Looking for origins of Alzheimer’s disease to find a treatment

Posted by: | August 19, 2023 | Comments

Scientists at the School of Medicine are at the forefront of research into how Alzheimer’s disease develops, with an eye on finding better ways to predict and treat the illness.

Six or so years ago, Frank Longo, MD, PhD, Stanford’s chair of neurology and neurological sciences, was optimistic that a treatment for Alzheimer’s disease was on its way. More than a decade earlier, pharmaceutical companies had begun testing drugs to eradicate one of its hallmark signs — clumps of protein sprinkled randomly throughout the brain. The drugs were antibodies that bind to the protein, called beta amyloid, or A-beta for short.

“They poured a lot of money into clinical trials of these antibodies in Alzheimer’s patients,” Longo said. “And by around five years ago, with the conclusion of early-stage trials, it looked like they might succeed. So, many in the field — including me — had some guarded optimism that when the pivotal phase-3 trials were completed, this approach would have at least some beneficial effect.”

On the order of 30 million people worldwide, including more than 5 million Americans, have Alzheimer’s, the most common form of dementia, which raids the brain and steals a person’s ability to remember, reason and imagine. Barring substantial progress in curing or preventing it, Alzheimer’s will affect 16 million U.S. residents by 2050, according to the Alzheimer’s Association. The group also reports that the disease is now the nation’s most expensive, costing over $200 billion a year. Recent analyses suggest it may be as great a killer as cancer or heart disease.

It’s not really clear what causes the disease, and even rendering a diagnosis involves some guesswork. Genetic factors have been shown to contribute to the likelihood of getting it, but none among them comes close to fully predicting or explaining its onset and progression. What’s known is that the diseased brain is characterized by the protein clumps outside of nerve cells and tangles of fibrous filaments within them, accompanied by an accelerating die-off of those nerve cells. And that there is no cure.

So it was unfortunate that three separate phase-3 trials testing the antibody strategy all failed to have any therapeutic effect on cognition. “I’d like to have something better to offer my patients,” said Longo, who directs the Stanford Center for Memory Disorders. “It’s profoundly disappointing when that doesn’t happen.”

In the wake of this disappointment, research to understand Alzheimer’s has shifted focus. Instead of trying to address signs and symptoms seen in the end stage of disease, researchers are looking at what goes wrong much earlier. Their insights have yielded promising new imaging techniques and new targets for therapeutic drugs, with at least a couple being tested by startup companies Stanford researchers have spun off.

When the brain’s brakes lock up

“By the time visible symptoms of dementia appear and a patient first sees a doctor about it, this process has been under way for years,” said Carla Shatz, PhD, a professor of neurobiology and of biology and the director of Bio-X, Stanford’s interdisciplinary biosciences institute.

A few promising early signals of impending Alzheimer’s do exist — for example, changes in amounts and ratios of certain chemicals in spinal fluid, or the changes observed by investigators via functional brain imaging. But wide-scale spinal taps or brain scans are hardly efficient ways to screen large numbers of people in the hopes of initiating therapeutic interventions earlier — even if there were something to intervene with. What would be great would be to find a molecular mechanism that not only provides a way to detect the approach of Alzheimer’s but also offers a window into the disease process.

Shatz’s recent work has turned up an unexpected player: a molecule once thought to be important only in the immune system but which she discovered over a decade ago also is found in the brain. The molecule, called PirB in mice, is a protein that acts like a brake dialing down the ferocity of the immune response — important if, for example, autoimmunity is to be avoided. Shatz found that in the brain PirB appears to serve as a brake on a different vehicle altogether: the synapse. Synapses are discrete, tiny but critical contact points at which each nerve cell conveys signals to others. Your memories are stored at brain circuits’ synapses. A single nerve cell can sport 10,000 or more synapses, each connecting with a different partner nerve cell. In response to our experience and development, synapses are in a throbbing state of flux: being born, enlarging and strengthening, diminishing and weakening, or disappearing altogether. This relentless fidgeting is the physiological basis of learning, ruminating and daydreaming; of remembering, forgetting and regretting.

But too-much, too-fast alterations in synaptic size and strength could be deleterious. They could, for example, trigger epilepsy. It’s good to have that brake pedal.

Shatz recently found that PirB-deficient mice, even when they’re carrying two mutations that strongly predispose people to Alzheimer’s, develop no symptoms of Alzheimer’s. They get through mazes just fine. Their memories seem intact…


  • Lane Simonian

    Scientists continue to nibble around the corners of Alzheimer’s disease. Alzheimer’s disease is the result of oxidative stress. Here is a short-list of factors that cause oxidative stress and can lead to Alzheimer’s disease: high glucose levels (from sugar and carbohydrates), high blood pressure, high fructose consumption, traumatic brain injury, stress, post traumatic stress disorder, certain chronic bacterial and viral infections, certain pesiticides and herbicides, air pollutants, aluminium fluoride, sodium fluoride, smoking, excessive alcohol consumption, lack of exercise, the osteoporosis drug Fosamax, the Apoe4 gene, amyloid protein precursor gene mutations, and presenilin gene mutations. Some of these risk factors for Alzheimer’s disease are modifiable and others are not.

    Amyloid and tau are the wrong targets. Oxidative stress can lead to amyloid oligomers and plaques and to tangles, but in the absence of oxidative stress (and/or in an intact antioxidant system), amyloid and tau do no damage. In conditions of oxidative stress various forms of amyloid can contribute to that stress, but the body keeps converting the amyloid into forms that are less toxic-from a c-terminal fragment of the amyloid precursor protein to amyloid oligomers to amyloid plaques.

    The primary oxidant in Alzheimer’s disease is peroxynitrite. Peroxynitrite inhibits the release and synthesis of neurotransmitters involved in short-term memory, sleep, mood, social recognition, and alertness. Peroxynitrite prevents the regeneration of neurons and contributes to the death of neurons.

    Alzheimer’s disease has been partially reversed in human clinical trials by methoxyphenols-which because of their electron and hydrogen donating capacities are particularly good peroxynitrite scavengers. This includes eugenol in rosemary essential oil via aromatherapy (Jimbo, et al.), eugenol and ferulic acid in a tincture of lemon balm (Akhondzadeh, 2003), and ferulic acid and syringic acid in red panax ginseng and heat-processed ginseng (Heo, et. al. 2011 and 2012).

    Once it is understood that Alzheimer’s disease is an oxidative disease that the pathways to preventing and treating the disease become much clearer.

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