Wilhelm Conrad Rontgen didn’t mean to discover the X-ray. Wilson Greatbatch made a mistake that created the first pacemaker.
And in the early 2000s, Suzanne de la Monte knocked out the insulin
receptor function in the brain with a “serendipitous” result: “I was
like, ‘Oh my gosh, this made Alzheimer’s,’” she said.
Prevailing theories at the time attributed Alzheimer’s disease — a
non-reversible neurodegenerative condition that causes dementia — to
“plaques and tangles,” the clumping of two different substances within
and between brain cells that interrupt function and cognition and
ultimately leads to cell, and human, death.
But de la Monte, professor of pathology and laboratory medicine and
neurology at Brown University, and her discovery fueled the emerging
idea that metabolic changes — ones strikingly similar to both Type 1 and
Type 2 diabetes — cause Alzheimer’s. And in 2005, she gave this concept
a name that raised eyebrows in the scientific community: Type 3 diabetes.
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Such a realization could have catapulted the field forward — and
maybe it did. But nearly two decades later, Alzheimer’s disease is still
a formidable foe as the seventh leading cause of death in the U.S., with 6.7 million Americans currently living with the disease and 132 million people around the world projected to join them by 2050.
Research — and treatment options — across the board remain relatively
rudimentary for Alzheimer’s dementia, with doctors doing their best to
help patients with what’s available while staring down a hefty body of
related research whose clinical applicability is still limited.
And it frustrates them.
“People who believe in plaque, they try to show that [plaque] causes
all of this. And [tangles] cause all of that. But if that’s the case,
then why are there no drugs that work?” de la Monte said. “They don’t.
You still die with Alzheimer’s disease.”
Lukewarm reception
De la Monte laughed when asked how her “Type 3 diabetes” concept was first received.
“That was funny. Some were like, ‘What are you talking about?’” she
said. “I thought, ‘That’s fine. There’s no reason to shove it down your
throat. It’ll be shown sooner or later as clearly correct.’”
The theory goes like this. Type 1 diabetes is due to a lack of
sufficient insulin, which prevents adequate glucose (otherwise discussed
as “sugar” or “energy”) from reaching cells. Type 2 diabetes is due to
cells that aren’t sensitive enough to the effects of insulin (and
therefore energy) as they should be. Both lead to excess glucose in the
bloodstream, which can harm cells and nerves and results in starving
cells.
According to de la Monte, all of those mechanisms are present in the
brains of those with Alzheimer’s, along with tangles and plaques and
other differences, making Type 3 diabetes an appropriate moniker for the
mechanism behind Alzheimer’s.
Maxim Hammer, St. Clair Health chief of neurology, was a resident back in 2005.
“My first reaction was, ‘Here’s another correlation study of one
disease with another. There are so many of these published constantly,
and most of them are clinically meaningless,’” he said.
Then, he waited for more research to link metabolic habits of diabetes with dementia diagnoses.
He — and the rest of the world — got it.
“Since that time, there’s been a great volume of literature published
that consistently reproduces this tight correlation,” he said. “Now,
it’s different.”
Now it’s well understood that diabetes, and/or high blood sugar, is
closely correlated to cognitive impairment and dementia. Insulin
resistance has a handful of known causes and is linked to cognitive
decline. And it’s known that diabetes confers a 1.25- to 1.91-fold increased risk for cognitive impairment and dementia.
De la Monte describes herself as “pretty humble,” but she’s noticed
the philosophical shift toward what she always knew was “clearly
correct.”
“Now, every time I’m reading a new study, it’s talking about
metabolism in Alzheimer’s disease,” she said. “It’s kind of refreshing.”
Refreshing, not practical
Alois Alzheimer, a clinical psychiatrist and neuroanatomist, first
described the disease in 1906. In 1997, the first paper was published
identifying Alzheimer’s as a metabolic disorder of the brain.
De la Monte gave that mechanism a name 99 years after the disease was
first recognized. And despite the swath of other research and
researchers, much of it still belongs to the realm of science rather
than clinical practice.
“Even though we’ve learned a lot about Alzheimer’s in the past 50 to
100 years, I think closer to the truth is we’re still looking at the tip
of an iceberg, where we have this disease that remains largely a
puzzle,” Hammer said. “Alzheimer’s seems to be the result of many
different types of pathologies that lead to it, including diabetes and
insulin resistance, but not exclusively diabetes and insulin
resistance.”
