Throughout his career, Duke University neurology professor Allen Roses has challenged what for decades has been the prevailing orthodoxy in Alzheimer’s research: namely, the “amyloid hypothesis,” which suggests that a protein called beta-amyloid clogs up the brain, killing neurons and causing the dementia associated with Alzheimer’s disease. But “beta-amyloid is the result [of Alzheimer’s], rather than a cause,” he says.
For more than 20 years, Roses, 72, has pursued a hunch that dementia in Alzheimer’s patients stems from an inability in the brain to metabolize energy sources, such as glucose and oxygen. The trigger, he argues, is variations in two genes—ApoE and TOMM40—which ultimately inhibit mitochondria from supplying energy to neurons, causing them to die. A growing body of published literature supports his theory, Roses says, but by and large, he “has been totally ignored” by the field.
Not recalling the name at all, indeed I find only 3 hits to 'roses' in our forum all of which refer to the flower, not this work. Per the article, his work is very APOE4 specific and also TOMM40. An important section from the article...
After decades of plugging away at the Alzheimer’s puzzle, Roses’ overarching explanation for what causes the late-onset form of the disease concerns the effect that gene variants, such as ApoE4, have on mitochondria—the “engines” that use oxygen and glucose to supply cells with energy.
Mitochondria are critical for the normal functioning of neurons, which need energy to communicate with each other. But unlike other cells in the body, neurons can’t reproduce. Consequently, when mitochondrial motors slow down—as they do with age—they deprive neurons of vital fuel. As energy-starved neurons die with nothing to replace them, the brain’s cognitive functions also deteriorate.
Necessary to normal mitochondrial function is a gene called TOMM40. In 2009, Roses’ team reported that different lengths of a genetic variation in TOMM40, in concert with variations in the ApoE gene—located next door on the same chromosome—interrupt mitochondrial function within neurons. In studies performed to date, Roses’ team has shown that by testing patients for variations in TOMM40 and ApoE, they can identify those who have degraded mitochondrial function and are therefore at the highest risk of losing memory and thinking skills due to Alzheimer’s before age 80.
The involvement of TOMM40 can also help explain the presence of beta-amyloid in late-onset Alzheimer’s patients, according to Roses. The gene makes a protein that shuttles aggregates of other proteins into the mitochondria—and one of those proteins is the precursor to beta-amyloid. “The amyloid plaque is not pure,” says Roses.
He also has a major randomized controlled trial underway for both a prediction algorithm and intervention via a drug called pioglitazone...
But the biggest test of Roses’ algorithm is a 5,800-subject, five-year, double-blind, randomized, placebo-controlled trial currently underway through a collaboration between his startup Zinfandel Pharmaceuticals and Japanese drug firm Takeda Pharmaceutical. If the study shows that the algorithm does what it’s designed to do, the findings could give the field what it desperately lacks: a way to predict if a person is at risk for developing cognitive problems from late-onset Alzheimer’s disease.
For participants deemed at high risk by the algorithm, the investigators are also testing whether a very low dose of a drug called pioglitazone can delay the onset of memory- and thinking-impairments. If a drug were available today that staves off dementia by five years, it would reduce the cost of patient care by $50 billion by 2020, the Alzheimer’s Association estimates. Rodent and human studies have already shown that low-dose pioglitazone improved mitochondrial function and enabled them to better metabolize energy sources.
“At a point in time when people are about to suffer from mitochondrial inadequacy in their brain, the aim of the study [with Takeda] is to double the number of mitochondria and increase their ability to metabolize glucose and oxygen," Roses says.
Anyone here looked into Dr. Roses' work or this angle before?