Lifespan Cognitive Reserve—A Secret to Coping With Neurodegenerative Pathology. Sylvia Villeneuve. JAMA Neurol. 2019;76(10):1145-1146. October 2019, doi:10.1001/jamaneurol.2019.2899
Given the limited success of therapeutic interventions for Alzheimer disease, there is increased interest in understanding whether modifiable factors can help cope with or postpone the appearance of brain pathology. It is estimated that about 35% of Alzheimer risk is modifiable.1,2 Epidemiologic studies have shown that lifetime exposures to higher education, higher occupational attainment, and cognitively stimulating activities are associated with reduced risk of Alzheimer dementia.3 Autopsy studies have shown interindividual differences in the amount of brain pathology people can tolerate before manifesting cognitive impairments, and autopsied brains of about one-third of individuals who are cognitively normal meet neuropathological criteria for Alzheimer disease.4 About a decade ago, the concept of cognitive reserve was proposed to account for the discrepancy between brain pathology and cognitive status.5 The broad hypothesis was that individuals with enriched lifelong exposures would be able to better tolerate with brain pathology in late life. Many studies have investigated how one can cope with brain damage using proxies of neurodegeneration or synaptic integrity. However, the gold standard for testing the reserve hypothesis is the direct measurement of brain pathology at autopsy.
In this issue of JAMA Neurology, Xu and colleagues6 used the resources of the Rush Memory and Aging Project for an empirical test of the reserve hypothesis. They first assessed whether individuals with lifelong protective factors have a reduced risk of dementia. More importantly, they examined the influence of Alzheimer pathology on this association, thereby providing a direct test of the reserve hypothesis. The Rush Memory and Aging Project is among the largest longitudinal studies that include both comprehensive in vivo and autopsy data. The study had 1602 participants without dementia, of whom 611 had died during the study follow-up period and had autopsy data available. Of interest, the authors6 derived the reserve score by combining weighted measures of education, lifelong cognitive activity, and late-life social activity. In theory, the use of a composite score as a proxy for reserve instead of a single factor score (eg, education) should be more accurate if reserve is built on diverse lifelong experiences, as is commonly thought. Over a mean 6-year study follow-up (range, 1-20 years), one-quarter of these participants developed dementia. As expected, a higher reserve composite was associated with reduced incidence of dementia. Thus, participants in the highest tertile of reserve had about a 40% reduction in occurrence of dementia compared with those in the lowest tertile. A dose-effect association was also evident, in that individuals in the middle tertile showed about a 20% reduction in risk of dementia. Stated another way, individuals with high reserve scores experienced a delay in dementia onset of more than 7 years. Targeting lifestyle factors that enhance reserve could therefore reduce the incidence of new cases, while providing more than half a decade of cognitive health to individuals who would ultimately develop dementia.
The contribution of individual factors to dementia risk was assessed in a secondary set of analyses. Here it was interesting to note that lifestyle behaviors in midlife and late life were the main protective factors of dementia, suggesting that preventive interventions should probably be started in midlife but may also be successful if started in late life. In 2015 the results of Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER),7 which involved physical exercise, nutrition, cognitive stimulation, and self-monitoring of heart health, suggested the possibility of preventing cognitive decline using a multidomain intervention among older individuals who were at risk. The FINGER model is now being adapted and implemented in North America (the Alzheimer's Association US Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk [US POINTER]), Asia (Singapore Intervention Study to Prevent Cognitive Impairment and Disability [SINGER] and the Multimodal Interventions to Delay Dementia and Disability in Rural China [MIND-CHINA]), Australia (the Maintain Your Brain [MYB] trial), and Europe (Multimodal Preventive Trial for Alzheimer’s Disease [MIND-AD]). It is estimated that a multidomain lifestyle intervention that achieves a 25% reduction in Alzheimer risk could prevent more than 3 million cases worldwide.1
Focusing on the autopsy findings, the positive association of reserve with reducing the risk of dementia onset was present even in individuals with high degrees of brain pathology. This was true for Alzheimer disease pathology, but also for gross infarcts and microscopic infarcts. No sex difference was reported for this association. A recent in vivo positron emission tomography (PET) study found that women exhibit higher tau burden than men in the preclinical phase of the disease,8 which could suggest that women can tolerate more pathology before developing cognitive impairments. Since women are at increased risk of developing Alzheimer dementia, particularly in late life, the role of sex differences in lifestyle-protective factors and associated resilience to the pathology will need further investigation.
