognition among those not meeting study criteria for probable AD.
Figure 1 Mean scores on the Cognitive Abilities Screening Instrument (CASI) mental status exam by head circumference categories in a sample of 1985 Japanese Americans age 65 and over (the Kame Study). Copyright 1996 from “Head Circumference as a Measure (more ...)
Borenstein-Graves et al52
later showed that head circumference was related to incidence of AD among initially nondemented older persons followed longitudinally who carried 1 or more e4 alleles for apolipoprotein E but not among people who did not carry this allele. The combination of a strong risk factor for Alzheimer neuropathology and a risk factor for clinical expression predicted who would become demented in the future.
Given the protective value of higher education and larger brain size, one can ask whether the combination of these two characteristics is more beneficial than either one in isolation. Recently, we examined this possibility using data from the Nun Study.56
The findings, summarized in , show that larger head circumference is an important protective risk factor for the clinical expression of dementia, but only among those with lower education. Either high education or a larger brain is sufficient to lower the risk of dementia appreciably, and the additional benefit from having both is small. Autopsy data from patients in this study showed that neither head circumference nor attained education was related to satisfying neuropathological criteria for AD, consistent with findings of other investigators.57
Figure 2 Percentage of Catholic sisters demented in six groups defined by educational attainment (high = bachelor's degree or more, low = less than a bachelor's degree) and head circumference tertile. Copyright 2003 from “Head Circumference, Education (more ...)
The result of further investigation of the modification of clinical status by education is shown in . Among those Catholic sisters with high (vs low) educational attainment, the frequency of dementia before death was reduced by 26% for those in milder neuropathological states of the disease (Braak neurofibrillary stages I-III) and 13% for those with more severe pathology (Braak neurofibrillary states IV-VI). Education has a powerful effect in reducing the severity of cognitive impairment in individuals with moderate AD pathology. As the severity of the pathology increases, the protective role of education remains but is diminished.
Percentages of non-demented Catholic sisters by educational attainment (high = bachelor's degree or more, low = less than a bachelor's degree) and Braak neurofibrillary stage at autopsy.