When researchers at the University of Kentucky compare brains donated from people who died with dementia, very rarely do they find one that bears only Alzheimer’s trademark plaques and tangles — no other damage.

If they do, “we call it a unicorn,” said Donna Wilcock, an Alzheimer’s specialist at the university’s aging center. Contrary to popular perception, “there are a lot of changes that happen in the aging brain that lead to dementia in addition to plaques and tangles.”

That hard-won lesson helps explain how scientists are rethinking Alzheimer’s.

For years, researchers have been guided by one leading theory — that getting rid of a buildup of a sticky protein called amyloid would ease the mind-robbing disease. Yet drug after drug has failed.

With $2.4 billion to spend on Alzheimer’s research this year — the focus has shifted to exploring multiple novel ways of attacking a disease now considered too complex for a one-size-fits-all solution.

Researchers are targeting the brain’s specialized immune system, fighting inflammation, even asking if simmering infections play a role.

Some even are looking beyond drugs, testing if electrical zaps in the brain, along a corridor of neural connections, might activate it in ways that slow Alzheimer’s damage.

BREAKING THE LINK

No one knows what causes Alzheimer’s but amyloid deposits were an obvious first suspect, easy to spot when examining brain tissue.

But it turns out that gunk starts building up 20 years before any memory loss, and by itself it’s not enough to cause degeneration.

Sometime after plaques appear, another protein named tau starts forming tangles inside neurons, heralding cell death and memory loss.

But again, not always: Autopsies show sometimes people die with large amounts of both plaques and tangles, yet escape dementia.

So something else also must play a role. One possible culprit: The brain’s unique immune cells, called microglia.

No surprise if you’ve never heard of microglia. Neurons are the brain’s rock stars, the nerve cells that work together to transmit information like memories. Microglia are part of a different family of cells long regarded as the neurons’ support staff.

But “it’s becoming clear they’re much more active and play a much more significant role,” said Dr. Richard Hodes, director of the National Institute on Aging.

One microglial job is to gobble up toxic proteins and cellular debris. Recently, a mutation in a gene called TREM2 was found to weaken microglia and increase the risk of Alzheimer’s.

Dr. David Holtzman at Washington University in St. Louis says microglia may be key to how the amyloid-tau duo turns toxic.

THE GERM CONUNDRUM

Could gum disease or herpes be to blame?

The idea that infections earlier in life could set the stage for Alzheimer’s decades later has simmered on the edge of mainstream medicine, but it’s getting new attention.

It sounds weird, but both the germ that causes gum disease and different strains of herpes viruses have been found in Alzheimer’s-affected brain tissue.

Whether the germ theory is a worthwhile pursuit was hotly debated at an international Alzheimer’s Association meeting in July.

A COMMON DENOMINATOR

One key commonality among emerging Alzheimer’s theories is how aggressively the brain’s immune system defends itself — and thus how inflamed it becomes.

Inflammation is a normal part of the body’s response to illness and injury. But when inflammation is too strong, or doesn’t go away, it’s like friendly fire that harms cells.

Remember how some people have lots of plaques and tangles but no dementia? A few years ago Massachusetts General researchers found strikingly little inflammation surrounded all the gunky buildup in the resilient brains — but the Alzheimer’s-affected brains harbored a lot.

Research since has found similar inflammatory effects with other forms of dementia — like vascular dementia, where tiny blood vessels that feed the brain are lost or blocked, and dementias caused by Lewy bodies or other toxic proteins.

A handful of drugs are being explored in the quest to tamp down inflammation’s damaging side without quashing its good effects.

AMYLOID’S STILL IN THE PICTURE

All those drug flops weren’t a waste of time.

“Every time there’s a failure it’s absolutely clear that we learn a lot,” Emory University neurologist Dr. Allan Levey said.

One lesson: Timing may matter. Most of the failed anti-amyloid drugs were tested in people who already had at least mild symptoms. Some studies seeking to prevent memory loss in the first place still are underway. Several anti-tau drugs also are being tested.

Another lesson: Most people have a mix of different dementias, which means they’ll need a variety of treatments.