Sci­en­tists re­think Alzheimer’s, di­ver­si­fy­ing drug search


WASH­ING­TON — 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. They might clear out the gunk, but they’re not stop­ping Alzheimer’s in­evitable wors­en­ing.

The new mantra: diver­sify. With more money — the govern­ment had a record $ 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. On the list, 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. 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.

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 al­ter na­tive ideas,” Wil­cock said.

Break­ing the plaque and tan­gle 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 silently 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 — maybe sev­eral other things — 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 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 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 — 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.”

Sep­a­rately, biotech com­pany Alec­tor Inc. has be­gun first- step pa­tient test­ing of a drug de­signed t o 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 t he stage f or 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.

Re­searchers in New York are test­ing the her­pes drug vala­cy­clovir in 130 peo­ple with mild Alzheimer’s 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 po­ten­tially neu­ron­dam­ag­ing sub­stances pro­duced by gin­givi­tis bac­te­ria.

Whether the germ theory is a worth­while pur­suit was hotly de­bated at an in­ter­na­tional Alzheimer’s As­so­ci­a­tion meet­ing in July. One skep­tic, Dr. Todd Golde of the Univer­sity of Florida, cau­tioned that germs’ mere pres­ence doesn’t mean they caused de­men­tia — they could be a con­se­quence of it.

Still, a 2018 study from Tai­wan of­fered a hint that treat­ing her­pes in­fec­tion might lower later de­men­tia risk. And a U. S. study found cer­tain her­pes viruses af­fected the be­hav­ior of Alzheimer’sre­lated genes.

“Maybe th­ese are just op­por­tunis­tic pathogens that have space to spring up in the brains of peo­ple af­fected with Alzheimer’s dis­ease,” said Ben­jamin Read­head of Ari­zona State Univer­sity, who coau­thored that U. S. paper. But, “it looks at least plau­si­ble that some of th­ese pathogens are ca­pa­ble of act­ing as ac­cel­er­ants of dis­ease.”

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, one method of fight­ing in­fec­tion or heal­ing wounds. 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 re­sili ent brains — but t he 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 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.”

Early on, be­fore there’s 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’s Wil­cock. The goal is to re­store the nat­u­ral bal­ance of a healthy brain’s en­vi­ron­ment, she said, so mi­croglia “can per­form their es­sen­tial func­tions with­out dam­ag­ing sur­round­ing tis­sue.”

Univer­sity of Ken­tUcKy via ap

Once a month, re­searchers at the Univer­sity of Ken­tucky gather to com­pare do­nated brains from peo­ple who died with de­men­tia.

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