summarize this "Most people tend to go to the doctor when they are sick or think
they might be. Nearly all my patients first come to see me when they are
relatively healthy, or think they are. That was the case with Stephanie, a fortyyear-old woman who walked into my office for her initial visit in early 2018
with no real complaint. She was simply “interested” in longevity.
Her family history was not remarkable. Three of her four grandparents
had died from complications of atherosclerosis in their late seventies or early
eighties, and the fourth had died from cancer. Pretty much par for the course
for the Greatest Generation. The only red flag was the fact that her mother,
otherwise healthy at seventy, was beginning to suffer some memory loss,
which Stephanie attributed to “old age.”
We set up another appointment for a week later to review her initial blood
work. I rely as much as one can on biomarkers, so we run a comprehensive
array of tests, but there are a few things that I immediately scan for when I
get a new patient’s results back. Among them is their level of Lp(a), the highrisk lipoprotein that we talked about in chapter 7, along with their apoB
concentration. A third thing that I always check is their APOE genotype, the
gene related to Alzheimer’s disease risk that we mentioned in chapter 4.
Stephanie’s labs revealed that she had the APOE e4 allele, which is
associated with a greater risk of Alzheimer’s disease—and not just one copy,
but two (e4/e4), which meant her risk of developing Alzheimer’s disease was
up to twelve times greater than that of someone with two copies of the
common e3 allele. The e2 version of APOE appears to protect carriers against
Alzheimer’s disease: 10 percent reduced risk for someone with e2/e3, and
about 20 percent for e2/e2. Stephanie was unlucky.
She was only the fourth patient I’d ever encountered with this quite
uncommon genotype, shared by only about 2 to 3 percent of the population,
and she had no idea she was at risk—although in hindsight, her mother’s
forgetfulness may have been a symptom of early Alzheimer’s disease. Now I
faced a double challenge: how to break the news to her, directly but gently;
and even more tricky, how to explain what it meant and what it didn’t mean.
In circumstances like this I generally think it’s best to get right to the
point, so after we sat down, I said something like, “Stephanie, there is
something we found in your blood test that may be of concern to me—not
because anything is wrong now, but because of the risk it poses in twenty to
thirty years or so. You have a combination of genes that increases your risk of
developing Alzheimer’s disease. But it’s also important that you understand
that what we’re about to discuss is only a marker for risk, not a fait accompli,
and I am convinced that we can mitigate this risk going forward.”
Stephanie was devastated. She was dealing with a lot of stress to begin
with: a divorce, a difficult work situation, and now this. It’s tough to explain
the nuances of genes and risk to somebody when their eyes are wide with fear
and they are hearing only I’m doomed. It took several discussions over the
course of many weeks before she began to understand the rest of the
message, which was that she was not, in fact, doomed.
Alzheimer’s disease is perhaps the most difficult, most intractable of the
Horsemen diseases. We have a much more limited understanding of how and
why it begins, and how to slow or prevent it, than we do with atherosclerosis.
Unlike with cancer, we currently have no way to treat it once symptoms
begin. And unlike type 2 diabetes and metabolic dysfunction, it does not
appear to be readily reversible (although the jury is still out on that). This is
why, almost without exception, my patients fear dementia more than any
other consequence of aging, including death. They would rather die from
cancer or heart disease than lose their minds, their very selves.
Alzheimer’s disease is the most common, but there are other
neurodegenerative diseases that concern us. The most prevalent of these are
Lewy body dementia and Parkinson’s disease, which are actually different
forms of a related disorder known (confusingly) as “dementia with Lewy
bodies.” The primary difference between them is that Lewy body dementia is
primarily a dementing disorder, meaning it affects cognition, while
Parkinson’s disease is considered primarily (but not entirely) a movement
disorder, although it does also result in cognitive decline. In the United States,
about 6 million people are diagnosed with Alzheimer’s disease, while about
1.4 million have Lewy body dementia, and 1 million have been diagnosed
with Parkinson’s, which is the fastest-growing neurodegenerative disease.
