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March 11, 2004

Loss of Smell Linked to Key Protein in Alzheimer’s Disease, New Penn Study Shows
First signal of disease could provide future test for early stages of neurodegenerative illnesses

(Philadelphia, PA) - Researchers at the University of Pennsylvania School of Medicine have linked smell loss in mice with excessive levels of a key protein associated with Alzheimer’s and Parkinson’s disease. Smell loss is well documented as one of the early and first clinical signs of such diseases. If smell function declines as the levels of this protein increase in brain regions associated with smelling, the research could validate the use of smell tests for diagnosing Alzheimer’s disease. Their findings appear in the March 12th issue of the journal Brain Research, the commemorative volume 1000.

“The loss of smell - or olfactory dysfunction - has been known for more than a decade as an early sign of several neurodegenerative diseases, but we have never been able to link it to a pathological entity that is measurable over time,” said Richard Doty, PhD, Professor and Director of Penn’s Smell and Taste Center, who is also the team leader of the study. “By tying decrements in the ability to smell to the presence of key disease proteins, such as tau, we may well be able to assess the degree of progression of selected elements of Alzheimer’s disease and related disorders by scores on quantitative smell tests.”

A total of ten mice were evaluated in this experiment - five mice that were genetically engineered to be a model for human Alzheimer’s and Parkinson’s disease, and five normal control mice that do not overexpress tau proteins. Olfactory dysfunction was evaluated by measuring the amount of time the mice spent investigating unfamiliar odors, such as peppermint or vanillin. Unlike normal mice, those with smell deficits do not spend much time investigating such odors, and do not show a preference for “novel” odors over “familiar” odors.

The results of the Penn study showed that only the control mice, with no excess of tau proteins, expressed an interest in new odors, indicating a normal sense of smell. The mice that had excess in tau protein showed little or no interest in such odors, implying olfactory dysfunction. Analysis of brain tissue from the diseased mice confirmed a link between the olfactory loss and the presence of excess tau proteins in brain structures important for smelling. Additionally, the genetically engineered mice exhibited a significant amount of neurofibrillary tangles, structures also linked to Alzheimer’s disease.

No test currently exists for the detection of Alzheimer’s disease. A definitive diagnosis is only confirmed upon death when the brain tissue becomes available for testing of the presence of such proteins and other physiological markers of the disease.

The process for diagnosis before death is less certain and involves several kinds of tests - for memory, problem solving, attention and counting - plus review of a patient’s complete medical history from a primary care physician, and possibly brain scans and consultations from other specialists. With several diagnostic tools and criteria, physicians can make a diagnosis of moderate to severe stages of Alzheimer's disease with 90 percent accuracy. However, diagnosis is less certain for the early stages of the illness.

No explanation exists for what causes the alterations in smell perception associated with neurodegenerative disorders. What is known is that key physiological markers for these illnesses - deposits of neurofibrillary tangles or amyloid plaques, Lewy bodies or tau and alpha-synuclein proteins - are commonly found in brain regions associated with the perception of odors in the bodies of people who suffer from these illnesses.

“The mice who overexpress tau, a protein associated with a family of neurological disorders that includes Alzheimer’s disease and Parkinson’s disease, have decreased ability to smell,” said Doty. “We next plan to study the progression of the disease entities in the brain as it relates to smell dysfunction. These experiments are part and parcel to better understanding the physical causes of such neurodegenerative diseases.”

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PENN Medicine is a $2.5 billion enterprise dedicated to the related missions of medical education, biomedical research, and high-quality patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System (created in 1993 as the nation’s first integrated academic health system).

Penn’s School of Medicine is ranked #2 in the nation for receipt of NIH research funds; and ranked #4 in the nation in U.S. News & World Report’s most recent ranking of top research-oriented medical schools. Supporting 1,400 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.

Penn Health System consists of four hospitals (including its flagship Hospital of the University of Pennsylvania, consistently rated one of the nation’s “Honor Roll” hospitals by U.S. News & World Report), a faculty practice plan, a primary-care provider network, three multispecialty satellite facilities, and home health care and hospice.



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