Ageing is the main risk factor common to most primary neurodegenerative
disorders. Indeed, age-related brain alterations have been long
considered to predispose to neurodegeneration. Although protein
misfolding and the accumulation of toxic protein aggregates have been
contemplated as causative events in neurodegeneration, several
biological pathways affected by brain ageing are also contributing to
pathogenesis. Here, we discuss the evidence showing the involvement of
the mechanisms controlling neuronal structure, gene expression,
autophagy, cell metabolism, and neuroinflammation in the onset and
progression of neurodegenerative disorders. Furthermore, we review the
therapeutic strategies currently under development or as future
approaches designed to normalize these pathways, which may then boost
brain resilience to cope with toxic protein species. Therefore, in
addition to therapies targeting the insoluble protein aggregates
specifically associated with each neurodegenerative disorder, these
novel pharmacological approaches may be part of combined therapies
designed to rescue brain function.