...and what Medical Science Can Do about It.
Last night, I headed down to the beautiful Bell House in the Gowanus section of Brooklyn, for this month's Secret Science Club lecture, featuring neurologist Dr Gregory Petsko of Weill Cornell Medical College and the Appel Alzheimer's Disease Research Institute. This lecture was sponsored by The Lasker Foundation.
Dr Petsko began his lecture by noting that his grandparents died while in their 50's, and noted that this was far from uncommon. In contrast, today, throughout much of Europe and in Japan, over 20% of the population is over the age of 65. In the year 2050, it is expected that this will be true throughout the world, except for Africa, where AIDS skews the numbers. Since the 19th Century, life expectancy has been increasing in a linear fashion. Dr Petsko noted that, in the time it would take to deliver his lecture, the average life expectency would increase by four minutes.
As life expectancy rises, fertility rates tend to decline. In societies in which the average life expectancy is over seventy, families have an average of two children. Currently, there are two billion children on the planet- Dr Petsko noted that the world may be at "peak children"- the number of children is likely to remain constant over the course of this century. The fastest growing demographic group on the planet is the over-eighty cohort. If current trends continue, there should be 31.6 million individuals over the age of eighty.
For the past 12,000 years, the assumption was that there would be more healthy young people than sick old people- Dr Petsko joked that life is a Ponzi scheme, the age "pyramid" will become unstable when there are as many "sick olds" as there are "healthy youngs". Dr Petsko offered three possible choices for this conundrum: global thermonuclear war, plague, or keeping elderly people healthy.
As individuals get older, their brains get smaller. Dr Petsko asked if this were a problem, and noted that we really don't know if it is. He then noted that aging individuals are at risk for three major neurodegenerative diseases: Alzheimer's disease, Parkinson's disease, and Lou Gehrig's disease.
There are over three-hundred thousand new Alzheimer's patients in the US yearly, with a new diagnosis occurring every seventeen seconds. Alzheimer's is inherited in classical Mendelian fashion. The average post-diagnosis lifespan of an Alzheimer's patient is twelve years, ten of them horrible. The incidence of neurodegenerative diseases is rising, and there are no effect treatments for them. Currently, there are approximately five million individuals with Alzheimer's disease in the US- by 2050, this number is projected to rise to thirteen million. Worldwide, this number is projected to hit 135 million by 2050. Dr Petsko noted that, if dementia were a country, it would dwarf Russia. The cost of caring for individuals with neurodegenerative diseases is approximately 250 billion dollars a year, while the annual NIH budget is approximately thirty million dollars. By 2050, the estimated cost for taking care of individuals with dementia will approximate one trillion dollars, while the GDP will be approximately seventeen trillion dollars. Unless there is a change in these statistics, this problem will bankrupt the country in forty years. For every neurodegenerative disease patient, there are an average of three caregivers- by the end of the century, there will be three billion caregivers by the end of the century.
Dr Petsko compared this to a comet about to hit the Earth. We know it's happening, we know when it's happening, but there's not enough money being spent to combat the problem. He noted that Alzheimer's spending is equal to AIDS spending, even though there are more Alzheimer's patients- he was quick to state that this is not an argument against AIDS spending. There was a request for two-and-a-half times more spending on Alzheimer's%, but this is still not enough. Since 2000, there has been a 99.8% failure rate for clinical trials for Alzheimer's treatment. Compared to research on cancer, Alzheimer's research lags by forty years- the medicine is equivalent to 1970s cancer medicine.
There are difficulties in the treatment of neurodegenerative diseases. Animal models are poor- lab animals don't live to their 80s, and animals don't have quite the same brain functions as humans. Not only are animal models poor- they may be irrelevant. The clinical trials for neurodegenerative diseases are poor- clinical trials are designed to fail, and there is a lack of understanding regarding who to include in clinical trials. It's unclear when to begin treatment for neurodegenerative diseases, and there are no objective clinical end points. The clinical trials tend to be based on cognitive ability, which is hard to define. Dr Petsko quipped that we can cure mice, but we can cure anything in mice. In order to conduct clinical trials, researchers need to use human neurons, not lab animals. He also noted that trial subjects should be individuals with a genetic predisposition to neurodegenerative diseases, not end-term patients. A good validation of human targets is needed, one using patient derived neurons. In one projected model
skin cells could be changed into stem cells which could be changed into neurons. Dr Petsko opined that not only must no stone remain unturned, but that new stones must be sought out and turned over.
Dr Petsko then shifted the topic to a history of Alzheimer's disease. In the early 20th century, German physician/psychiatrist Alois Alzheimer examined a patient named Auguste Deter, who exhibited early onset dementia while in her 50s. After Deter's death, Alzheimer examined her brain and detected "senile plaques", now known as amyloid plaques and tangles of what are now known to be misfolded and aggregated tau proteins. Alzheimer's examination of Deter's brain occurred before the science of genetics was understood- luckily, scientists located samples of Deter's brain cells recently and discovered a new mutation that is associated with early-onset Alzheimer's.
