Blame the bulk of the blame for Alzheimer’s disease on good health. Better sanitation, expanded vaccination, ever-more-expert medical care, and abundant, if not always improved, nutrition have boosted life expectancies immensely over the last century or two.

So, guess what: More of us are living long enough to get Alzheimer’s, for which age is the single biggest risk factor.

Nearly 1 in 9 Americans over age 65 have Alzheimer’s. For those 85 or older, the chances are 1 in 5.

“Alzheimer’s disease cases are increasing dramatically as our population ages,” said Stanford Medicine neuroscientist Kati Andreasson, MD, the Edward F. and Irene Thiele Pimley Professor of Neurology and Neurological Sciences.

But why is that? Unlike skin cells or the ones that line your stomach and intestinal lining, the nerve cells, or neurons, in your brain are built to last. Lucky thing, too, because each neuron’s complicated components are customized: continually reshaped by your experiences. If it blows up or burns out, you can’t just trade it in for an off-the-shelf replacement, like an auto part.

So, what makes neurons burn out? What’s age got to do with it?

In Alzheimer’s-disease research, a long-held theory attributes the disorder’s primary pathology to the pile-up, over the years, of brain-based blobs composed mostly of A-beta: a small, sticky snippet of a protein that’s made in the brain (and discussed in Part 1 and elsewhere in this series).

Rethinking Alzheimer’s

Stanford Medicine researchers are exploring alternative approaches to understanding – and, possibly, treating – Alzheimer’s disease.

Part 1: A gene variant called APOE4
Part 2: The sticky tangles of tau
Part 3: The brain’s outside agitators
Part 4: Tiny balls of fat

Decades before a person starts exhibiting Alzheimer’s disease’s classic outward symptoms (among other things, loss of memory and clarity of thought), spaces between that person’s brain cells begin to accumulate an overabundance of gummy A-beta-rich deposits known as amyloid plaques – a diagnostic hallmark of Alzheimer’s disease.

Amyloid plaques themselves are increasingly suspected of being an end-product rather than the cause of the disorder. Eliminating amyloid plaques, at any rate, is no magic bullet. The latest batch of costly drugs to be deployed against Alzheimer’s do expunge those plaques from patients’ brains, but don’t seem to restore mental ability or even stave off its decline.

A-beta is made by neurons not just in humans but in creatures as evolutionarily divergent from us as coelacanths, indicating this molecule’s been around for at least 400 million years. If it wasn’t contributing to brain health in some important way, why would nature hold on to it for so long?

In fact, it’s been found that molecules of A-beta are secreted in small, manageable amounts whenever a neuron in the brain fires. Andreasson says it may strengthen connections between neurons in a way that improves learning ability.

There’s also evidence that small bundles of A-beta molecules (they tend to glom together) can trap bacteria and fungi – a nice trick if your brain happens to get infected. The fact that neuropathologists routinely find microbes trapped in amyloid plaques like flies embedded in amber could mean that these plaques may be, to some extent, fossil remnants of earlier, possibly protective A-beta action.

There’s a problem, though: These same A-beta bundles – as opposed to the A-beta singlet molecules they’re made of, or the amyloid plaques into which they can coalesce – are toxic to neurons, so they need to be constantly mopped up before their numbers build up. Fortunately, our brains have several ways of ridding themselves of excess A-beta. But as we get older, these mechanisms begin to fail us, and those A-beta bundles keep on bulking up and bunching up until they become Alzheimer’s plaques.

A-beta bundles not only eventually form amyloid plaques between brain cells, but in the shorter run also trigger a process within neurons whereby molecules of a neuronal-shape-stabilizing substance called tau (see Part 2 of this series) begin to become sticky – and tau, too, starts clumping into large deleterious deposits called neurofibrillary tangles inside of neurons, clogging and misshaping them and wrecking their ability to work right.

Crabby immune cells can kick-start cognitive decline

Andreasson has been looking into the increasingly popular idea that chronic inflammation – an age-linked condition in which the immune system simultaneously upshifts into overdrive, loses control of its steering wheel, and starts honking its horn too damn much – fuels brain aging in general and Alzheimer’s disease in particular. Andreasson’s research shows how this crazy driving, though originating outside of the brain, can affect what’s inside the brain.

Prominent among the many types of immune cells gliding through our blood and lymph systems are cells called macrophages (the name comes from two Greek words meaning “big eaters”). Macrophages hang out in our every organ and tissue – accounting for 10-15% of the cells in the liver and close to half of the cells in a big pot belly.

In placid times, the roughly 200 billion macrophages in each adult’s body perform important housekeeping chores: nibbling away at decaying detritus left in a wound after an injury, secreting substances that speed tissue repair, gobbling garbage (such as the trillions of every living person’s cells that die every day), and patiently looking out for trouble.

When trouble comes along – say, not-yet-identified entities displaying strong signs of being viral, bacterial, or fungal pathogens – macrophages go on offense, morphing from nicely nibbling nannies into macho warriors, engulfing and digesting the microbial intruders and recruiting other immune cells as reinforcements – which all adds up to a jolt of inflammation. That fast response buys time, stalling the invaders while fussier, focused cells of our immune systems figure out what hit us and, once they do, engineer precise ways of taking out the offending pathogen while leaving the body’s healthy cells alone.

