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A COMMON protein in the blood may help to explain why some people develop
Alzheimer’s disease, a fatal form of dementia. In particular, the protein
may explain why people suffering from this disease have abnormally high
levels of aluminium in their brains.

Researchers have found that people with Alzheimer’s have a defective
form of the protein, which is normally responsible for binding aluminium
and removing it from the bloodstream. Because of this defect, the researchers
believe, increased amounts of the metal are free to circulate in a form
that can enter the brain.

The discovery, announced this week by a British team, has two important
implications: first, it opens up the possibilities in future for a simple
blood test, and even a treatment, for people with the defective protein,
who may be susceptible to Alzheimer’s disease. Secondly, it offers the first
explanation of why some people seem to be much more vulnerable to aluminium
poisoning that others.

Paul Altmann at The London Hospital, Gillian Farrar and John Blair at
the University of Aston in Birmingham, and their colleagues, say there is
a lot more research to be done. ‘Now we may be able to open an important
door into the study of Alzheimer’s,’ says Altmann.

Å®ÉúСÊÓƵs have been hampered by their lack of knowledge about the causes
of Alzheimer’s disease, for which there is currently no cure. The disease
is also difficult to diagnose (see New Å®ÉúСÊÓƵ, Science, last issue).
Certainly, aluminium is involved: but the link between the metal and the
disease has remained unclear.

The incidence of Alzheimer’s disease appears to be higher in areas where
the concentration of aluminium in drinking water is high (This Week, 21
January 1989). In addition, several studies have shown that the brains of
people with Alzheimer’s contain large amounts of the metal.

More recently, work by Altmann and Blair has shown that aluminium affects
certain neurotransmitters – the chemical messengers between nerve cells
– in the brain, causing specific changes in the nerve signals. These changes
are similar in people with aluminium poisoning and Alzheimer’s.

But if the metal had a direct, causal relationship with the disease,
scientists would expect to find a higher rate of Alzheimer’s in certain
groups exposed to very large amounts of aluminium, such as kidney patients
and others who have to take drugs containing the metal. But these groups
are no more likely to develop Alzheimer’s disease.

Now, the team has compared blood samples from various groups of people
to see how well the protein transferrin in their blood binds the metal.
Aluminium is difficult to observe in biological experiments, so the team
substituted another metal that behaves in a very similar way, gallium.

Transferrin’s normal function is to bind iron and other metals and transport
them to specific transferrin receptors on cells. Once bound, the complex
of protein and metal is very large – too big to cross the blood-brain barrier.
The transferrin-metal complex ‘docks’ on the cell receptor, to be taken
into a compartment inside the cell where conditions are acid enough to detach
the metal from its carrier. The transferrin molecule then returns to the
blood for more.

In healthy people, there is more than enough transferrin ‘carrying capacity’
to bind the aluminium in the blood. But in some people, it appears, this
is not the case. The researchers took samples from 62 people: of these,
13 had Alzheimer’s, 12 had Down’s syndrome, 10 suffered from dementia as
a result of strokes, five were on dialysis for kidney failure – exposed
to relatively large amounts of aluminium – and 22 were healthy controls.
The team added the radioisotope gallium-67 to the samples.

For the stroke group and the dialysis group, the average percentage
of gallium that was bound to transferrin was the same as the control group.
But in the Alzheimer’s and Down’s groups, less than half as much gallium
was bound as in the controls (The Lancet, vol 335, p 747). As a result,
the researchers say, there is more metal free to circulate in a form that
can enter the brain.

The results from the dialysis patients, the team suggests, may explain
why this group is no more likely to develop Alzheimer’s than others. Because
most of these patients have normal transferrin, they may be protected against
aluminium entering the brain, unless levels of the metal are so high that
the transferrin becomes fully saturated.

Two questions clearly arise from these results. First, is there a genetic
factor that causes a different form of transferrin in people with Alzheimer’s
and people with Down’s? Secondly, is there a genetic link between the two
conditions? As far as the first question is concerned, says Altmann, ‘we
are completely in the dark’. But, he adds: ‘The likelihood is that it is
genetically determined. We are assuming that there is either a gene defect
causing synthesis of a defective transferrin molecule, or that another gene
interacts with transferrin to disrupt its normal function.’ The next step
will be to find out more about the molecular mechanisms.

Whether Alzheimer’s and Down’s are genetically linked is a complex question.
People with Down’s tend to develop Alzheimer’s disease and several studies
have found that the brains of people over 30 with Down’s have many features
that resemble the characteristic plaques and tangles found in Alzheimer’s
brain tissue.

In recent years, some researchers have suggested that a substance called
amyloid precursor protein offered a clue to the answer. The protein is found
in the brains of Alzheimer’s patients, and the gene that encodes it happens
to be on chromosome 21 – the same chromosome that has an extra copy in Down’s
syndrome.

But other researchers have found the protein in people with other forms
of dementia, so many researchers, including Altmann and his colleagues,
are not convinced by the amyloid hypothesis.

The next step will be to identify the defect in transferrin at the molecular
level. This, say the researchers, could open the way to ‘diagnostic and
therapeutic interventions’ in future. And the team says there will have
to be much larger population study involving hundreds of people and lasting
perhaps several years. Also, the transferrin binding test will have to be
improved because it is very time-consuming at present.