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Renegade Science

I’m not going to sugar-coat it, because Dr. Mark A. Smith never would.

He was a no-BS guy.

Dr. Mark A. Smith spent his life looking for the answers only science can provide Photo by Renjith Krishnan

When he died in a hit-and-run accident just before Christmas, the Alzheimer’s research world lost one of its most outspoken leaders – the author of more than 800 scientific papers, most of which challenged mainstream thought about the disease.

The accident that claimed his life happened around 2 a.m. on Dec 19.  Dr. Smith – professor of pathology at Case Western University and the director of basic science research at its Memory and Cognition Center – was walking home from a local bar. Another man, driving home from the same bar, struck Dr. Smith, apparently killing him on impact, according to a police report quoted in the Chagrin Solon Sun, a local newspaper.

The driver, Daniel V. Neesham, didn’t stop. Instead he drove home. Ironically, he apparently died in his house soon after. A preliminary coroner’s report suggested that he might have died from a drug overdose, but the final results may not be known for months, Solon Sun reporter Joan Rusek told me.

When we put questions about his death aside, when we put the tragedy aside, when we put aside sympathy and sadness – what remains of Mark A. Smith?


In 2005, when I started to report on the snowballing of antiamyloid drugs, Dr. Smith was one of a tiny handful of researchers who weren’t jumping on the amyloid bandwagon. “There are a few of us who don’t worship at the Church of the Holy Amyloid,” he said in an interview that year. “There is a thought that amyloid plaques are a response to the disease, rather than the cause of the disease, and that they could even be performing some kind of protective function. It’s certainly less sexy theory, but it’s out there.”  He was always good for a quote – some witty, some funny, and some perhaps not entirely suited for publication.

As enthusiasm for antiamyloid drugs gathered steam, he stuck to his scientific guns, continually pointing out studies hinting that beta amyloid might not be the be-all and end-all of Alzheimer’s. His own research suggested that getting rid of amyloid plaques might even do more harm than good – a theory that may have played into the failure of an experimental immunotherapy. Testing stopped abruptly in 2002, when about 6% of those receiving it developed encephalitis, despite later autopsies that clearly showed decreasing amyloid load.

Swimming upstream won Dr. Smith his controversial reputation – something he took not only with good grace, but a certain amount of pride. Last summer,  Forbes reporter Robert Langreth called him a “renegade” over his stance that antiamyloids could actually harm patients.

And despite the 2005 predictions of nearly every top researcher – that we would have Alzheimer’s “licked” within 5 years – the disease rages on. In the last 4 years, four highly anticipated antiamyloid treatments failed their phase III trials. Nor could Dimebon, a drug presumed to stimulate failing neuronal mitochondria, live up to its promising phase II data. All along the way, Dr. Smith pursued his own line of inquiry, focusing on oxidative stress as the disease’s initiating event.

One of his most recent papers suggested that preventing Alzheimer’s with antioxidant therapy could be much easier than curing it with antiamyloid therapy.  Reactive oxygen species damage metabolically active cells – like neurons – the quickest, he said, sparking a cascade of self-perpetuating events that cause even more oxidative stress and the inevitable mental decline of Alzheimer’s. Treating early with potent antioxidants might avoid the downward spiral , he theorized.

Even if Dr. Smith’s ideas ultimately prove incorrect, his consistent pecking at the amyloid theory, coupled with the multiple drug failures, are nudging Alzheimer’s research onto a different path. The idea of preventing neuronal damage before it occurs is quickly overriding the drive for an antiamyloid disease-modifying drug.

Which brings us back around to science, and our most basic question: What exactly is it?

Science is faith, backed up by fact. Belief buttressed with data. Like democracy, it can be loud and messy. Dissenting voices clash, but ultimately work together to uncover reality. World-changing discoveries can’t be made without mistakes along the way, without collisions of opinion and thought, without “renegades” who refuse to jump on the latest research bandwagon – those who pursue, instead, their own ideas.

Ultimately, as generations of parents have warned, “The truth will out.”

And dissenters like Dr. Mark A. Smith will help make that happen.

– Michele G. Sullivan (on Twitter @MGsullivan)

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