11 Sep 2001

One of the most pressing needs in Alzheimer's research today is the ability to identify, among normal elderly people, those who will likely go on to develop AD. A paper published today in the Proceedings of the National Academy of Sciences brings researchers a step closer to attaining this goal, which would make it possible to recruit presymptomatic patients into clinical trials of experimental treatments before the disease has had time to kill large swaths of neurons in their brains.

A team of scientists led by Mony de Leon at New York School of Medicine used MRI-guided PET to image reductions in glucose metabolism in 48 cognitively normal people over a period of three years. They wondered whether reduced glucose metabolism in the entorhinal cortex (EC) would be able to predict subsequent hypometabolism in other brain areas and cognitive decline. This hypothesis grew out of previous work suggesting that AD pathology may start in the EC and then spread to the hippocampus and temporal neocortex (Braak and Braak, 1991), as well as other studies showing that layers 2 and 4 of the EC already have lost 40 percent or 60 percent of their neurons, respectively, when AD is barely diagnosable (Gomez-Isla et al., 1996) Previous imaging studies (Killiany et al., 2000; Jack et al., 2000; others) have managed to predict who will develop AD among people with mild cognitive impairment (MCI), but not among normal subjects.

In this study, 12 of the 48 participants declined cognitively, 11 to MCI and one to AD. Glucose hypometabolism in the entorhinal cortex that was detectable at baseline accurately predicted this decline, the authors write. It also predicted that a similar hypometabolic state would develop in the temporal lobe neocortex and, less so, in the hippocampus. People heterozygous for the ApoE4 allele showed a steeper metabolic decline in the lateral temporal lobe.

The authors conclude that a particular EC stage exists prior to diagnosable AD, which can be detected in normal elderly people. By contrast, a more widespread assortment of brain areas serve to predict progression to AD in people with MCI. This again confirms the notion that EC changes precede damage in other brain areas.

The authors caution, however, that their method is not widely applicable. It is expensive, needs to be confirmed independently and in larger samples, and cannot explain the mechanism underlying impaired glucose metabolism.—Gabrielle Strobel