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Some hypotheses can be proposed to explain the mecha- nism of the « 2 allele’s action on longevity. The hypocholes- « terolemia typical of middle-aged 2 carriers is believed to protect from atherosclerosis and vascular disease (4). How- ever, the effect of the E2 protein isoform on serum choles- terol attenuates with age (30). Thus, it is unlikely that the « increased frequency of the 2 allele in centenarians is medi- ated by its hypocholesterolemic effect.

« Alternatively, the 2 allele might enhance the efficiency of the neuroendocrine system. The neuroendocrine system might play a key role in aging and longevity (31), and it has been shown that function of APOE is directly related to that of the hypothalamic-pituitary-adrenal axis in response to acute and chronic stresses in mice (32).

Finally, 2 carriers might be more resistant to the insults of aging and disease in general. In addition to being less susceptible to Alzheimer’s disease, it has been shown that « the brains of subjects carrying the 2 allele are also less sus- ceptible to traumatic and vascular lesions (33), as well as to the chronic insults of inherited metabolic diseases (34). It has been suggested that this effect is due to the greater effi- ciency of the E2 protein isoform in repairing nervous tissue damage (33). However, longevity is due to successful aging, not only of the brain, but of the whole body machinery. Al- though it is presently unknown whether the beneficial effect of the E2 isoform extends to tissues and organs outside the nervous system, anecdotal reports indicate a surprising re- sistance of some centenarians to a series of adverse general medical events occurring during their lifetimes (35).

Acknowledgments

This study was supported by a grant from the IRCCS San Giovanni di Dio–FBF, Brescia, Italy.

Address correspondence to Giovanni B. Frisoni, MD, Laboratory of Ep- idemiology and Neuroimaging, IRCCS San Giovanni di Dio–FBF, via Pilastroni 4, I-25123 Brescia, Italy. E-mail: frisoni@master.cci.unibs.it

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