DECEMBER 15, 2005


Is Alzheimer's really just type III diabetes?

A lack of insulin may cause AD, but statins could keep it in check

Ever heard of type III diabetes? Tens of thousands of Canadians could be suffering from it, according to a new study. They just know it by a different name: Alzheimer's disease.

Levels of insulin and of its receptors diminish significantly in the brain in early Alzheimer's, and continue to fall as the disease progresses, according to research published in the November issue of the Journal of Alzheimer's Disease. "Insulin disappears early and dramatically in Alzheimer's disease," senior author Dr Suzanne M de la Monte, a neuropathologist and professor of pathology at Brown Medical School, said in a press release. "And many of the unexplained features of Alzheimer's, such as cell death and tangles in the brain, appear to be linked to abnormalities in insulin signalling. This demonstrates that the disease is most likely a neuroendocrine disorder, or another type of diabetes."

Dr de la Monte analyzed insulin and insulin receptor function in 45 postmortem brains from either normal elderly patients or Alzheimer's patients at various stages of disease. They found that insulin expression declined in step with Braak stages, the standard system of neurodegeneration classification. "In the most advanced stage of Alzheimer's, insulin receptors were nearly 80% lower than in a normal brain," Dr de la Monte said. What's more, the ability of insulin and its related growth factor IGF-I to bind to corresponding receptors also diminished, creating a cellular resistance to these proteins that ultimately led to cell death.

One task of insulin in the brain is to stimulate the expression of choline acetyltransferase (ChAT), the enzyme responsible for making acetylcholine, the researchers discovered. This provides them with a causal link between their own findings and acetylcholine deficiency, a known marker of Alzheimer's disease.

Whether this brings us any closer to a treatment is another question. It's hardly reassuring to know that the incurable disease Alzheimer's has now been linked to the incurable disease diabetes. Dr de la Monte is optimistic but cautious: "If you could target the disease early, you could prevent the further loss of neurons. But you would have to target not just the loss of insulin but the resistance of its receptors in the brain."

While this research offers a mechanism but offers no immediate treatment, a paper published in the Journal of Neurology, Neurosurgery and Psychiatry reports on a treatment with no obvious mechanism. French researchers investigating the relationship between cholesterol and cognitive decline found that Alzheimer's patients who took lipid-lowering drugs saw slower disease progression than those who didn't.

The study followed 342 Alzheimer's patients at a memory clinic over three years. Roughly one-third had dyslipidemia, or high cholesterol, and were taking lipid-lowering agents, another third had untreated dyslipidemia, and the remaining had normal cholesterol levels. Those taking lipid-lowering agents, either statins or fibrates, showed significantly slower declines on a mini-mental state examination, losing an average of 1.5 points a year off their score compared to 2.5 in the other groups.

What's most striking about these findings is that the drugs' effect on Alzheimer's progression appeared to be independent of cholesterol levels. Patients with high cholesterol who took lipid-lowering agents declined slower than healthy ones who weren't on the meds. And patients with normal lipid levels fared no better in terms of cognition than dyslipidemic patients who didn't take anything. In other words, it appeared that some other quality in the drugs, independent of their cholesterol-busting properties, was giving a protective effect.

Regrettably, the study was too small to allow statistically meaningful comparison between the fibrate-taking patients and those prescribed statins. Both drug types have anti-inflammatory and antioxidant qualities that could be behind the cognitive effects. The best way to tease out the truth, said the authors, is to design studies that test the impact of lipid-lowering agents in Alzheimer's patients who don't have high cholesterol.



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