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鈥檚 trademark plaques and tangles 鈥� no other damage.

If they do, 鈥渨e call it a unicorn,鈥� said Donna Wilcock, an Alzheimer鈥檚 specialist at the university鈥檚 aging center. Contrary to popular perception, 鈥渢here are a lot of changes that happen in the aging brain that lead to dementia in addition to plaques and tangles.鈥�

That hard-won lesson helps explain how scientists are rethinking Alzheimer鈥檚. For years researchers have been guided by one leading theory 鈥� that getting rid of a buildup of a sticky protein called amyloid would ease the mind-robbing disease. Yet drug after drug has failed. They might clear out the gunk, but they鈥檙e not stopping Alzheimer鈥檚 inevitable worsening.

With more money 鈥� the government had US$2.4 billion to spend on Alzheimer鈥檚 research this year 鈥� the focus has shifted to exploring multiple novel ways of attacking a disease now considered too complex for a one-size-fits-all solution. On the list, researchers are targeting the brain鈥檚 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鈥檚 damage. Recently doctors at Barrow Neurological Institute in Phoenix announced they had implanted a pacemaker-like 鈥渄eep brain stimulation鈥� device into the first of more than 200 patients for an international study.

Most of the fresh starts for drugs are in the earliest research stages. It鈥檚 far from clear that any will pan out, but 鈥渢he field is now much more open-minded than it ever was to alternative ideas,鈥� Wilcock said.

No one knows what causes Alzheimer鈥檚 but amyloid deposits were an obvious first suspect, easy to spot when examining brain tissue. But it turns out that gunk starts silently building up 20 years before any memory loss, and by itself it鈥檚 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 must play a role. One possible culprit: the brain鈥檚 unique immune cells, called microglia (my-kroh-GLEE鈥�-ah).

No surprise if you鈥檝e never heard of microglia. Neurons are the brain鈥檚 rock stars, the nerve cells that work together to transmit information like memories. Microglia is part of a different family of cells long regarded as the neurons鈥� support staff. But 鈥渋t鈥檚 becoming clear they鈥檙e much more active and play a much more significant role,鈥� 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鈥檚. Dr David Holtzman at Washington University in St Louis took a closer look 鈥� and says microglia may be key to how the amyloid-tau duo turns toxic.

In donated human brains, his team found more tau tangles clustered around amyloid plaques when people harbored microglia-weakening TREM2 mutations. The researchers altered the TREM2 gene in mice and seeded their brains with a little human tau. Sure enough, more tangles formed next to plaques in mice with weak microglia than in those with functional immune cells, they recently reported in Nature Neuroscience.

Why? Normal microglia seem to restrict amyloid plaques, which limits damage to surrounding tissue 鈥攄amage that can make it easier for tau to take hold, he explained. While it was known that amyloid buildup drives tau tangles, 鈥渨e never had a good clue as to how it is doing that,鈥� Holtzman said. The new findings 鈥渨ould argue that these cells are sort of a missing link.鈥�

Separately, biotech company Alector Inc has begun first-step patient testing of a drug designed to boost TREM2 and better activate microglia.

The germ conundrum

Could gum disease or herpes be to blame? The idea that infections earlier in life could set the stage for Alzheimer鈥檚 decades later has simmered on the edge of mainstream medicine, but it鈥檚 getting new attention. Both the germ that causes gum disease and different strains of herpes viruses have been found in Alzheimer鈥檚-affected brain tissue.

Researchers in New York are testing the herpes drug valacyclovir in 130 people with mild Alzheimer鈥檚 who have evidence of infection with certain herpes strains. And Cortexyme Inc is enrolling more than 500 early-stage patients around the country to test a drug that targets neuron-damaging substances produced by gingivitis bacteria.

Whether the germ theory is a worthwhile pursuit was hotly debated at an international Alzheimer鈥檚 Association meeting in July. One skeptic, Dr Todd Golde of the University of Florida, cautioned that germs鈥� mere presence doesn鈥檛 mean they caused dementia 鈥� they could be a consequence of it.

A 2018 study from Taiwan says treating herpes infection might lower later dementia risk. And a US study found certain herpes viruses affected the behavior of Alzheimer鈥檚-related genes.

鈥淢aybe these are just opportunistic pathogens that have space to spring up in the brains of people affected with Alzheimer鈥檚 disease,鈥� said Benjamin Readhead of Arizona State University, who co-authored that US paper. 鈥淏ut, it looks at least plausible that some of these pathogens are capable of acting as accelerants of disease.鈥�

One key commonality among emerging Alzheimer鈥檚 theories is how aggressively the brain鈥檚 immune system defends itself 鈥� and thus how inflamed it becomes.

Inflammation is a normal part of the body鈥檚 response to illness and injury, one method of fighting infection or healing wounds. But when inflammation is too strong, or doesn鈥檛 go away, it鈥檚 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 鈥� but the Alzheimer鈥檚-affected brains harbored a lot.

Vascular dementia

Research since has found similar inflammatory effects with other forms of dementia 鈥� 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 growing list of genes linked to inflammatory processes also may play a role.

A handful of drugs are being explored in the quest to tamp down inflammation鈥檚 damaging side without quashing its good effects. Take those microglia, which Holtzman said 鈥渕ay be a two-edged sword.鈥�

Early on, before there鈥檚 too much plaque, revving them up may be good. But later on, a hyperactive swarm around growing plaques spews out inflammatory molecules.

In addition to their immune system job, microglia also secrete molecules that help nourish neurons, noted Kentucky鈥檚 Wilcock.

The goal is to restore the natural balance of a healthy brain鈥檚 environment, she said, so microglia 鈥渃an perform their essential functions without damaging surrounding tissue.鈥�

All those drug flops weren鈥檛 a waste of time. 鈥淓very time there鈥檚 a failure it鈥檚 absolutely clear that we learn a lot,鈥� Emory University neurologist Dr Allan Levey said.