All neurodegenerative diseases are characterized by aggregates of misfolded proteins that mess up the brain's "machinery".
In the amyloid plagues, APP (amyloid beta precursor protein), which may play a role in the brain's development, is cut into peptides which aggregate and tangle. Most clinical trials have involved attempts to dissolve these plaques. Dr Petsko asked, what if the plaques are not the problem? What if the plaques are a "dumping ground" for the real problem? How can a disease be treated if the cause is unknown? If the protein aggregates are the problem, how can the "cutting" be stopped?
The inside of a neuron is crowded, Dr Petsko likened it to Times Square on New Year's Eve. In order to figure out treatments, "landmarks" must be found, once locations are located, trafficking procedures must be noted- traffic problems in the brain are responsible for Alzheimer's. Are proteins recycled or dumped? If proteins are dumped, they can become toxic waste? Continuing the sanitation metaphor, APP "bags" the proteins- proteins are recycled by the Golgi apparatus and they are dumped in the lysosomes. A suite of proteins known as retromer determines the balance of dumped proteins to recycled proteins. Too little retromer cause plaque accumulations. It is possible that boosting retromer levels could result in better cleanup. Individuals with a genetic predisposition to Alzheimer's have a mutation which affects retromer. Perhaps pharmacological "chaperoning" could make retromer more stable, chemical glue would bolster it- if retromer is not degraded, it builds up. A similar pharmacological approach is used to treat Fabry's disease. Retromer is a huge protein compex, the weak link in retromer is the protein Vps29.
A new drug has been developed to stabilize retromer, which results in plaque reduction in patient-derived neurons. The drug also reduces tangles in the neurons. Unfortunately, the drug is not safe enough to give to patients for the ten or so years that they would need to use it to combat Alzheimer's. Dr Petsko then asked, who do we conduct clinical trials on? He indicated that the drug which is too dangerous to administer long-term could be use to treat people with acute traumatic brain injuries, which also result in the buildup of plaques and tangles. He cited the case of NFL player Junior Seau, whose brain was characterized by the plaques and tangles typical of an 88 year-old. In the case of a traumatic brain injury, the experimental drug could be administered immediately after the injury.
Oddly enough, Alzheimer's patients tend to have reduced cancer risks while cancer patients tend to have reduced risk for Alzheimer's. Dr Petsko ruefully noted that cancer researchers and Alzheimer's researchers don't talk, with one exception- his own Weill Cornell Medical College.
Dr Petsko gave us some tips on reducing our risk of neurodegenerative disease. He indicated that caffeine may play a protective role. He told us to avoid head injuries- wear a helmet if you must. He told us to avoid bird flu, which may increase the risk of Parkinson's disease. He told us to eat more fish high in Omega-3 fatty acids, but to avoid fish with high mercury content, but put the burden of shopping for the right fish on us (here's where I note that my beloved purslane has a high Omega-3 content). He told us to keep our blood pressure low. He told us to stay mentally stimulated, to exercise regularly, and to support biomedical research. He then delivered a line from Macbeth Act 5, Scene 3: Canst thou not minister to a mind diseased? His answer was yes.
Dr Petsko noted that the history of medicine is the history of patients such as Auguste Deter. He mentioned Doug Whitney (PDF), a resident of Washington state whose family ,embers are typically beset by early onset Alzheimer's- one of out every two members of his family dies of Alzheimer's by the age of 55. He was found to have the same mutation that Auguste Deter had, but he doesn't have Alzheimer's at age 63- what protects him? Is there a way to beat Alzheimer's?
In the Q&A session, the Bastard was unable to get a question in- the house was packed for the night. The questions were really excellent though. Women are more likely to get Alzheimer's than men, but men are more likely to get Parkinson's and Lou Gehrig's diseases. Alzheimer's disease pathways are better understood than those of the other two big neurodegenerative diseases. Alzheimer's is primarily genetic, there are no known environmental factors, though Parkinson's risk may be increased by exposure to certain pesticides. At any rate, aluminum cookware is safe to use. As far as the retromer glue side effects, it caused death in lab animals- it's not terribly toxic, but each dose lingers in the body, and high doses are applied often. Regarding plaques in non-Alzheimer's patients- most people have plaques, but not tangles, some people have tangles but not plaques... at any rate some memory loss is normal with aging. Regarding the role of the glia, which don''t convey information like neurons, but provide structure, research is in its initial stages- Parkinson's might start in the glia, then spread to the neurons. We don't know where to look yet.
Here's a short video of Dr Petsko delivering a condensed version of his lecture:
Chug a beer while watching that, and you can capture some of the Secret Science Club magic, which is merely a sufficiently advanced technology.
Once again, the Secret Science Club dished out a fantastic lecture- here's a heartfelt show of gratitude to Dr Petsko, Margaret and Dorian, the Lasker Foundation, and the staff of the beautiful Bell House. Kudos to all.