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"Alzheimer Gene" Increases Risk of Lewy Body Dementias

Lewy body disease is the underlying biological process in the brain associated with Lewy body dementia and Parkinson’s disease. While Lewy body disease can exist in a "pure" form with little or no co-existing Alzheimer’s disease, at least half of individuals with Lewy body disease also have significant amounts of Alzheimer’s pathology.

Until now, research has not revealed why people can possess the pathological hallmarks of one or both diseases. However, a new study has revealed that a genetic variant previously known to increase the risk of developing both early-onset and late-onset Alzheimer’s disease is also a risk factor for Lewy body dementias.

The study, led by Debby Tsuang, M.D., Professor of Psychiatry and Behavioral Sciences at the University of Washington and Veterans Affairs Puget Sound Health Care System (VAPSHCS), included 640 people with dementia and 269 healthy individuals and included autopsies on all participants. Clinical and neuropathological assessments resulted in the following dementia categorizations:

Category No. of People
Parkinson’s Disease Dementia (PDD) 81
Pure Dementia with Lewy Bodies (pDLB) 91
Co-existing Alzheimer’s Disease and Lewy Body Disease (LBD-AD) 224
Alzheimer’s Disease (AD) 244
Healthy Controls 269

After adjusting for age and sex, and using the healthy controls as a reference group, the APOE variant was strongly associated with all four forms of dementia:

  • 10-fold increase in the risk of pure Alzheimer’s
  • 13-fold increase in the risk of Alzheimer’s with Lewy bodies
  • 6-fold increase in the risk of pure Lewy body dementia
  • 3-fold increase in the risk of Parkinson’s dementia

Senior author Cyrus P. Zabetian, M.D., Associate Professor of Neurology at the University of Washington and VAPSHCS stated, “APOE ɛ4 is the first genetic risk factor we know of that is shared among AD, pure DLB, and PDD. That indicates that these three diseases might also share some of the same root causes. If this proves to be true, it gives us hope that future therapies aimed at one of these diseases could be effective in treating the others.”

While the APOE variant is a well-established risk factor for Alzheimer’s disease, analysis showed an association between pDLB and PDD which was unexpected. In humans this variant is thought to accelerate the accumulation of amyloid protein. Toxic buildup of amyloid ultimately leads to the development of Alzheimer’s "plaques" and neurodegeneration. In this study, however, the absence of Alzheimer’s pathology in individuals with Lewy body disease indicates the possibility that this genetic variant may influence neurodegeneration through other pathways.

Another implication of the study is that APOE might play a role in determining whether someone with Lewy body disease is diagnosed with DLB or PDD. DLB is diagnosed when dementia occurs before or concurrently with parkinsonism, whereas in PDD, parkinsonism precedes dementia by at least one year. Findings from the study suggest that individuals with Lewy body disease who have the APOE variant are more likely to experience dementia first and thus to be diagnosed with DLB rather than PDD.

Members of LBDA’s Scientific Advisory Council who collaborated on this study include Debby Tsuang, M.D., James B. Leverenz, M.D., Oscar Lopez, M.D., Daniel Weintraub, M.D., Doug Galasko, M.D., and Cyrus P. Zabetian, M.D. The study was first published online on November 19, 2012 in Archives of Neurology and was funded by grants from the Department of Veteran’s Affairs and the National Institutes of Health.