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Targeting gene linked to Alzheimers may reduce dementia risk in Parkinsons

Clumps of the Parkinsons protein alpha-synuclein (red) are visible inside neurons (green) in the brain of a mouse. Researchers at Washington University School of Medicine in St. Louis have discovered that the genetic variant APOE4 long linked to dementia spurs the spread of harmful clumps of Parkinsons proteins through the brain. The findings suggest that therapies that target APOE might reduce the risk of dementia for people with Parkinsons disease.

Dementia is one of the most debilitating consequences of Parkinsons disease, a progressive neurological condition characterized by tremors, stiffness, slow movement and impaired balance. Eighty percent of people with Parkinsons develop dementia within 20 years of the diagnosis, and patients who carry a particular variant of the gene APOEare at especially high risk.

In new research, scientists at Washington University School of Medicine in St. Louis have found a clue to the link between Parkinsons, APOEand dementia. They discovered that harmful Parkinsons proteins spread more rapidly through the brains of mice that have the high-risk variant of APOE, and that memory and thinking skills deteriorate faster in people with Parkinsons who carry the variant. The findings, published Feb. 5 in Science Translational Medicine, could lead to therapies targeting APOEto slow or prevent cognitive decline in people with Parkinsons.

Dementia takes a huge toll on people with Parkinsons and their caregivers, said Albert (Gus) Davis, MD, PhD, an assistant professor of neurology and the studys lead author. The development of dementia is often what determines whether someone with Parkinsons is able to remain in their home or has to go into a nursing home.

An estimated 930,000 people in the U.S. live with Parkinsons. The disease is thought to be caused by toxic clumps of a protein called alpha-synuclein that build up in a part of the brain devoted to movement. The clumps damage and can kill brain cells.

Cognitive problems tend to arise many years after the motor symptoms. The protein clusters implicated in movement problems also are linked with dementia, but how this happens is not clear. Davis and his colleagues including senior author David Holtzman, MD, the Andrew B. and Gretchen P. Jones Professor and head of theDepartment of Neurology saw a clue in the risky nature of APOE.

A variant of APOE known as APOE4 raises the risk of Alzheimers disease threefold to fivefold. Like Parkinsons, Alzheimers is a neurodegenerative condition caused by the spread of toxic protein clusters throughout the brain, although some of the proteins involved are different. APOE4 increases the chance of Alzheimers dementia partly because it spurs Alzheimers proteins to collect into clumps that injure the brain. The researchers suspected that APOE4 similarly triggers the growth of toxic clusters of Parkinsons proteins.

Studying mice with a form of alpha-synuclein prone to clumping, Davis, Holtzman and colleagues genetically modified the mice to carry human variants of APOE APOE2, APOE3 or APOE4 or no APOE at all.

The researchers found that APOE4 mice had more alpha-synuclein clusters than APOE3 orAPOE2mice. Further experiments showed that the clumps spread more widely in APOE4 mice as well. Together, the findings showed that APOE4 was directly involved in exacerbating signs of disease in the mices brains.

What really stood out is how much less affected the APOE2 mice were than the others, Davis said. It actually may have a protective effect, and we are investigating this now. If we do find that APOE2 is protective, we might be able to use that information to design therapies to reduce the risk of dementia.

To study the effect of APOEvariants on dementia in people with Parkinsons, the researchers analyzed publicly available data from three separate sets of people with Parkinsons. Two of the cohorts one from the Parkinsons Progression Markers Initiative, with 251 patients, and the other from the Washington University Movement Disorders Center, with 170 patients had been followed for several years. In both cohorts, cognitive skills declined faster in people with APOE4 than in those with APOE3. People with two copies of APOE2 are very rare, but none of the three patients in the group with two copies of APOE2showed any cognitive decline over the period of the study.

The third cohort, fromthe NeuroGenetics Research Consortium, was made up of 1,030 people with Parkinsons whose cognitive skills had been evaluated just once. The researchers found that people with APOE4 in the cohorthad developed cognitive problems at a younger age and had more severe cognitive deficits at the time they were evaluated than people with APOE3 or APOE2.

Parkinsons is the most common, but there are other, rarer diseases that also are caused by alpha-synuclein aggregation and also have very limited treatment options, Davis said. Targeting APOE with therapeutics might be a way to change the course of such diseases.

APOE doesnt affect the overall risk of developing Parkinsons or how quickly movement symptoms worsen, so an APOE-targeted therapy might stave off dementia without doing anything for the other symptoms. Even so, it could be beneficial, Davis said.

Once people with Parkinsons develop dementia, the financial and emotional costs to them and their families are just enormous, Davis said. If we can reduce their risk of dementia, we could dramatically improve their quality of life.

Davis AA, Inman CE, Wargel ZM, Dube U, Freeberg BM, Galluppi A, Haines JN, Dhavale DD, Miller R, Choudhury FA, Sullivan PM, Cruchaga C, Perlmutter JS, Ulrich JD, Benitez BA, Kotzbauer PT, Holtzman DM. APOE Genotype Regulates Pathology and Disease Progression in Synucleinopathy. Science Translational Medicine. Feb. 5, 2020. DOI: 10.1126/scitranslmed.aay3069

This work was supported by an American Academy of Neurology/American Brain Foundation (Clinical Research Training Fellowship); the BrightFocus Foundation; the Mary E. Groff Charitable Trust; the Dobbins Family Fund; the Foundation for Barnes-Jewish Hospital (Elliot Stein Family Fund); the Riney Foundation; the American Parkinson Disease Association; the Greater St. Louis Chapter of the American Parkinson Disease Association; The JPB Foundation; and the National Institutes of Health (NIH), grant numbers K08NS101118, R01AG044546, RF1AG053303, RF1AG058501, U01AG052411, U01AG058922, NS075321, NS097799, R01NS090934 and R01AG047644.

Washington University School of Medicines 1,500 faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Childrens hospitals. The School of Medicine is a leader in medical research, teaching and patient care, ranking among the top 10 medical schools in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Childrens hospitals, the School of Medicine is linked to BJC HealthCare.

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Gene ID'd as potential therapeutic target for dementia in Parkinson's - Washington University School of Medicine in St. Louis