Citation: Cammisuli, D.M.; Franzoni, F.; Scarfò, G.; Fusi, J.; Gesi, M.; Bonuccelli, U.; Daniele, S.; Martini, C.; Castelnuovo, G. What Does the Brain Have to Keep Working at Its Best? Resilience Mechanisms Such as Antioxidants and Brain/Cognitive Reserve for Counteracting Alzheimer’s Disease Degeneration. Biology 2022, 11, 650. https://doi.org/10.3390/ biology11050650 Academic Editor: Chiara Villa Received: 22 March 2022 Accepted: 22 April 2022 Published: 24 April 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). biology Review What Does the Brain Have to Keep Working at Its Best? Resilience Mechanisms Such as Antioxidants and Brain/Cognitive Reserve for Counteracting Alzheimer’s Disease Degeneration Davide Maria Cammisuli 1 , Ferdinando Franzoni 2 , Giorgia Scarfò 2 , Jonathan Fusi 2 , Marco Gesi 3 , Ubaldo Bonuccelli 2 , Simona Daniele 4 , Claudia Martini 4 and Gianluca Castelnuovo 1,5, * 1 Department of Psychology, Catholic University, 20123 Milan, Italy; davide.cammisuli1@unicatt.it 2 Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy; ferdinando.franzoni@unipi.it (F.F.); giorgiascarfo91@gmail.com (G.S.); jonathan.fusi@gmail.com(J.F.); ubaldo.bonuccelli@unipi.it (U.B.) 3 Department of Translational Research on New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy; marco.gesi@med.unipi.it 4 Department of Pharmacy, University of Pisa, 56126 Pisa, Italy; simona.daniele@unipi.it (S.D.); claudia.martini@unipi.it (C.M.) 5 Psychology Research Laboratory, Istituto Auxologico Italiano IRCCS, 28824 Milan, Italy * Correspondence: gianluca.castelnuovo@auxologico.it Simple Summary: Alzheimer’s disease currently represents one of the major challenges of modern society in relation to social and medical costs. As people age, they often experience mild changes in cognitive functioning that may be due to an initial degeneration of cerebral networks. Advances in neurobiology research including antioxidants intake and brain capacity to resist damage is relevant in order to support elderly people in the adoption of healthy lifestyles able to counteract dementia onset. Abstract: Here we performed a narrative review highlighting the effect of brain/cognitive reserve and natural/synthetic antioxidants in exerting a neuroprotective effect against cognitive deterioration during physiological and pathological aging. Particularly, we discussed pathogenesis of Alzheimer’s disease, brain and cognitive reserve as means of resilience towards deterioration, and evidence from the literature about antioxidants’ role in sustaining cognitive functioning in the preclinical phase of dementia. During aging, the effects of disease-related brain changes upon cognition are reduced in individuals with higher cognitive reserve, which might lose its potential with emerging cognitive symptoms in the transitional phase over the continuum normal aging-dementia (i.e., Mild Cognitive Impairment). Starting from this assumption, MCI should represent a potential target of intervention in which antioxidants effects may contribute—in part—to counteract a more severe brain deterioration (alongside to cognitive stimulation) causing a rightward shift in the trajectory of cognitive decline, leading patients to cross the threshold for clinical dementia later. Keywords: antioxidants; aging; Alzheimer’s disease; mild cognitive impairment; subjective cognitive decline; brain reserve; cognitive reserve; rehabilitation 1. Introduction: Population Aging and Dementia Emergency The average human lifespan is rapidly increasing and the maintenance of functional well-being in older age represents a current challenge in modern societies. The number of elderly people will dramatically increase in the near future as a consequence of progressive population aging. By 2050, 25% of people living in Europe and North America could be aged 65 or over [1]. Cognitive functioning is a major determinant of quality-of-life in the elderly and plays a critical role for the maintenance of personal and instrumental autonomy Biology 2022, 11, 650. https://doi.org/10.3390/biology11050650 https://www.mdpi.com/journal/biology