Cell Death and Membrane Disruption

ApoE4 also has adverse effects on cell membranes. When neuronal cells were treated with aggregated Aß, Gladstone scientists found much more lysosomal leakage and cell death in apoE4- than in apoE3-expressing cells. Cell death or apoptosis required apoE inside the cell. In other studies with artificial phospholipid bilayer vesicles, the scientists noted that apoE4 disrupted the vesicles to a greater extent than apoE3.

These findings are consistent with the notion that apoE4 exists in a molten globule state that avidly binds phospholipid and may insert into the lysosomal membrane, destabilizing it and causing lysosomal leakage and apoptosis in response to Aß.

AD: Facts and Figures An estimated 4.5 million Americans have AD. One in 10 persons over 65 and nearly half of those over 85 have AD. A small percentage of people as young as their 20s and 30s get the disease. A person with AD will live an average of eight years and as many as 20 years or more from the onset of symptoms. U.S. society spends at least $100 billion a year on AD. Neither Medicare nor most private health insurance covers the long-term care most patients need. More than 7 of 10 people with AD live at home. Almost 75% of the home care is provided by family and friends. The remainder is “paid” care costing an average of $12,500 per year. Families pay almost all of that out-of-pocket. Half of all nursing home residents suffer from AD or a related disorder. The average cost for nursing home care is $42,000 per year but can exceed $70,000 per year in some areas of the country. The average lifetime cost per patient is $174,000. Source: The Alzheimer’s Association. Toxic ApoE Fragments In recent studies, Gladstone researchers demonstrated that proteolytic processing of apoE4 may be an important mechanism in AD. Fragments of apoE, truncated at the carboxyl terminus, were found in cultured neurons and in the brains of patients with AD. These truncated fragments induce the formation of intracellular neurofibrillary tangles—a pathological hallmark of AD—and result in neurodegeneration. The apoE4 fragments caused neurofibrillary tangle–like inclusions in up to 75% of transfected neuronal cells, but not in nonneuronal cells. Significantly, apoE4 was much more susceptible to fragmentation than apoE3. Further studies at Gladstone have shown that the enzyme that produces the apoE fragments is a chymotrypsin-like serine protease. This apoE cleavage enzyme is a potential target for drugs aimed at preventing or reversing AD. Converting ApoE4 to ApoE3 The structural differences between apoE3 and apoE4 suggest an intriguing strategy for developing AD therapies: convert apoE4 into a molecule that more closely resembles apoE3. For example, perhaps a small drug could be found that would bind to apoE4 to block the domain interaction. The resulting apoE4-drug complex might assume more of the beneficial characteristitcs of apoE3. Gladstone scientists are aggressively pursuing this approach. Conclusion Although the exact involvement of apoE in the pathogenisis of AD remains unknown, there is little doubt that this protein is a major part of the problem and of the solution. Research at Gladstone is racing ahead to define that role. "As the baby-boom generation ages, more and more people will know first hand the tragedy of Alzheimer's," said Dr. Mucke. "Fortunately, the pace of scientific discovery in this area is increasing rapidly, and that gives me great hope for the future."

Symptoms of AD The symptoms of AD worsen over time. How fast the disease progresses varies from person to person. Various scales are used to measure the progression of symptoms. For general purposes, three broad stages of AD are typically recognized : mild, moderate, and severe. The stages may overlap, and AD patients may not experience all of these symptoms. AD Symptoms by Stage of Disease Mild Symptoms Confusion and memory loss Disorientation; getting lost in familiar surroundings Problems with routine tasks Changes in personality and judgment Moderate Symptoms Difficulty with activities of daily living, such as eating and bathing Anxiety, suspiciousness, agitation Sleep disturbances Wandering, pacing Difficulty recognizing family and friends Severe Symptoms Loss of speech Loss of appetite; weight loss Loss of bladder and bowel control Total dependence on caregiver Source: Gwyther LP. Care of Alzheimer's Patients: A Manual for Nursing Home Staff, Chicago: AHCA and AA, 1985

The Silent Epidemic The Alzheimer’s Association has identified an emerging public health crisis among African-Americans: a silent epidemic of AD. Among the findings from the research highlighted in the report: Alzheimer’s disease is more prevalent among African-Americans than among Caucasians, with estimates ranging from 14% to almost 100% higher. There is a greater familial risk of AD among African-Americans. Genetic and environmental factors may work differently to cause AD in African-Americans. A growing body of evidence suggests that vascular disease may contribute to or mimic AD. Data from longitudinal studies suggest that high cholesterol and high blood pressure may be significant risk factors for AD. The implications of these discoveries are enormous for African-Americans, among whom vascular disease and its risk factors are disproportionately present. Effective therapies for primary and secondary prevention of vascular disease already exist, including cholesterol-lowering drugs (statins) and antihypertensive medications. Now, observational studies indicate that these drugs may also protect against cognitive impairment and AD. Source: African-Americans and Alzheimer’s Disease: The Silent Epidemic. [www.alz.org]