The protective effect of lifespan cognitive reserve on the incidence of dementia in individuals with high pathology was also found when removing individuals with baseline mild cognitive impairments from the analysis. This last point is important, because individuals who are cognitively normal are the targets of preventive trials and therefore increasing effort is devoted toward a better understating of the factors that could protect this group from developing cognitive impairment. Additionally, it is possible that some reserve-associated phenomena are only quantifiable at a certain stage of the disease, stressing the need to explore reserve-associated phenomena at different disease stages. For instance, a new study9 has shown that, while high reserve was associated with a slower cognitive decline in individuals without dementia, it was associated with a faster decline in individuals with dementia. One interpretation for this unexpected finding is that when individuals with high reserve can no longer cope with the pathology, their clinical decline is faster than individuals with lower reserve because the disease stage is more advanced.5
Evidence from PET research further suggests that some lifestyle factors that can enhance cognitive reserve might also postpone manifestation of brain pathology. This new concept has been called resistance.10 Thus, while the term reserve refers to the ability to cope with AD pathology, resistance refers to the ability to avoid the pathology in the first place. For instance, enriched cognitive and physical activities have been associated with a reduced amyloid burden in individuals who are cognitively normal.11-13 It has even been proposed that protective lifestyle factors could partially offset the negative influence of the APOE ε4 allele on the risk of developing Alzheimer pathology.14,15 In their study, Xu and colleagues6 found no evidence supporting the resistance hypothesis, with individuals with high and low reserve scores exhibiting similar amounts of pathology. The results were similar when removing individuals with baseline mild cognitive impairment from the analysis or using cognitive status as an interactive term. The association between protective lifestyle factors and brain pathology, if it exists, might not be linear but rather closer to a U-shaped distribution and therefore extremely difficult to detect in cross-sectional studies. Plausibly, as soon as individuals with high reserve develop Alzheimer pathology, they are no longer resisting the pathology but are limited to coping with it.
This last point may serve as a reminder that cognitive reserve is a dynamic and therefore complex concept for study. Amyloid and tau PET imaging, even if they only give estimates of pathology, should be extremely powerful tools to quantify reserve-associated processes in real time, since they allow tracking of evolution of pathology in vivo. They can also contribute to simultaneous measurement of protective lifestyle factors, Alzheimer pathology, and cognitive performance. Even more interestingly, PET imaging can permit concurrent quantitation of the effects of preventive lifestyle interventions on Alzheimer pathology and associated cognitive decline.
The article by Dr Xu and colleagues6 provides strong evidence that individuals with higher reserve can tolerate more brain pathology and therefore experienced a reduced risk of dementia compared with others. While autopsy studies will probably remain the gold standard for testing the reserve hypothesis, their limitations in testing the dynamic of this phenomenon are obvious. New fluid, PET, and magnetic resonance imaging techniques for tracking Alzheimer and vascular pathology in vivo will certainly add to comprehension of reserve phenomena in the years to come.
Check also Association of Lifespan Cognitive Reserve Indicator With Dementia Risk in the Presence of Brain Pathologies. Hui Xu et al. JAMA Neurol. 2019;76(10):1184-1191, July 14, 2019, doi:10.1001/jamaneurol.2019.2455
Key Points
Question Is high lifespan cognitive reserve (CR) indicator associated with a reduction in dementia risk, and how strong is this association in the presence of high brain pathologies?
Findings In this cohort study including 1602 dementia-free older adults, high lifespan CR was associated with a decreased risk of dementia. This association was present in people with high Alzheimer disease and vascular pathologies.
Meaning Accumulative educational and mentally stimulating activities enhancing CR throughout life might be a feasible strategy to prevent dementia, even for people with high brain pathologies.
Abstract
Importance Evidence on the association of lifespan cognitive reserve (CR) with dementia is limited, and the strength of this association in the presence of brain pathologies is unknown.
Objective To examine the association of lifespan CR with dementia risk, taking brain pathologies into account.
Design, Setting, and Participants This study used data from 2022 participants in the Rush Memory and Aging Project, an ongoing community-based cohort study with annual follow-up from 1997 to 2018 (mean follow-up, 6 years; maximum follow-up, 20 years). After excluding 420 individuals who had prevalent dementia, missing data on CR, or dropped out, 1602 dementia-free adults were identified at baseline and evaluated to detect incident dementia. During follow-up, 611 died and underwent autopsies. Data were analyzed from May to September 2018.
Exposures Information on CR factors (education; early-life, midlife, and late-life cognitive activities; and social activities in late life) was obtained at baseline. Based on these factors, lifespan CR scores were captured using a latent variable from a structural equation model and was divided into tertiles (lowest, middle, and highest).
Main Outcomes and Measures Dementia was diagnosed following international criteria. Neuropathologic evaluations for Alzheimer disease and other brain pathologies were performed in autopsied participants. The association of lifespan CR with dementia or brain pathologies was estimated using Cox regression models or logistic regression.
Results Of the 1602 included participants, 1216 (75.9%) were women, and the mean (SD) age was 79.6 (7.5) years. During follow-up, 386 participants developed dementia (24.1%), including 357 participants with Alzheimer disease–related dementia (22.3%). The multiadjusted hazards ratios (HRs) of dementia were 0.77 (95% CI, 0.59-0.99) for participants in the middle CR score tertile and 0.61 (95% CI, 0.47-0.81) for those in the highest CR score tertile compared with those in the lowest CR score tertile. In autopsied participants, CR was not associated with most brain pathologies, and the association of CR with dementia remained significant after additional adjustment for brain pathologies (HR, 0.60; 95% CI, 0.42-0.86). The highest CR score tertile was associated with a reduction in dementia risk, even among participants with high Alzheimer disease pathology (HR, 0.57; 95% CI, 0.37-0.87) and any gross infarcts (HR, 0.34; 95% CI, 0.18-0.62).
Conclusions and Relevance High lifespan CR is associated with a reduction in dementia risk, even in the presence of high brain pathologies. Our findings highlight the importance of lifespan CR accumulation in dementia prevention.
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