Alzheimer's Treatment: I think your treatment will kill people,

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Debate over Alzheimer's origins causes divisions

- SHARON BEGLEY, The Wall Street Journal

Friday, August 6, 2004

 

(08-06) 05:53 PDT (AP) --

 

Although the exchange did not quite descend to the

level of name-calling, it was not what you usually

hear at scientific conferences. Halfway into a debate

on whether Alzheimer's disease is caused by the

accumulation in the brain of sticky " plaques " made of

a protein called beta-amyloid, as the leading theory

holds, and whether therapies that target amyloid are

the best bets, one scientist let loose.

 

" I think your treatment will kill people, " said

neuropathologist Mark Smith of Case Western Reserve

University, Cleveland, referring to anti-amyloid

therapies. To which neuroscientist Todd Golde of the

Mayo Clinic, Jacksonville, Fla., responded,

" Ethically, I would say you're not in the right

place. "

 

Behind the scenes at last month's 9th International

Conference on Alzheimer's Disease (the amyloid debate

was not part of the official program), you could

almost trip on the ideological lines drawn in the

sand.

 

Beliefs about what causes this merciless disease have

taken on such a religious fervor that one group is

called tauists, after a protein called tau that forms

" neurofibrillary tangles " inside the neurons and, say

these scientists, kills neurons responsible for memory

and thought. Another is called baptists, after the

beta-amyloid protein that forms plaques around brain

neurons and, say its accusers, causes neuron-killing

tau tangles or kills neurons directly, or both.

Apostates think amyloid plaques sop up neurotoxic

proteins along with poisonous metals such as zinc and

copper, and that eliminating plaques could therefore

harm patients. Hence Dr. Smith's accusation.

 

As I wrote last April, there are growing doubts that

amyloid is guilty as charged. Autopsies of people with

early-stage Alzheimer's show that the tangles form

first, before plaques, in brain regions initially

affected by the disease. " If you look at the evidence,

it's the tangles that cause neuronal degeneration, and

they come first, before the amyloid, " says neurologist

Patrick McGeer of the University of British Columbia,

Vancouver, who was awarded one of the Alzheimer's

Association's top scientific prizes at the meeting.

 

Another problem for the amyloid dogma is that " almost

all aged brains have extensive amyloid deposition,

even in people who die with no symptoms of

Alzheimer's, " says neurologist Peter Davies of the

Albert Einstein College of Medicine in the Bronx.

Worse, adds neurobiologist Nikolaos Robakis of Mount

Sinai School of Medicine, New York City, autopsies of

the brains of Alzheimer's victims show that " plaques

don't correlate with neuronal death. The amyloid is

here and the dead neurons are somewhere else. "

 

The amyloid debate has taken on added urgency, for

many Alzheimer's therapies now in the pipeline are

predicated on the guilt of amyloid. A vaccine being

developed by Elan Corp., Dublin, for instance, targets

amyloid plaques; unfortunately, it also shrank the

brains of many volunteers it was tested on. Drugs

being developed by Eli Lilly & Co., Indianapolis, and

Neurochem, Laval, Quebec, target amyloid, too.

 

" The question is, if we are successful in controlling

amyloid, will we be successful in helping patients?, "

says Zaven Khachaturian, who ran the Alzheimer's

program at the National Institute on Aging. " The field

doesn't have a clue. "

 

But it might soon. Scientists who believe that amyloid

causes Alzheimer's have one indisputable fact on their

side: Mutations in three genes which cause the

familial, inherited form of the disease all pump up

amyloid levels in the brain. Surely this proves

amyloid's guilt?

 

In the huge diversity of views presented at the

meeting -- there were 4,500 scientists and 2,000

presentations -- you could hear the beginnings of an

answer. " There were some faint suggestions that these

'amyloid' mutations do something besides affect

amyloid, " says Dr. McGeer.

 

For instance, an Alzheimer's gene once thought to do

nothing but make lots of amyloid turns out to have a

second job, said Dr. Robakis: It also stabilizes

proteins that help keep neurons alive. When this gene

(it's called PS1) is mutated, it speeds the death of

neurons by triggering those toxic tau tangles and by

making neurons more likely to commit suicide. A second

Alzheimer's gene, called APP and also thought to

simply be a source of amyloid, also seems to

moonlights. When mutated, it pushes neurons to change

in ways that lead to suicide, finds Rachael Neve of

Harvard Medical School, Boston.

 

In other words, mutations in " amyloid " genes wreak

havoc in ways that don't involve amyloid.

 

Interestingly, suicidal neurons seem to release

amyloid. Perhaps that has fooled scientists into

concluding that the amyloid around dead neurons is the

killer, when it is actually an innocent by-stander.

 

No existing drug stops, let alone reverses, the

inexorable cognitive and memory decline of

Alzheimer's. The one thing baptists, tauists and

apostates agree on is that drugs that prevent the

disease will not cure it, and drugs effective against

early Alzheimer's won't be the same as those that work

against late Alzheimer's. We'll need a whole

armamentarium.

 

Will any of the treatments target amyloid? " If amyloid

were the answer, " says Dr. McGeer, " the disease would

have been solved by now. "

 

 

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