Biological aging processes underlying cognitive decline and neurodegenerative disease

Abstract

Alzheimer's disease and related dementias (ADRD) are among the top contributors to disability and mortality in later life. As with many chronic conditions, aging is the single most influential factor in the development of ADRD. Even among older adults who remain free of dementia throughout their lives, cognitive decline and neurodegenerative changes are appreciable with advancing age, suggesting shared pathophysiological mechanisms. In this Review, we provide an overview of changes in cognition, brain morphology, and neuropathological protein accumulation across the lifespan in humans, with complementary and mechanistic evidence from animal models. Next, we highlight selected aging processes that are differentially regulated in neurodegenerative disease, including aberrant autophagy, mitochondrial dysfunction, cellular senescence, epigenetic changes, cerebrovascular dysfunction, inflammation, and lipid dysregulation. We summarize research across clinical and translational studies to link biological aging processes to underlying ADRD pathogenesis. Targeting fundamental processes underlying biological aging may represent a yet relatively unexplored avenue to attenuate both age-related cognitive decline and ADRD. Collaboration across the fields of geroscience and neuroscience, coupled with the development of new translational animal models that more closely align with human disease processes, is necessary to advance novel therapeutic discovery in this realm.

Figure 1. Interactions of biological aging processes with CNS changes.

The hallmarks of aging, such as epigenetic modifications, cellular senescence, metabolic dysfunction, and aberrant autophagy, as well as other phenotypes of brain aging, including inflammation, vascular dysfunction and loss of blood brain barrier integrity, and lipid dysregulation, interact to contribute to age-related processes in the CNS, including cognitive decline, neuropathological protein accumulation, and brain morphology changes. These same factors are further dysregulated in neurodegenerative disease. Further investigations are necessary to determine the specific factors and sequences that force the transition between normative age-related changes and manifest neurodegenerative disease in some individuals while others remain cognitively resilient.