In the article “Before Night Falls” in the New Yorker magazine, Dr. Jerome Groopman details the on-going debate among researchers seeking to understand the causes of Alzheimer’s. As Dr. Groopman points out, researchers have been working on a treatment for three decades, yet understanding the cause of Alzheimer’s and developing an effective treatment remain out of reach.

What researchers do know is that Alzheimer’s patients accumulate two types of protein in their brains:  beta amyloid (also known as A Beta) and tau. A Beta causes plaques to form on the outside of brain cells. Tau causes “tangles” within the neurons themselves.

Tau and A Beta appear in different parts of the brain. No one fully understands the function of these proteins or what, if any, interplay there may be between them. The research world has divided into different camps: those who think that beta amyloid causes Alzheimer’s (the “baptists”) those who think that tau is the culprit (the “tauists”), and those who think the cause is likely to be more complex than the action of any one protein.

The Case for A Beta

The baptists focus on the presence of ABeta in the brains of Alzheimer’s victims. The typical form of A Beta is a chain of 40 amino acids. However, A Beta has a longer form, with 2 more amino acids, and it is the longer form of this protein which appears to “stick” to the outside of the brain cells, developing into plaques, as illustrated by a Columbian family.

The Colombian Connection:  Accumulating “Sticky” ABeta

An extended family in Colombia carries a mutated gene that results in a over a third of its family members developing Alzheimer’s in their 40s. Their brain scans show significant ABeta plaque deposits of family members as young 20.  Genetic testing revealed that the family carries a mutated gene that results in the production of the longer form of the A Beta protein, the form that “sticks” to the brain surfaces. However, the occurrence of this early onset form of Alzheimer’s is rare; the connection between the origins of early onset disease and late onset is not well understood.

The Iceland Factor: Prevention of “Sticky” ABeta

Geneticists last year discovered a group in Iceland with a genetic mutation that seems to prevent the production of the long form of the A Beta protein.  These Icelanders have little history of dementia. The correlation between the presence of a gene mutation resulting in no sticky ABeta and the lack of Alzheimer’s in this population gives further credence to the baptists’ theories.

APOE

The growing understanding of the APOE gene and its mutations also supports the link between A Beta and Alzheimer’s. This gene produces a protein that clears A Beta from the brain.  One variant of the APOE gene, APOE4, is highly correlated with the development of Alzheimer’s.  Researchers surmise that mutations in the APOE4 gene prevent the clearing of accumulated ABeta, and results in Alzheimer’s, a theory that again points to ABeta as a critical factor.

The Case for Tau

Tauists think the culprit behind the Alzheimer’s epidemic is not beta amyloid, but tau proteins. When functioning normally, tau helps support the structure of the long axons of brain cells and transport nutrients throughout the brain cell. The tau in the brains with people with Alzheimer’s twists into tangles within the brain cell. These tangles are presumed to interrupt the flow of nutrients within the cell, resulting in cell death.

Impact on the Hippocampus

The tauists point to the regions of the brain where tau tangles are found to support their theory. One of the early symptoms of Alzheimer’s disease is the loss of short-term memory. The brain’s hippocampus processes short-term memory. Brain scans of people diagnosed with Alzheimer’s show accumulations of tau in the hippocampus region of the brain, not beta amyloid.

Evidence of Cell Death

The tau tangles kill off the brain cells, which is consistent with knowledge that the brains of Alzheimer’s patients shrink. How beta amyloid plaques might kill brain cells is not understood. As imaging for plaques has expanded, researchers see scans showing accumulations of plaques in people who have no symptoms of the disease. The baptists explain the lack of symptoms as a timing issue: it takes a long time for the ABeta deposits to cause cognitive impairment. The tauists think ABeta plaques might be a protective response of the brain to inflammation from tau or another agent, and not the source of the disease.

Failure of Clinical Trials Targeting ABeta

The tau supporters point, with frustration, to the failure to develop any effective treatment based on ABeta after two decades of work. They think research should be expanded to pursue other theories of the disease process.

The most recent NIH grants on Alzheimer research are structured to determine if giving drugs targeting ABeta to people before they are symptomatic will be effective. (See earlier blogs on this). As the number of people suffering from this disease looms ever larger, there is increasing pressure to find an effective treatment.  If the current trials are not successful, researchers are likely to pursue other theories. For the families caring for loved ones with dementia, the answers cannot come too soon.