THE ARTiCLE By GAiNES AND WHiTEHOUSE (2006) raises key questions about the uncertain relationship between (i) the intrinsic,“normal” aging process, and (ii) the clinicopathologic states represented by the labels of Alzheimer’s disease (AD) and mild cognitive impairment (MCI). This short commentary offers a perspective on this debate that is drawn from a consideration of underlying biological mechanisms.

Because age is unquestionably the greatest single risk factor associated with AD and MCI, I begin by asking what we know about the intrinsic processes of aging. The central feature of current understanding of intrinsic aging is that it consists of the gradual, lifelong accumulation of a wide variety of molecular and cellular faults that begins very early in life and eventually leads to overt functional impairments resulting in age-related frailty, disability, and disease (Kirkwood 2005). This is an essentially bottom-up process. A strong consensus has emerged in recent years that there