Bret S. Stetka, MD


June 24, 2013

In This Article

Genetic Insights

Adding to the improved understanding of AD are genetic advances. Early genetic studies looked at families with autosomal dominant inheritance patterns, namely involving presenilin and APP gene mutations that result in early-onset disease. Though these patients represent less than 1% of those who develop AD, those with a family history of AD can be tested for the mutations and receive genetic counseling. The ongoing Dominantly Inherited Alzheimer Network is a multicenter, international initiative studying families with a rare genetic variant causing early-onset AD. The hope is to uncover insights into what causes AD and how the disease develops preclinically.

The APOE ε4 risk gene is far more common, present in over 1 in 5 people, and typically results in late-onset AD. But, as Small pointed out, it is "neither necessary nor sufficient to get the disease." A study out of Washington University[12] found that people with APOE ε4 were not demented and had less amyloid in their brain if they had a history of exercise. "So genetics is not the whole story," Small commented.

Genome-wide association studies have helped identify a number of other genes associated with late-onset AD, including BIN1, CLU, PICALM, and CR1. Also among them is TREM2; the mutation is uncommon but, when present, triples AD risk. Of note, the TREM2 protein is expressed on the surface of microglia, supporting a growing school of thought that AD pathogenesis involves inflammatory hyperactivity. As Small pointed out, many of the behaviors associated with AD prevention -- exercise, diet, healthy sleep habits -- are actually anti-inflammatory strategies. Inflammation is a normal physiologic process that helps repair and protect us from harmful stimuli such as trauma or infection. But with aging, our inflammatory systems become overly active, representing a potential pathophysiologic target in treating cognitive decline.

Small then presented data[13] his group had gleaned by combining genetic and imaging tests, again speaking to the value of combining diagnostic markers. FDG-PET scans found that in older people with APOE ε4, glucose metabolism in some brain regions may be reduced by nearly 20%. Another functional MRI study found that the brains of those with this genetic risk for AD actually work harder on memory tests to complete the same task.[14]


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