Important Role of Brain Reserve in Lowering the Risk of Alzheimer‘s Disease

We have proposed that there are two distinct sets of risk factors for Alzheimer‘s disease (AD), those for the pathology of the disease and those for its clinical expression [1–3]. Although Alzheimer pathology is necessary for the diagnosis, it likely is not sufficient. Autopsy studies have shown that approximately a third of individuals meeting strict criteria for neuropathological AD remain nondemented at the time of their death [2]. Furthermore, people with similar severities of Alzheimer pathology have a very wide distribution of cognitive presentations before death, ranging from intact cognitive function to severe dementia [4].

The ability of individuals to maintain a relatively high level of cognitive function in the presence of substantial Alzheimer pathology provides strong support for the presence of the second set of risk factors for AD, those for its clinical expression. In 1995, I proposed “that clinical expression of AD requires two conditions to be met: first, a propensity, which is largely genetically determined, to accumulate Alzheimer lesions over the life course at a sufficiently rapid rate to meet neuropathological criteria for AD at death; and second, the attainment of a critical threshold of brain reserve beyond which normal cognitive function cannot be maintained” [1]. The existence of a threshold of functioning brain tissue has been appreciated for decades in the case of Parkinson‘s disease, where 80% or more of the dopaminergic cells in the substantia nigra pars compacta must be lost in order for the initial symptoms of this illness to become apparent [5]. As early as 1966, Martin Roth noted that dementia does not occur until a critical number of lesions or volume of brain softening secondary to infarcts is reached [6]. The presence of varying amounts of brain or cognitive reserve buffering the onset of dementia is now widely accepted as a possible explanation for the dissociation between neuropathological severity at autopsy and the cognitive status before death.

Brain and cognitive reserve could reflect several variables, including the number and size of neurons and their density of interconnection at the time of maturity in early adulthood, the collection of cognitive strategies for solving problems or taking neuropsychological tests, the loss of functioning brain tissue over the life course, and the growth and maintenance of brain tissue as a result of mental and/or physical exercise.

Besides genes, three risk factors related to the clinical expression of AD are determined early in life: educational attainment, IQ and brain volume. Numerous studies have shown that low educational attainment is a strong risk factor for dementia of the Alzheimer type [3]. For example, in an epidemiologic study of the East Boston, Massachusetts, USA community, the incidence of AD over 3 years was eight-times higher in participants with an elementary school education or less compared with those with a high school education or more [7]. Although years of education can be reliably measured, access to education may be limited in many populations by socioeconomic status [8]. Furthermore, it is unlikely that merely attending school for a number of years protects one from getting AD. More likely, greater education is a surrogate for other risk factors, including higher IQ and greater cognitive activity during life. Higher IQ has been shown to reduce the risk of AD and dementia in late life and to have a stronger association with dementia than education [9,10]. Since IQ has a heritability of approximately 0.50, some of the association between attained education and dementia attributable to IQ may be genetically mediated [11]. However, the association of lower education with dementia remains strong even when monozygotic co-twins discordant for dementia are compared with eachother [12].

Brain volume at any age reflects genetic, nutritional, vascular, inflammatory, oxidative, hormonal and other processes that have occurred since conception. However, an upper limit is placed on the size of the brain by intracranial volume, which is determined largely prior to age 10 years [13]. In 1988, Katzman reported that among people with numerous Alzheimer plaques at autopsy, those who scored in the upper quintile on cognitive and functional performance had significantly higher brain weights and greater numbers of neurons in the cerebral cortex, suggesting that a larger endowment of neurons in childhood might offer protection from cognitive loss in the presence of Alzheimer neuropathology [14]. This finding was followed by studies showing that larger brain sizes inferred from larger intracranial cross-sectional areas, head circumferences or intracranial volumes were associated with later ages of onset of AD, less severe clinical symptoms and lower incidence of cognitive decline and AD [3,15,16]. In a recent study of over 15,000 elderly residents from seven low and middle income countries, small head circumference was found to be significantly related to prevalence of dementia [17]. When education and head circumference are considered together, small head circumference is only a risk factor among those with low education [16]. Finally, intracranial volume is correlated with both education [18] and IQ [19], and education and IQ are correlated with one another [9]. The consequence of these correlations is that sufficient brain reserve to reduce the risk of dementia may be afforded by either high IQ, higher education or large brain volume, so that in studies in which most participants have one of these characteristics, it may be impossible to see associations with the others.