Beyond that, there are a variety of less common but also serious
neurodegenerative conditions such as amyotrophic lateral sclerosis (ALS, or
Lou Gehrig’s disease) and Huntington’s disease.
All these result from some form of neurodegeneration, and as yet, there is
no cure for any of them—despite the billions and billions of dollars that have
been spent chasing these complex conditions. Maybe there will be a
breakthrough in the near future, but for now our best and only strategy is to
try to prevent them. The only shred of good news here is that while these
disorders have traditionally been considered as completely separate and
distinct diseases, evolving evidence suggests that there is a larger continuum
between them than has previously been recognized, which means that some
of our prevention strategies could apply to more than one of them as well.
—
Many doctors shy away from APOE gene testing. The conventional wisdom
holds that someone with the high-risk e4 allele is all but guaranteed to
develop Alzheimer’s disease, and there is nothing we can do for them. So why
burden the patient with this terrible knowledge?
Because there are two types of bad news: that about things we can
change, and about things that we can’t. Assuming that a patient’s e4 status
falls into the latter category is, in my opinion, a mistake. While it is true that
over one-half of people with Alzheimer’s disease have at least one copy of e4,
merely possessing this risk gene is not the same as being diagnosed with
dementia due to Alzheimer’s disease. There are e4/e4-carrying centenarians
without any signs of dementia, likely because they have other genes that
protect them from e4; for example, a certain variant of the gene Klotho (KL),
called kl-vs, seems to protect carriers of e4 from developing dementia. And
plenty of “normal” e3/e3 carriers will still go on to develop Alzheimer’s.
Having the e4 gene variant merely signals increased risk. It’s not a done deal.
The other point I tried to make to Stephanie was that time was on her
side. The disease rarely progresses to a clinical stage before about age sixtyfive, even in patients with two copies of e4. That gives us about twenty-five
years to try to prevent or delay her from developing this horrible illness with
the tools currently at our disposal. In the interim, hopefully, researchers might
come up with more effective treatments. It was a classic asymmetric situation,
where doing nothing was actually the riskiest course of action.
Understanding Alzheimer’s
Although Alzheimer’s disease was first named in the early 1900s, the
phenomenon of “senility” has been remarked on since ancient times. Plato
believed that because advancing age seemingly “gives rise to all manners of
forgetfulness as well as stupidity,” older men were unsuited for leadership
positions requiring acumen or judgment. William Shakespeare gave us an
unforgettable portrayal of an old man struggling with his failing mind in King
Lear.
The notion that this might be a disease was first suggested by Dr. Alois
Alzheimer, a psychiatrist who worked as medical director at the state asylum
in Frankfurt, Germany. In 1906, while performing an autopsy on a patient
named Auguste Deter, a woman in her midfifties who had suffered from
memory loss, hallucinations, aggression, and confusion in her final years, he
noticed that something was clearly wrong with her brain. Her neurons were
entangled and spiderweb-like, coated with a strange white dental substance.
He was so struck by their odd appearance that he made drawings of them.
Another colleague later dubbed this condition “Alzheimer’s disease,” but
after Alzheimer himself died in 1915 (of complications from a cold, at fiftyone), the disease he had identified was more or less forgotten for fifty years,
relegated to obscurity along with other less common neurological conditions
such as Huntington’s and Parkinson’s diseases as well as Lewy body
dementia. Patients with the kinds of symptoms that we now associate with
these conditions, including mood changes, depression, memory loss,
irritability, and irrationality, were routinely institutionalized, as Auguste Deter
had been. Plain old “senility,” meanwhile, was considered to be an inevitable
part of aging, as it had been since Plato’s day.
It wasn’t until the late 1960s that scientists began to accept that “senile
dementia” was a disease state and not just a normal consequence of aging.