It’s also not only “plaques and tangles,” as they’ve been found in
varying degrees within the brains of Alzheimer’s patients but are also
present in cases of frontotemporal dementia and Parkinson’s disease,
making them an inspecific identifier of the disease.
“Clinically, knowing that we don’t yet fully understand what’s going
on with the disease itself, it becomes very difficult to use the little
we have to inform our patients,” Hammer said. “What can we do today in
2023? We can definitely focus on medical health,” the health of the
whole patient, “to try and slow the progression of Alzheimer’s.”
Use what you (will) have
De la Monte likens the mixed reactions to “Type 3 diabetes” to when a
bacterium was first proposed as a cause of stomach ulcers.
“People were treating ulcers with Mylanta and stuff like that. Then,
some guy,” Barry James Marshall in 1982, “came along and said, ‘This is H. pylori. This is a bug,’” de la Monte said. “That guy was basically shouted out of a meeting, then was finally proven to be correct.”
The analogy ends there, though. While Helicobacter pylori — which can
cause stomach ulcers and gastritis — is now treated with antibiotics,
clinicians struggle to treat Alzheimer’s with satisfying results, which
is why physicians like Hammer focus on the overall medical health of
patients to give them the most longevity while fighting Alzheimer’s.
Supported by research
that shows exercise can decrease the likelihood of dementia, and other
studies that demonstrate potential value for those already diagnosed, he
focuses on cardiovascular exercise, calling it “one of the most potent
treatments” for the disease, though few patients heed those
recommendations.
He also keeps a close eye on patients’ lipid profiles, specifically
low-density lipoprotein (also called LDL, or “bad” cholesterol).
“There’s a very tight relationship between LDL and cognitive impairment that remains a little bit under-explored,” he said.
But the issue isn’t just cholesterol’s contribution to
atherosclerosis, or narrowed arteries, which can limit blood flow and
nutrients to brain tissue. “We know that LDL is involved in the
mechanism of depositing unwanted proteins,” those that contribute to
plaques and tangles, “in the brain,” he said. “So, that’s not related to
circulation but a direct effect.”
Getting the chance to emphasize these lifestyle changes when it
really counts, however, is one of the biggest challenges of treating the
disease, according to Hammer.
“We know that the disease begins to take its effect on the brain
decades before any cognitive impairment even occurs,” he said. “By the
time patients are coming to us, it’s already quite late in the game.”
Cutting-edge care
While science can’t yet predict the disease decades in advance, a
blood test capable of predicting the development of Alzheimer’s within
five years could reach consumers sooner rather than later, according to a
study published in Frontiers of Neurology in October.
Also on the cutting edge of care are a handful of phase 2b and phase 3 drug trials, aimed at taming Alzheimer’s by acknowledging the role of metabolism.
And for those inclined to let food be thy medicine, there’s promise for Alzheimer’s patients via the ketogenic diet.
By limiting carbohydrates, the body is forced to burn fat rather than
carbohydrates. A byproduct is ketones, which — and here’s the
cutting-edge part — can be used as energy by brain cells, skipping the
metabolic snafu theorized to be one of the root causes of Alzheimer’s.
“Ketogenic diets are almost impossible to stick with, but this is the
kind of stuff that, as a geriatrician, you would be free to say, ‘Let’s
try this,’” de la Monte said. “But you can only do something about it
if doctors know enough about nutrition and lifestyle that they can give
that advice. The amount of nutritional information we’re given in
medical school is pretty limited, one class if you’re lucky.”
And while de la Monte finds the momentum toward brain metabolism
“refreshing,” it’s no accident. It’s the result of work she and others
set in motion around a quarter-century ago. But where it’s led is less
than satisfying.
“These people with Alzheimer’s are in bad shape. I cut their brains. I
study them. I just feel horrible that the field, with all of the money
spent, hasn’t really moved as far as it should have,” she said.
“Clinical trials are very slow. We do need some way to fast forward the process rather than wait five or 10 more years.”
Abby Mackey is a registered nurse and can be reached at amackey@post-gazette.com and IG @abbymackeywrites
First Published December 16, 2023, 5:30am
