**4. Conclusions**

The understanding of the mechanisms involved with successful aging is far from straightforward and the growing number of publications in this field shows the interest of the scientific community to understand the importance of complex related concepts in its promotion. In this chapter, we focused on several socio-behavioral CR proxies identified as protective factors against cognitive decline and dementia and how they impact EF by means of neural compensation mechanisms related to the increased functional activity of the frontal lobe.

The relationship between CR proxies and the maintenance of cognitive efficiency in the context of age-related changes/brain pathology is dynamic. Not only do the skills, social involvement, and occupational attainment developed throughout life have a mediating role in improving neural connections (i.e., in terms of activation, flexibility, and efficiency), but also this enhancement of brain connectivity patterns expresses itself in better cognitive performance. Despite its vulnerability to the effects of senescence, the frontal lobes play a key role in CR allowing for the preservation of the overall cognitive function by means of enrichment of EF (e.g., planning, sequencing, inhibitory control, abstract reasoning) via a higher CR. Indeed, people with high CR show an advantage in the use of these more developed EF, thus increasing frontal lobe activity. The use of alternative task-relevant circuits compensates for effectiveness (e.g., MTL, especially relevant for memory and selectively affected in AD) thus mitigating the clinical expression of dementia. In this compensation mechanism, DAN and FPN networks are particularly relevant, with a sub-region in the LFC being identified as a potential candidate for a neural marker of CR.

Several caveats still, however, need to be fully addressed. First and foremost, it is unclear how CR proxies may specifically influence different aetiologies of dementia and modulate different cognitive trajectories. Second, EF cannot have a double role as an age−/pathology-dependent measure and as a factor that changes the relationship. As a consequence, all EF may not be appropriate measures for CR, since it is not stable throughout life and is vulnerable to age-related changes. Thus, according to the gain/loss hypothesis, one should carefully select aspects of EF that are robust and resistant to aging, in order to include them as components of CR. Stern et al. [99] considered that this approach should be better explored in the future, despite currently presenting some limitations that are difficult to overcome. From the outset, the fact that the brain measures used to predict cognition only partially capture brain pathology or physiology and different lifestyles cannot be explained by known brain predictors can lead to a high risk of including many aspects that are not reserved. Third, the differential impact of CR depending on the demographic characteristics of the population or discrepancies in measuring CR measures or outcomes (i.e., cognitive or functional) needs to be addressed as well. In fact, precise operational definitions of CR and other related theoretical constructs are needed. Advances in multimodal imaging, preferably longitudinal studies, will allow a better understanding of the neural mechanisms underlying CR. Future work should focus on the design of studies that will help to clarify the relationship between CR proxies

and brain reserve, as well as improve their measurement. These studies will make it possible to improve and integrate the existing conceptual models of the moderation of CR in cognitive performance. Further, it is expected that the contribution of these investigations could lead to objective guidelines and strategies for the development of differentiated, validated, and accessible intervention programs aimed to provide more functionality and better quality of life in older adults [17].

If the existence of a compensatory capacity in individuals with a high CR seems to be clear, it is consensual that it is still not entirely clear what reserve consists of in neural terms. Potential candidates have been proposed but the discovery of this neural basis is particularly relevant as, in addition to traditional cognitive and psychosocial stimulation techniques, it could also open doors to more direct brain stimulation allowing the use of a whole arsenal of new non-invasive brain stimulation technologies which is predicted to have increasing importance in intervention.
