Alzheimer's Isn't a Single Disease, Say Scientists

Certain prion conditions and Alzheimer's diseases can be caused by a mutation in a given protein – but Alzheimer's can be caused by other mutations too. Conclusion: It's not the same Alzheimer's.

Ruth Schuster
Ruth Schuster
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Surprisingly, it turns out that certain prion conditions (of which Mad Cow is notorious) and Alzheimer's in some families can be caused by similar mutations.
Surprisingly, it turns out that certain prion conditions (of which Mad Cow is notorious) and Alzheimer's in some families can be caused by similar mutations. Credit:
Ruth Schuster
Ruth Schuster

While working on mad-cow disease and other neurodegenerative conditions chiefly affecting the aged, researchers in Jerusalem concluded that doctors have been lumping together different maladies and conditions under the catchall word "Alzheimer's," when they may be different things entirely.

Also, as different diseases may require different treatments, this catchall diagnosis might lead to ineffective treatment, postulates the international research team, led by Prof. Ehud Cohen and Dr. Tziona Ben-Gedalya at The Institute for Medical Research Israel – Canada at the Hebrew University’s Faculty of Medicine

Neurodegenerative diseases are incurable conditions that damage or kill nervous system cells, from nerve to brain cells. The list includes familiar villains such as Alzheimer's Disease and Parkinson's Disease, and maladies caused by prions, the most notorious of which is Mad Cow disease. These nervous system disorders all boil down to being the result of aberrant proteins. (Prions are simply another form of aberrant protein. It bears noting that Alzheimer's and Parkinson's are not contagious, but certain prion conditions can be, when you eat infected nervous tissue. Conclusion: don't eat the neighbors' brains.)

The eureka moment for the team at the Hebrew University of Jerusalem was the conclusion that the development of Alzheimer's in certain families, and of a prion disorder in other families, originated from very similar mutational patterns. But other people develop Alzheimer's due to entirely different mutations.

In other words, there seems to be more than one cause of Alzheimer's, which begs the thought that there is more than one kind of Alzheimer's, which begs the thought that the different Alzheimer's conditions will require different treatment.

Mutation-based neurodegenerative conditions may run in families, or arise sporadically (in every family, somebody has to be the first), and they almost always appear late in life.

Conditions such as prion disorders, Alzheimer's Disease and Parkinson's Disease share two key features: they emerge as a result of aberrant protein folding and aggregation, and their onset is late in life. By the way, unlike the other conditions, prion-driven disease can be infectious.

Gray hair, wrinkles and convoluted proteins

Doctors have been wondering why people with disease-linked mutations show no clinical signs until their 50s at the earliest. They also wonder why this late onset is typical of mutation-linked neurodegenerative conditions in general, given that they have no other real common features. One hypothesis is that younger people have better DNA-repair and metabolic cleansing systems.

These are the observations leading to the research that concluded Alzheimer's is not one single beast. The professors set out to elucidate what mechanisms are "negatively regulated" by aging, allowing neuro-degeneration to proceed in the elderly.

It is known that neurodegenerative disorders result from aberrant protein folding. The team postulated that proteins that help other proteins fold properly simply don't work well in the elderly.

To identify such mechanisms, they searched for similar mutational patterns in different proteins linked to the development of distinct neurodegenerative disorders.

They found that Alzheimer's in certain families and prion diseases in other families originated from a very similar mutational pattern: malfunctioning cyclophilin B, a protein that helps nascent proteins to attain their proper spatial structures, is responsible for the manifestation of both maladies.

After studying the mechanism underlying the development of Alzheimer's disease in the people with these mutations, they found zero relevance to emergence of the disease in patients with other Alzheimer's-linked mutations, the team stated.

"Our study proposes that the failure to develop efficient Alzheimer's therapy emanates from the pooling, in clinical experiments, of patients who suffer from distinct disorders that eventually lead to Alzheimer's symptoms," stated Dr. Cohen. "Therefore it is essential to carefully characterize and classify the mechanisms that underlie Alzheimer's disease, in order to allow for the development of novel therapies that can be prescribed to the individual patient according to their relevant disease subtype."

The paper's co-authors include researchers at the Institute for Dental Sciences, Faculty of Dental Medicine, Hebrew University of Jerusalem; Dept. of Physiology and Pharmacology at the Sackler Faculty of Medicine at Tel Aviv University; Dept. of Biochemistry and Molecular Biology, Wise Faculty of Life Sciences, Tel Aviv University; and Bone and Extracellular Matrix Branch, NICHD, National Institutes of Health (NIH), USA. Among the study's founders were the European Research Council, the National Institute for Psychobiology in Israel, the Israel Science Foundation and the Rosalinde and Arthur Gilbert Foundation.



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