Alzheimer's Disease: Realizing the Promise of Molecular Medicine
Description: In 1906, when Alois Alzheimer first described the disease that bears his name, it was a rarity; life expectancy in the US was around 50 years, and few people lived long enough to develop Alzheimer's disease (AD). But as life expectancies have risen around the world, AD has become vastly more prevalent, and it is now one of the major public health problems of our time. In this lecture, Steven Paul, former Executive Vice President at Lilly, reviews our current understanding of the pathological mechanisms and implications for future treatments of this disease.
People with AD experience a progressive loss of memory and other cognitive abilities, the result of slow degeneration within the brain. Postmortem examination of patients' brains reveals myriad deposits known as amyloid plaques and neurofibrillary tangles, especially within the forebrain areas that underlie memory and higher cognitive functions.
The behavioral signs of AD usually appear in the 70's or later, and the risk of the disease rises sharply with age. But it now thought that the pathological process begins many years earlier, before the condition is diagnosed. The aim of therapy, Paul argues, should be to slow the process and thus delay onset of symptoms; even a five"year delay in onset would reduce the prevalence of the disease by 50%, a huge public benefit.
Clues to the mechanisms that may cause AD have come from genetic studies, especially of rare early"onset cases. These cases are caused by mutations in any of several genes, all of which lead to increased production of a peptide known as Abeta42 (A_42), the major component of amyloid plaques.
But these mutations are rare and cannot account for most cases of AD. By far the most important genetic risk factor is a gene known as ApoE, of which there are three common variants in the human population. The variant known as ApoE4 increases risk, especially in people who inherit two copies. The ApoE3 variant is intermediate, and the ApoE2 version has the lowest risk.
Paul and his colleagues were able to replicate this effect in transgenic mice genetically engineered to develop AD, and to express one or more of the human ApoE variants that either worsen or alleviate the disease. Their results support the idea that the protective E2 version of the protein is expressed at higher levels than the other versions, and that raising the expression of the gene in humans might be beneficial. Lilly has developed a compound that does this, and which is currently being tested in mice.
The ApoE protein is involved in cholesterol transport within the blood, but its role in the brain is less well understood. Paul presents evidence that ApoE works in microglial cells to clear A_42 from the brain before it can accumulate to form damaging plaques.
Paul ends his talk by discussing what these insights may mean for the prospects of new therapies. By the time a person is diagnosed with AD, the accumulation of Abeta may already be complete. So even if a therapy could prevent such accumulation, it may be too late to be effective. Instead, Paul argues, we need biomarkers that predict at an earlier age who is at risk for the disease, and then treat these people preventatively -- perhaps in their 50s or earlier, as is done with statins for cholesterol and cardiovascular disease. He is optimistic that current research will lead to strong predictive biomarkers; the main challenge now is to develop drugs that can be given safely over long periods to prevent the accumulation of Abeta aggregates within the brain.
About the Speaker(s): Steven Paul has more than 17 years of management experience in the pharmaceuticals industry and 35 years of scientific research experience. He retired in February 2010 as Executive Vice President for Science and Technology and President of the Lilly Research Laboratories of Eli Lilly and Company, a position he held since June 2003. He joined Lilly in April 1993 and served in roles of increasing responsibility within the Lilly research environment. Prior to joining Lilly, Dr. Paul served as Scientific Director of the National Institute of Mental Health. Dr. Paul has authored or coauthored more than 450 papers and serves on the editorial boards of numerous scientific journals and as a grant reviewer for several extramural and intramural committees. He is the recipient of many honors and scientific recognitions; in 1997, Paul was elected to membership in the Institute of Medicine of the National Academy of Sciences. He has been listed as one of the most highly cited neuroscientists in the world (1980"2000) by the Institute for Scientific Information in Philadelphia.
Host(s): School of Science, McGovern Institute for Brain Research at MIT
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