Innate intelligence or aspects of life experience like educational or occupational attainment may supply reserve, in the form of a set of skills or repertoires that allows some people to cope with pathology better than others.

Epidemiological data supporting the CR hypothesis include observations that lower educational and occupational attainment is associated with increased risk for incident dementia (Stern et al., 1994). Similarly, lower linguistic ability (as expressed by idea density and grammatical complexity) in early life and childhood mental ability scores are strong predictors of poor cognitive function and dementia in late life (Snowdon et al., 1997; Whalley et al., 2000). This is consistent with the prediction that people with more reserve can cope with advancing AD pathology longer before it is expressed clinically. In addition it has been shown that AD patients with higher educational and occupational attainment have more rapid cognitive decline than those with lower attainment, consistent with the idea that, at any level of clinical severity, the underlying AD pathology is more advanced in patients with more CR (Stern, Tang, Denaro, & Mayeux, 1995).

At least three studies have used structural equation modeling in longitudinal data to address this question. Schooler and Mulatu (2001), reported that initial high levels of intellectual functioning leads to high levels of environmental complexity, which in turn raises the levels of intellectual functioning over a 20-year period. Gold et al. (1995) reported that individuals with higher levels of intellectual ability, education and socioeconomic status are more likely to develop an engaged lifestyle, which in turn contributes to the maintenance of verbal intelligence in later life. Similar observations were reported in a 250 individual sample tested three times over 6 years: intellectually engaging activities seemed to buffer against decline in cognitive functioning (Hultsch et al., 1999). Nevertheless, an alternative model in this study suggested that findings were also consistent with the hypothesis that high-ability individuals lead intellectually active lives until cognitive decline in old age limits their activities.

There have been only few prospective longitudinal studies examining the influence of socially and intellectually engaged lifestyle to incident dementia. In a survey sample of 422 elderly subjects the relation of various indicators of socio-economic status to incident dementia was investigated (Bickel & Cooper, 1994). Only poor quality living accommodations were associated with increased risk of incident dementia, while indicators of social isolation such as low frequency of social contacts within and outside the family circle, low standard of social support and living in single person household did not prove to be significant.

In another cohort, the average minute per day participation in cognitively challenging “complex” (i.e., playing a musical instrument, handicrafts) and basic “simple” (dressing, eating) activities was assessed for 1877 subjects (Zabar, Corrada, Fozard, Costa, & Kawas, 1996). Regular participation in complex (relative to simple) activities did reduce the risk of developing dementia within 2 years but not within 5, 10 or 15 years, suggesting that the effect near the time of diagnosis may reflect changes in activities due to early dementia. Unfortunately, this study has been published only in an abstract form and no details are available.

Another study evaluated social and leisure activity data in 2040 nondemented elderly community residents from Gironde (France) and recorded incident dementia on follow-up visits (Fabrigoule et al., 1995). Traveling, doing odd jobs and knitting were associated with lower risk of incident dementia when occupational status was controlled for. However, the analyses were not controlled for either ethnic group, gender, educational attainment, cerebrovascular risk factors or depressive symptomatology. In addition, for doing odd jobs and knitting, the effect was significant only when subjects who did the activities without difficulty were compared to subjects who did not do them because of deficiencies or disabilities. When the comparison group was subjects who were not engaged in these two activities for other reasons, no significant influence was noted. Therefore, the reasons for engaging in leisure activities, rather than the leisure activities per se, seemed to affect incident dementia in this study.

There have been at least three large prospective studies that demonstrated a clear association between engaged lifestyle and incident dementia. In one of them, social ties (spouse, living arrangements, contacts with friends and relatives, confidant reciprocity and group membership) and participation in productive activities (helping others with daily tasks, paid work and volunteer work) were assessed for 2486 community-dwelling Japanese-American men (free of dementia at baseline) who were followed for 3 years (Balfour, Masaki, White, & Launer, 2001). Both social engagement and productive activities were significantly and inversely associated with risk of incident dementia. With each additional social tie, the OR for dementia decreased by 16% and with each additional productive activity, the OR for dementia decreased by 72% and the effect of the two scales was synergistic. This study is available only in an abstract form.

We recently reported the results of a study involving a total of 1772 nondemented individuals aged 65 years or older, living in Northern Manhattan New York who were identified and followed longitudinally in a community based cohort incidence study for up to 7 years (mean 2.9 years; Scarmeas, Levy, Tang, Manly, & Stern, 2001). In the initial visit, an interview elicited self-reported participation in a variety of leisure activities of intellectual (reading magazines or newspapers or books, playing cards or games or bingo, going to classes etc.), social (visiting or being visited by friends or relatives, etc.) and even physical (walking for pleasure or excursion, physical conditioning, etc.) nature. Figure 1 presents the cumulative risk for developing dementia in the high and low leisure activity groups, as calculated from survival analysis models. Even when factors like ethnic group, education and occupation were controlled for, subjects with high leisure activity had 38% less risk of developing dementia. The risk of incident dementia was reduced by approximately 12% for each additional leisure activity adopted. The effect of leisure activities on incident dementia was still present even when baseline cognitive performance, health limitations interfering with social activities, cerebrovascular disease and depression were considered.

In another prospective study, frequency of participation in common cognitive activities (i.e., reading a newspaper, magazine, books) was assessed at baseline for 801 elderly Catholic nuns, priests and brothers without dementia (Wilson et al., 2002). During a mean follow-up of 4.5 years, 1-point increase in the cognitive activity score was associated with a 33% reduction in the risk for AD. Additionally, engagement in cognitive activities was also associated with slower rates of cognitive decline. The results held even when many potential confounders were controlled for and even when subjects with memory impairment at baseline evaluation were excluded from the analyses.

It is also possible that both education-occupation-IQ and engagement in stimulating vocational activities are markers of innate capacities. Innate might refer to either genetic background or early life developmental factors or a combination of them. These innate capacities might in turn lead to higher levels of education, more engagement in stimulating vocational activities and lower risk of cognitive decline.

It can also be that there is another yet not identified causal factor-characteristic that confounds or mediates the inverse association between engaged lifestyle and incident dementia.

Finally, it is conceivable that factors that affect CR may even result in hindering the development of the disease pathology per se. Involvement in challenging avocations during life may even decrease neurodegeneration. This could be mediated via a variety of underlying neurobiological processes such as enhanced chronic neuronal activation associated with increased brain work, increased regional cerebral blood flow, and increased glucose and oxygen metabolism (Friedland, 1993) or even via higher ability for generation of new neurons into adulthood (Eriksson et al., 1998; Johansson, Svensson, Wallstedt, Janson, & Frisen, 1999; Kukekov et al., 1999) that might help to make up cell loses with cell gains.

The hypothesis of lifestyle modifications affecting brain disease outcome becomes even more exciting in the face of increasing animal research literature about neuronal plasticity and its association with learning, and physically and socially enriched environment. Exposure to an enriched environment, defined as a combination of more opportunities for physical activity, learning and social interaction, produces not only a host of structural and functional changes in the brain but also influences the rate of neurogenesis in adult and senescent animal models (Kempermann, Kuhn, & Gage, 1997a, 1997b; van Praag et al., 1999).