Inflammation, at its best, is a front-line play that keeps us from getting sick, or sicker as the case may be.

Kati Andreasson’s team has identified a chain of molecular events, set in motion largely by macrophages outside the brain, that can change the brain’s internal environment in a way that may lead to Alzheimer’s. | Jim Gensheimer

But macrophages’ street-fighting tactics are a little sloppy. They tend to shoot first and ask questions later. They fight dirty. And they sometimes don’t know when to stop. This takes a toll on our healthy tissue.

Worse: As we grow older, macrophages tend to become increasingly crotchety. Hardened by lifelong exposure to inflammation-inducing assaults (for one thing, our gut wall gets less tight with advancing age, allowing bacteria or bits of them to get into our bloodstreams and arouse our immune system), their behavior gets more slapdash, overblown, and toxic. That spells chronic inflammation, and it manifests in many, although not all, aging individuals, predisposing us to everything from cancer to heart trouble to Alzheimer’s disease.

Preceding macrophages’ pugnacious stance, their surfaces sprout copious copies of an inflammation-amplifying molecule called TREM1, which in peaceful circumstances isn’t very abundant. Not much has been known, or cared, about TREM1 until recently. But in a study published in Nature Immunology in 2019, Andreasson and her colleagues found, in mice, that TREM1 activation was dramatically associated with stroke severity and, negatively, with degree of recovery.

TREM1 is almost exclusive to macrophages and to certain other related immune cells, collectively called myeloid cells, that participate in inflammatory dust-ups. Andreasson suspected that in humans, TREM1-loaded macrophages might be promoting age-associated detrimental immune responses relevant to the development of Alzheimer’s disease.

Very few macrophages ordinarily get into a healthy brain, because they can’t easily cross a selective cellular fence called the blood-brain barrier. Yet Andreasson’s team has identified a chain of molecular events, set in motion largely by macrophages outside the brain, that can change the brain’s internal environment in a way that may lead to Alzheimer’s.

A study led by Andreasson and published in March 2024 in Nature Neuroscience has shown that elevated TREM1 levels in people’s blood are associated with heightened risk for Alzheimer’s disease – and, in mice, that forcing macrophages to forgo their display of TREM1 can calm things down in those macrophages and, resultingly, in the brain. So maybe muzzling TREM1 might be therapeutic in countering cognitive decline.

Less is best

Amyloid plaques don’t normally appear in mice’s brains. But they do pop up in the brains of mice that have been bioengineered to develop early overproduction of A-beta. Those mice wind up developing classic Alzheimer’s symptoms: for example, forgetting how to escape from a maze even with practice, or failing to recognize what should be a familiar object (and instead treating it as a novelty).

These same mice can be further bioengineered so they can’t produce TREM1. Absent that macrophage surface molecule, the A-beta-bundle buildup in the mice’s brains, albeit still unchecked, no longer messes up their navigation or recall. They no longer suffer age-related cognitive decline.

“We were able to delete the gene for TREM1 from mice’s genomes entirely, and we saw no side effects,” Andreasson said. “In fact, the mice were much healthier.”

Old mice’s immune-cell goings-on were restored to factory settings if TREM1 was knocked out of commission. These TREM1-knockout mice performed like young mice on tests of memory (recognizing previously encountered objects as familiar rather than novel, and navigating a maze).

Indeed, knocking down TREM1 even in young A-beta-overproducing mice improved their memory, even though it didn’t affect their continuing A-beta overproduction or amyloid-plaque accumulation.

When Andreasson’s team looked at blood samples from 35,559 Icelanders along with 75,024 Alzheimer’s patients and 397,844 controls from the UK Biobank, they found that TREM1 levels in blood predicted Alzheimer’s risk.

This was also true of post-mortem brain-tissue samples from Alzheimer’s patients. TREM1 levels – TREM1-expressing cells, presumably infiltrating from outside the brain – were higher in deceased Alzheimer’s patients’ brains than in those of Alzheimer’s-free donors.

Andreasson concludes that bloodborne inflammatory chemicals emitted by inflamed macrophages outside of the brain can be transmitted through the blood-brain barrier into the brain proper, driving Alzheimer’s disease risk and cognitive aging.

“What’s really new here is that inflammation doesn’t have to be coming from inside the brain,” she said. “These macrophages really pack a big punch. And they’re throwing it from outside the brain, when they become compromised with age and stress.”

At the moment, no drug capable of knocking TREM1 out of commission without collateral damage is available. Until now, there’s been very little incentive to look for such a drug.

If drugs that selectively block TREM1 proliferation or activation on macrophages’ surfaces can be developed, the blood-brain barrier would no longer pose a challenge. The drugs could be given peripherally – by infusion, by injection, or in a pill.

We can probably live without functioning TREM1, Andreasson said, because it’s just one of the many inflammation-inducers our immune systems use to fire up when an unidentified pathogen gets into our bodies.

“Targeting TREM1 on macrophages and other myeloid cells in the body could lead to therapies for more than Alzheimer’s disease,” Andreasson suggested, possibly extending to a range of conditions triggered by systemic inflammation, including fraility, ulcerative colitis, rheumatoid arthritis, non-alcoholic fatty liver disease, hepatitis, and, according to studies in mice, perhaps Parkinson’s disease.

If you could fix these “outsider” macrophages, Andreasson said, “that might lift so many other boats.”

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