If there are two distinct sets of risk factors, risk factors for clinical expression should be independent of the severity of pathology. Recent clinicopathologic studies have supported this claim, showing a lack of association of head circumference and educational attainment with the severity of Alzheimer lesions at autopsy [16,20].

Given the protective effect of larger brains and higher education, what are the implications of these findings for prevention? Brain size at maturity, while in part genetically controlled, is also determined by under- or malnutrition during the first few years of life [21]. In the future, improved nutrition in early childhood could lower the incidence of AD by maximizing the size of the mature brain. Improvements in education could also lead to reduction in dementia occurrence by providing individuals with more efficient and flexible cognitive strategies for addressing problems – what has been termed active cognitive reserve [22] – as well as stimulating greater intellectual activity over the adult life course. Although more efficient use of the brain is unlikely to be reflected in anatomically detectable differences, increased mental exercise among those who are better educated could well be reflected in synaptic or neuronal growth. To date, few human studies have assessed the role of education in brain growth or maintenance of functioning tissue. One exception was a study of MR images obtained from London taxi drivers, which showed that the length of time spent as a taxi driver was associated with the degree of redistribution of gray matter from the anterior to the posterior part of the right hippocampus, a region known to be involved in spatial localization [23]. It is likely that higher education, or associated experiences, can affect the growth of brain tissue in a similar manner to how physical exercise of specific muscles affects their growth.

Although it is impossible to increase intracranial volume after childhood, loss of functional brain tissue within the cranium can be ameliorated, particularly through control of risk factors for cerebrovascular disease and stroke, including hypertension, diabetes and hypercholesterolemia. Most studies suggest that infarcts appear to contribute to dementia primarily by modifying the risk caused by Alzheimer lesions. In the Nun Study, for example, the risk of dementia among individuals satisfying neuropathological criteria for AD was increased 20-times by the presence of one to two lacunar infarcts [24]. Therefore, prevention and control of vascular risk factors and cerebrovascular disease has the potential to greatly reduce the incidence of clinical AD.

Another intervention with potential to increase brain reserve is aerobic physical exercise. Most longitudinal epidemiologic studies have shown a decreased risk of incident dementia or AD in individuals who exercise regularly [25–27]. Other studies have examined the effects of physical exercise on cognitive decline, again with most showing positive effects [28]. Colcombe and collaborators performed a randomized 6-month clinical trial comparing aerobic exercise with stretching and toning in 50 healthy but sedentary volunteers, aged 60–79 years, who received two MRIs [29]. Significant increases in brain volume of both gray and white matter regions occurred in the aerobic exercise group but not in the group who did stretching exercises. Increases in brain volume may reflect increases in the number or size of neurons, increases in the number of dendritic connections, increased capillary bed volume and/or increases in glial cell size and number.

In conclusion, although most of the risk of Alzheimer dementia is attributable to genetic inheritance [30], a variety of factors attributable in part to the environment, including attained education, intracranial volume, intelligence, absence of vascular risk factors and cerebrovascular disease, and mental and physical exercise, significantly modify the risk of this condition in late life by increasing brain reserve. Since these factors are potentially modifiable, they offer a way to decrease the incidence of this condition in the presence of significant Alzheimer brain pathology. Randomized clinical trials, utilizing mental and physical exercise interventions, are needed to demonstrate the effectiveness of these interventions in preventing AD and related dementias in the general population.

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.