The impact of aging in dementia: It is time to refocus attention on the main risk factor of dementia

Alzheimer’s disease (AD) represents the most common form of dementia among old age subjects, and despite decades of studies, the underlying etiopathogenetic mechanisms remain unsolved, and no cure is available. The amyloid hypothesis has been recently questioned due to the failure of amyloid-centered treatments. The fact that cognitively normal old age subjects have substantial amyloid deposition in the brain comparable to the levels observed in AD patients suggests that amyloid accumulation may enter into the normal process of aging and what really triggers neuronal death and clinical manifestation is the loss of function due to an energetic failure. With this viewpoint article, we aim to challenge the traditional view of amyloid as the leading cause of AD. Conversely, we propose the core feature of aging, that is the progressive brain energy decline, as the main risk factor for dementia in older persons. Thus, a bioenergetic deficit secondary to mitochondrial dysfunction may lead to progressive neuronal death and clinical expression of dementia. The optimization of brain energetics should become a key component in future strategies for preventing and treating dementia.