Richard Isaacson’s Plan to Defeat Alzheimer’s Disease
Last December, a neurologist called Richard Isaacson presented a clinical case study at a medical conference. The patient — male, 52 years old — presented signs of mild cognitive impairment. A PET scan had confirmed the presence of amyloid plaque in his brain — these are clumps of proteins whose build-up in the brain affects neuronal function and a tell-tale sign of Alzheimer’s disease. Genetic tests detected a copy of apolipoprotein epsilon-4 (commonly known as as APOE4), a gene associated with late-onset Alzheimer’s. One copy of APOE4 roughly doubles the relative risk of contracting the disease.
This patient also had high cholesterol and had been taking statins over twenty years. “APOE4 plus the statins: oh oh.” Isaacson says. “I’m pro-statin but it’s not for everybody”. According to Isaacson, statins reduce the levels of desmosterol, a percursor of cholesterol, in the brain and studies have shown that low levels of this molecule affect cognition. Furthermore, whole genome sequencing also found a problem with the PCSK9 gene — “a weird gene issue that I’d never seen before”.
Isaacson’s treatment plan involved replacing the statins with Zetia, a plant sterol, and a PCKS9 inhibitor, a new class of drugs that lowers cholesterol.
After six months, Isaacson reported, the patient’s cognitive test scores improved.
One year later, he no longer presented any symptoms. “He still has amyloid in his brain, but he’s preclinical Alzheimer's, meaning he had no cognitive complaints.”
This was unprecedented: a patient in the early stages of Alzheimer’s disease turning back the clock on the typically inexorable cognitive decline that characterises the disease. A case so implausible that a few in the audience thought it impossible. “The director of their brain health centre came to me after my talk and says, ‘If he's gotten better, by definition, it's not Alzheimer's, because there is nothing that improves Alzheimer’s’,” Isaacson says. “That’s how backwards the dogma is.”
This is a dogma that he has been fighting all his life. Isaacson’s first contact with the disease happened around the time he started medical school at Harvard and his great-uncle Bob got diagnosed. Isaacson was shocked by how the disease steadily reduced his once lively and gregarious relative to an individual a shadow of his former persona, unable to even take care of himself. This encounter with Alzheimer’s forged Isaacson’s career path. He was adamant he was going to find a way to treat these patients.
Later, as an associate professor of clinical neurology at the university of Miami, he gained a reputation for the zealous care he took with all his patients: when they were discharged, he would always print out a pamphlet of fifteen pages — frequently jamming the printer in the neurology department as a result— with detailed and bespoke plans on nutrition, supplements, lifestyle, exercise, and medication.
These pamphlets eventually became a book, published in 2012, titled “Alzheimer’s Treatment Alzheimer’s Prevention”. The title itself attracted much criticism: the Alzheimer’s Association warned him that he couldn’t use the word “prevention”; clinicians questioned his integrity; his own departmental colleagues wrote scathing reviews.
The hostile reception led him to realise that what he needed to conduct large-scale clinical trials to prove beyond a doubt that his interventions worked in a real-life setting. For that, he would need the backing of a large medical research institution. However, most medical institutions he applied to rejected the idea of launching an Alzheimer’s prevention clinic, on the basis that Alzheimer’s and prevention didn’t belong in the sentence.
The exception was Cornell. There he was given fifteen minutes with the Dean to argue his case. Isaacson, who had prepared intensely for that moment, listed all the reasons why she should back his idea: because contrary to common assumption, Alzheimer’s disease actually started decades before first symptoms appear; because new diagnostic tools could detect those early signs; because something could be done in that window of time before the damage was irreversible. She was persuaded and, in 2013, the Alzheimer's Prevention Clinic at NewYork-Presbyterian and Weill Cornell Medical Center was founded. It was the first of its kind in the world.
At Isaacson’s clinic, clients typically undergo a battery of physical, from body composition to blood-based biomarkers, and mental examinations, along with extensive questionnaires on medical history, family history and behaviour. MRI scans checked for early signs of amyloid plaque buildup, and computer-based apps were used to detect pre-symptomatic signs of the disease. On the basis of this extensive assessment, Isaacson prescribed personalised treatments.
In 2019, he published a breakthrough study that showed that his personalised lifestyle interventions not only stopped cognitive decline in people at risk for Alzheimer’s, but actually improved their cognitive skills. “We give people an average of twenty-one different interventions based on the data,” he says. These include keeping blood sugar and weight in check, managing bad stress and avoiding high levels of homocysteine, an amino acid that can damage arteries. “Everyone gets something different. People get better and they have better cognitive function. That never actually been shown before. I believe at least one out of every three cases of Alzheimer's may be preventable.”
In early 2020, plans for further clinical trials were put on hold, as the Covid pandemic hit the United States. “Suddenly we couldn’t see patients in person,” Isaacson says. “So we decided to go deeper instead, and started taking a deeper genetic dive at the patients.” His team performed whole genome sequencing on a cohort of twenty-five patients. Isaacson was patient number one. TV celebrity doctor Dr. Oz was patient number 25.
Isaacson’s whole genome sequencing allowed him to look deeper into factors like mitochondrial genomics and different combinations of the APOE genes. In nearly half his cohort of twenty-five, he managed to find something in the genetic code that lead to change in the initial treatment plan. His first successful outcome was the 52-year old male patient. Others followed. “It was crazy,” he said. “You got to be really careful when you say stuff like this, because I don't want people to get too excited but I'm seeing this over and over: what we do can actually work.”
In spite of this successful experiment, Isaacson doesn’t believe there’s a future in whole genome sequencing when it comes to treating Alzheimer’s. “It’s too much, it’s hard and expensive,” he says. “It took $60,000 of personnel time and genomic sequencing to figure this stuff out and a lot of times, we do all the sequencing and we find nothing.” However, the study did give him enough data to confirm that a small subset of genetic information — about the APOE genes and the MTFHR gene (which codes for an enzyme that breaks down homocysteine) — should suffice to inform most clinical care. “The genetics is gravy,” he says. “Forty percent of the time, it gives us extra tools in the toolbox.”
Last November, Isaacson returned to Florida to build a new Alzheimer’s Prevention Clinic from scratch, at the Center for Brain Health at Florida Atlantic University. The centre plans to begin seeing patients by July. Alongside the usual battery of tests, every six months patients will be also be monitored blood-based biomarkers amyloid plaque and serum tau, a protein that in the brain of Alzheimer’s patients is found to be mishappen. “These are the best biomarkers to track,” Isaacson says. “I’m hoping to democratise Alzheimer's prevention, in a precision-medicine way, through blood-based testing. Within a couple of years, I will be able to show whether we're truly preventing Alzheimer's or that all this was a sham and I was just improving vascular cognitive health. I will be the first to admit it if I was wrong.”