Three British psychiatrists, Garry Blessed, Bernard Tomlinson, and Martin
Roth, examined the brains of seventy patients who had died with dementia
and found that many of them exhibited the same kinds of plaques and tangles
that Alois Alzheimer had observed. Further studies revealed that a patient’s
degree of cognitive impairment seemed to correlate with the extent of
plaques found in his or her brain. These patients, they concluded, also had
Alzheimer’s disease. A bit more than a decade later, in the early 1980s, other
researchers identified the substance in the plaques as a peptide called
amyloid-beta. Because it is often found at the scene of the crime, amyloidbeta was immediately suspected to be a primary cause of Alzheimer’s
disease.
Amyloid-beta is a by-product that is created when a normally occurring
substance called amyloid precursor protein, or APP, a membrane protein that
is found in neuronal synapses, is cleaved into three pieces. Normally, APP is
split into two pieces, and everything is fine. But when APP is cut in thirds,
one of the resulting fragments then becomes “misfolded,” meaning it loses its
normal structure (and thus its function) and becomes chemically stickier,
prone to aggregating in clumps. This is amyloid-beta, and it is clearly bad
stuff. Laboratory mice that have been genetically engineered to accumulate
amyloid-beta (they don’t naturally) have difficulty performing cognitive tasks
that are normally easy, such as finding food in a simple maze. At the same
time, amyloid also triggers the aggregation of another protein called tau,
which in turn leads to neuronal inflammation and, ultimately, brain shrinkage.
Tau was likely responsible for the neuronal “tangles” that Alois Alzheimer
observed in Auguste Deter.
Scientists have identified a handful of genetic mutations that promote very
rapid amyloid-beta accumulation, all but ensuring that someone will develop
the disease, often at a fairly young age. These mutations, the most common of
which are called APP, PSEN1, and PSEN2, typically affect the APP cleavage.
In families carrying these genes, very-early-onset Alzheimer’s disease is
rampant, with family members often developing symptoms in their thirties
and forties. Luckily, these mutations are very rare, but they occur in 10
percent of early-onset Alzheimer’s cases (or about 1 percent of total cases).
People with Down syndrome also tend to accumulate large amounts of
amyloid plaques over time, because of genes related to APP cleavage that
reside on chromosome 21.
It was not a huge leap to conclude, on the basis of available evidence, that
Alzheimer’s disease is caused directly by this accumulation of amyloid-beta
in the brain. The “amyloid hypothesis,” as it’s called, has been the dominant
theory of Alzheimer’s disease since the 1980s, and it has driven the research
priorities of the National Institutes of Health and the pharmaceutical industry
alike. If you could eliminate the amyloid, the thinking has been, then you
could halt or even reverse the progression of the disease. But it hasn’t worked
out that way. Several dozen drugs have been developed that target amyloidbeta in one way or another. But even when they succeed in clearing amyloid
or slowing its production, these drugs have yet to show benefit in improving
patients’ cognitive function or slowing the progression of the disease. Every
single one of them failed.
One hypothesis that emerged, as these drugs were failing one after
another, was that patients were being given the drugs too late, when the
disease had already taken hold. It is well known that Alzheimer’s develops
slowly, over decades. What if we gave the drugs earlier? This promising
hypothesis has been tested in large and well-publicized clinical trials involving
people with an inherited mutation that basically predestines them to earlyonset Alzheimer’s, but those, too, failed in the end. A broader clinical trial
was launched in 2022 by Roche and Genentech, testing early administration
of an anti-amyloid compound in genetically normal people with verified
amyloid accumulation in their brains but no clear symptoms of dementia;
results are expected in 2026. Some researchers think that the disease process
might be reversible at the point where amyloid is present but not tau, which
appears later. That theory is being tested in yet another ongoing study.
Meanwhile, in June of 2021, the FDA gave approval to an amyloidtargeting drug called aducanumab (Aduhelm). The drug’s maker, Biogen, had
submitted data for approval twice before and had been turned down. This was
its third try. The agency’s expert advisory panel recommended against
approving the drug this time as well, saying the evidence of a benefit was
weak or conflicted, but the agency went ahead and approved it anyway. It has
met a tepid reception in the marketplace, with Medicare and some insurers
refusing to pay its $28,000 annual cost unless it is being used in a clinical trial
at a university.
"