A key issue for AD model development is whether AD is a pathological process or whether it is part of the normal sequence of aging. It is not as easy to decide this as it might seem. Sporadic AD is a condition of advanced age; average onset in the general population is 80-85 years. In fact, advancing age is the single most important risk factor for AD. Some of the symptoms and many of the lesions of AD are observed in normal persons as they age, a significant number of whom never develop dementia. Would all of them develop dementia if they were to live long enough? This issue remains unresolved, although it is clear at least that the initiation and trajectory of AD pathogenesis vary widely among aging persons.
Advanced age is not a requirement for AD pathology. Familial (genetic) forms of AD clearly fit the criteria for a disease, as the pathology occurs decades earlier than for the sporadic form of AD. One mutation (presenilin-1, P117L) causes disease onset as early as the 20s (Wisniewski et al., 1998). Early onset AD is not a progeric disorder, as other signs of advanced age are not observed. The difference between a disease and aging blurs when the processes involved overlap.
In terms of therapeutics, the prospects for blocking an aberrant process are significantly greater than for discovering a fountain-of-youth agent that halts aging. Disease models based on current hypotheses of what is driving AD pathology address the former condition while general aging models concentrate on the latter. The two approaches are not exclusive. Aging provides a substrate for the pathological processes in AD. Much can be learned from both types of models, and from considering how they interact and overlap.
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