Scientists rethink Alzheimer’s, diversifying the drug search

Lauran Neergaard

WASHINGTON (AP) — 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 ageing centre. Contrary to popular perception, “there are a lot of changes that happen in the ageing 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 build-up 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’re not stopping Alzheimer’s inevitable worsening.

The new mantra: Diversify.

With more money, 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 targetting the brain’s specialised 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. On Tuesday, doctors at Barrow Neurological Institute in Phoenix announced they had implanted a pacemaker-like “deep brain stimulation” device into the first of more than 200 patients for an international study .

Brain samples in storage at the Sanders-Brown Center in Lexington. PHOTOS: AP

Most of the fresh starts for drugs are in the earliest research stages. It’s far from clear that any will pan out, but “the field is now much more open-minded than it ever was to alternative ideas,” Wilcock said. 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 silently building up 20 years before any memory loss, and by itself it’s not enough to cause degeneration But again, not always: Autopsies show sometimes people die with large amounts of both plaques and tangles, yet escape dementia.

So something else — maybe several other things — also must play a role. One possible culprit: The brain’s unique immune cells, called microglia. 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 took a closer look — 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 harboured 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 — damage that can make it easier for tau to take hold, he explained.

While it was known that amyloid buildup drives tau tangles, “we never had a good clue as to how it is doing that,” Holtzman said. The new findings “would argue that these cells are sort of a missing link.” One key commonality among emerging Alzheimer’s theories is how aggressively the brain’s immune system defends itself — and thus how inflamed it becomes. But when inflammation is too strong, or doesn’t go away, it’s like friendly fire that harms cells.

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 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’s damaging side without quashing its good effects.

Take those microglia, which Holtzman said “may be a two-edged sword.”