By Alvin Powell, Harvard Staff Writer
Sixth in an occasional series by the Gazette on how Harvard researchers are tackling the problematic issues of aging.
What if the bad-boy protein of Alzheimer’s disease—amyloid beta—isn’t so bad after all?
Harvard researchers found themselves asking that question several years ago after noticing remarkable similarities between amyloid beta, thought to be a major player in the disease’s progression, and proteins active in the body’s immune system.
That discovery has blossomed into a new avenue of investigation against the nation’s leading cause of dementia, sixth-deadliest illness, and—according to a 2011 survey—the runner-up to cancer in health fears among the public.
Led by Robert Moir, an assistant professor in neurology at Harvard Medical School (HMS) and Massachusetts General Hospital (MGH), and Rudolph Tanzi, Joseph P. and Rose F. Kennedy Professor of Child Neurology and Mental Retardation at HMS and MGH, the work is focused on whether the development of amyloid beta plaques in the brain—a hallmark of Alzheimer’s disease and the target of several recent drug candidates—might in many cases be a response to infection.
Proven correct, the explanation would fill a significant blank in our framework for the causes of Alzheimer’s disease, create a new understanding of amyloid beta’s role in the body, and possibly open new fronts for treating or preventing the condition by attacking infection before plaques begin to form.
It also has the potential to lump Alzheimer’s with diabetes and other autoimmune diseases in which a revved-up immune system goes too far and turns on the body. Scientists have already noted enough similarities between Alzheimer’s and diabetes that some have wondered whether Alzheimer’s should be thought of as “type 3 diabetes.”
Though knowledge about Alzheimer’s has advanced in recent decades, its causes are only partially understood. In the late 1980s and early 1990s, Tanzi played a role in discovering a trio of genes that cause early onset Alzheimer’s, which runs in a small number of families and can strike before age 50. That condition, also called familial Alzheimer’s, accounts for only about 5 percent of cases.
The remaining cases, called sporadic Alzheimer’s, typically occur later in life, in a person’s mid-60s or beyond. Advancing age is the biggest risk factor—scientists don’t know exactly why—and genetics also plays a role, though less so than in early onset Alzheimer’s.
A variant of the gene APOE, or alipoprotein E, has been identified as a risk factor in sporadic Alzheimer’s. But having the variant doesn’t make the disease inevitable, and not having it doesn’t rule it out. Which has left scientists wondering what other non-genetic factors are at play.
A significant roadblock to discovery has been a lack of clarity on the role of amyloid beta in the body. The Alzheimer’s community has largely viewed it as an aberrant byproduct that serves no useful purpose in the brain—“metabolic garbage,” as Tanzi once put it.
That view has persisted even as understanding of other aspects of Alzheimer’s has advanced. The prevailing hypothesis today is that amyloid beta aggregates to form plaques in the brain. Those plaques then cause the development of tangles made up of the protein tau within nerve cells. This triggers inflammation—a natural immune response that in this case compounds the damage. Connections between nerve cells are severed and the cells die. Cognitive ability inexorably declines, producing the disease’s most feared outcome.
The idea that Alzheimer’s disease might be caused by infection isn’t new, Moir noted. In fact, in the 1970s and 1980s, some scientists considered it the strongest hypothesis. That changed in 1984 with the discovery of amyloid beta, which came to dominate subsequent research.
Though support for what came to be called the “pathogen hypothesis” has endured, Tanzi, director of MGH’s Genetics and Aging Research Unit, said that the disease outline he and Moir are developing differs in important ways. While the pathogen hypothesis is most often offered as an alternative to the amyloid beta hypothesis, Moir and Tanzi’s model is not an alternative, but rather fits within the amyloid beta-tau-inflammation paradigm. It fills in blanks, offering an explanation for how the process starts and for the true nature of amyloid beta.
Circumstantial evidence for the importance of amyloid beta is significant, Moir said. It appears to have developed some 400 million years ago and has not only survived evolutionary pressures to appear in humans today, but is present in 60 percent of vertebrates, including fish, reptiles, and birds.
Further, when Moir started to look more closely at the protein, he noticed similarities to key infection-fighting proteins called antimicrobial peptides in the innate immune system—the body’s first and most ancient line of defense.
“It tells you, first, it’s doing something important,” Moir said. “When we started to look at amyloid beta we realized this thing looked similar to antimicrobial peptides.”