Alzheimer’s Isn’t That Simple: The theories keep coming but the cures remain elusive
“Don’t you know what day it is, dear?” The elderly woman smiled sweetly as she leaned forward and attempted to respond with a joke to the question during the mental status exam. It was her go-to response when she couldn’t remember the city where she lived, the building we were in or the year, date, or month of the year.
One of the hundreds of men and women in a national clinical trial for a new treatment for Alzheimer’s disease, she would use humor to cover dementia. Her response to the examiner’s blank look was a laugh. Still able to engage socially, she had made the cut to become a subject. But the disease was relentless and her memory was failing worse now.
Not every patient was capable of humor. One woman, a former professor, scowled and responded to each question with the same line from a poem she’d learned as a child. “Mary had a little lamb…” she’d fairly shout as the testing intensified her frustration and anger. It was useless. She couldn’t meet the exam cutoff score and would be sent for evaluation for another clinical protocol testing corn oil supplements.
Our research was based on a medication formerly used to treat pinworms at the turn of the 20th Century. The clinical trial’s target was an acetylcholinesterase inhibitor, an enzyme involved in breaking down the neurotransmitter that maintains communication between brain cells and, theoretically, memory.
The repurposing of old meds for new research had been shown to have some efficacy by one researcher in an Alzheimer’s patients’ sample. Now it would be tried all over the United States by the titans in that disease research.
Maintaining acetylcholine levels by inhibiting this enzyme might spare memory. But Alzheimer’s proved finding the key wasn’t that simple.
Small changes were noted in social interactions, but the medication failed to meet researchers’ expectations in halting the march of Alzheimer’s into dementia and death. Neither pills nor applications via the nose worked.
Stemming the Tide of Alzheimer’s
The graying of America makes finding medications for Alzheimer’s all that more important. It’s been called the silver tsunami, and it will overwhelm the healthcare profession and the purse of nations around the world.
What theories have been explored, and what have they garnered in terms of benefit to the patients? The efforts have included:
- plaques and tangles theory: Although it has been assumed that senile plaques and neurofibrillary tangles are hallmarks of Alzheimer’s disease, their involvement remains in contention. Questions include a) the relationship between the lesions and the degree of dementia, b) if the tangles are related to the senile plaques, and c) what is the link of the plaques and tangles to the pathogenesis of Alzheimer’s. To date, the search goes on as new theories continue to be offered.
- tau is a protein most associated with the formation of microtubules that provide brain cells with nutrients. However, for unknown reasons, tau can collapse into tangles, thereby making the microtubules unable to provide the essential nutrients and eventually leading to cell death
- glucose metabolism via the brain’s mitochondria. “…a number of mitochondrial-dependent functions are found to be impaired during aging and AD.”
- brain enhancers — a new approach to finding the genesis of brain degeneration in Alzheimer’s is proposed by a team led by Dr. Vivienne Labrie, who indicated that in the brain there are “genetic volume dials” called enhancers. These enhancers, which would normally be dormant in the adult brain, become overactive “in a suite of genes involved in Alzheimer’s pathology in brain cells, spurring the formation of plaques and tangles and reactivating the cell cycle in fully formed cells — a highly toxic combination.”
Worldwide various groups have estimated that 44 million people now are living with Alzheimer’s or a form related to it. The United States has approximately 5.5 million people with Alzheimer’s (AD), and most of them are over the age of 65.
However, younger persons can also develop Alzheimer’s, and perhaps 200,000 people under 65 now have the disease. Dominant primarily in women, possibly because of hormonal involvement, the statistics indicate 3.3 million women age 65 and older have Alzheimer’s and 2 million men.
“Reports from the National Institute on Aging indicate that the prevalence of Alzheimer’s disease doubles every five years beyond the age of 65. As the population ages, the disease impacts a greater percentage of people. At present, someone in the US develops Alzheimer’s disease every 66 seconds. It is thought that by the middle of the century, someone in the US will develop the disease every 33 seconds, and the total number of people with Alzheimer’s disease in the US could rise to as high as 16 million people by 2050.”
At present, Alzheimer’s is the sixth-leading cause of death in the US. It is an illness with a life expectancy of 4 to 8 years and may begin before full-blown symptoms are evident.
A Potential Ray of Hope
The Massachusetts Institute of Technology has developed an AI (artificial intelligence) model, which they believe can be used to evaluate and create drug treatments as well as identifying cognitive decline in Alzheimer’s patients two years before they show symptoms.
“Accurate prediction of cognitive decline from 6 to 24 months is critical to designing clinical trials,” says Oggi Rudovic, a Media Lab researcher. “Being able to accurately predict future cognitive changes can reduce the number of visits the participant has to make, which can be expensive and time-consuming. Apart from helping develop a useful drug, the goal is to help reduce the costs of clinical trials to make them more affordable and done on larger scales.”
A database comprising of 1,700 participants in Alzheimer’s clinical trials was used to develop the new model and instrument. Not only were cognitive tests used, but the database also included MRI scans, demographic and genetic information, and cerebrospinal fluid measurements.
The next phase in the research study, which MIT is planning, will implement new clinical trials in real-world situations along with pharmaceutical firms. It is hoped that the model can be generalized not only for Alzheimer’s but other diseases as well.
AI may provide both the speed and the rapid exploratory datasets needed, which are currently being assessed on a trial-and-error basis, one theory at a time.