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he defective proteins that are widely thought to kill brain neurons and cause, or at least indicate, Alzheimer’s disease do not always have that calamitous result, scientists reported on Monday, raising more doubts about conventional approaches to diagnosing and finding treatments for Alzheimer’s.

The researchers analyzed the brains of eight people who died in their 90s and who had excellent recall until then. Three of the eight brains had the defining amyloid plaques and tau tangles of Alzheimer’s, yet somehow were “immune to [their] effects,” said neurologist Changiz Geula, of Northwestern University Feinberg School of Medicine, who led the study and presented the results at the annual meeting of the Society for Neuroscience in San Diego. “What’s significant about these findings is that they show there can be high densities of plaques and tangles in the brains of some elderly individuals who are cognitively normal or even superior.”

Although the study was small and preliminary, outside scientists were impressed. “This is an exciting paper,” said Dean Hartley, director of science initiatives at the Alzheimer’s Association, adding that Geula and his colleagues were “producing very solid work.”

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Previous studies have shown that some people with numerous amyloid plaques did not have Alzheimer’s or other signs of cognitive pathology before they died, but “these findings are clearer than prior ones because the patients are older,” said George Perry, dean of the College of Sciences at the University of Texas, San Antonio. That is, by 90-something, amyloid plaques and tau tangles should have wreaked their terrible havoc.

The findings raise the obvious question of why some people are immune to molecules widely thought to be lethal to brain neurons and synapses. Geula and his colleagues plan to look for genetic, dietary, and environmental factors that might protect against both amyloid plaques, the sticky blobs that form between neurons, and tau tangles, twisted strands of a protein that build up within neurons.

Inside a healthy brain, proteins called beta amyloids are destroyed; in the brains of people with Alzheimer's disease, they are not and accumulate to form sticky plaques. Dom Smith/STAT

Two main explanations for “Alzheimer’s brains” that don’t develop Alzheimer’s are emerging.

One, known as cognitive reserve, holds that if people are well-educated and intellectually engaged throughout life, they won’t show the memory and cognitive impairments that otherwise come with the loss of synapses and death of neurons in the brain’s memory and thinking regions. Such people have enough backup neurons and redundant synapses to withstand some losses, much as an external hard drive lets a computer withstand the loss of, say, the Word files in a computer’s internal memory.

“What you do in your life somehow protects against these otherwise toxic molecules, allowing you to lose cells and synapses and still function,” said Hartley.

The other possibility is even more intriguing. Perhaps biochemical or genetic mechanisms prevent cognitive decline even when the brain is riddled with pathological amyloid and tau. For instance, some people might produce molecules that make amyloid nontoxic, in which case even if plaques build up they don’t destroy synapses. Or, some genetic or other factor might make synapses strong enough to endure even the toxicity of amyloid. If such protective molecules were discovered, they might inspire lab-made versions to prevent or treat Alzheimer’s.

Scientists are intently looking for such molecules, but in the meantime the finding that an amyloid-ridden brain is not necessarily a brain with Alzheimer’s underlines a longstanding concern about the brain scans sometimes used to diagnose Alzheimer’s.

Since 2012, US health regulators have approved three molecular tracers that bind to amyloid and can be used to visualize it via PET or other neuroimaging, which costs from $3,000 to $7,000 and is not covered by Medicare. Some experts have called for screening everyone older than about 50 for signs of amyloid. But even before this study, research as far back as 1991 showed that “many people have amyloid plaques in the brain but have no symptoms of cognitive decline or Alzheimer’s disease,” according to the Alzheimer’s Association.

Scans can therefore “give false positives,” said Perry, a longtime skeptic of the idea that amyloid plaques are the chief cause of Alzheimer’s. “The value of the tests as a public health measure is questionable,” he said, and the Alzheimer’s Association does not recommend their routine use to diagnose the disease.

Geula’s team studied the brains of eight people older than 90 who were part of the 90+ Study at the University of California, Irvine. Soon before their deaths, the volunteers scored extremely high on memory tests compared to 90-somethings with a normal (for their age) score. After they died, their brains were scrutinized for telltale signs of Alzheimer’s.

Three had the characteristic amyloid plaques and tau tangles. (The other five brains looked normal.) But cells in the memory-forming hippocampus and the higher-order-thinking frontal cortex were relatively intact, somehow withstanding the toxic effects of amyloid and tau. The search is on for what’s protecting them.

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  • My mother’s problems began when she began to take cholesterol drugs and developed Diabetes. I don’t think that these statins are helping the elderly. I have an aunt, who is ninety three and my mother in law, eighty eight, with high cholesterol and they have refused to take statins. They are alive and very lucid.

  • The third possibility dovetails with what we know: ad pathology starts up 15 years prior to onset of symptoms. These people had preclinical disease.

  • There is another issue relating to Alzheimer’s disease that is often not talked about: studies have shown that elevated activity of the default network (DMN) of the brain is significantly associated with Alzheimer’s disease – elevated activity of the DMN happen through mental proliferation, stress, worries, rumination, etc. On the other hand, studies have also shown that activities that decrease DMN activity (engaging in goal-directed cognitive tasks) decrease Alzheimer’s: this would explain why educated people (i.e., people often engaged in active cognitive tasks) have less Alzheimer’s. Interestingly, a recent study showed that the practice of meditation leads to reduced activity in the DMN even beyond being engaged in an active task (check out the article titled ‘Meditation leads to reduced default mode network activity beyond an active task’ published in Cogn Affect Behav Neurosci), thus, engaging in mindfulness meditation may prevent Alzheimer’s disease (also check out the article titled ‘Potential benefits of mindfulness-based interventions in mild cognitive impairment and Alzheimer’s disease: an interdisciplinary perspective’ published in Behav Brain Res.)

  • There is another issue relating to Alzheimer’s disease that is often not talked about: studies have shown that elevated activity of the default network (DMN) of the brain is significantly associated with Alzheimer’s disease. Elevated activity of the DMN happen through mental proliferation, stress, worries, rumination, etc. On the other hand, studies have also shown that activities that decrease DMN activity (engaging in goal-directed cognitive tasks) decrease Alzheimer’s: this would explain why educated people (i.e., people often engaged in active cognitive tasks) have less Alzheimer’s. Interestingly, a recent study showed that the practice of meditation leads to reduced activity in the DMN even beyond being engaged in an active task (http://www.ncbi.nlm.nih.gov/pubmed/25904238 ), thus, engaging in mindfulness meditation may prevent Alzheimer’s disease (also see: http://www.ncbi.nlm.nih.gov/pubmed/24893317 )

  • The key to Alzheimer’s disease is not amyloid plaques and neurofibrillary tangles; the key to Alzheimer’s disease is oxidative stress. As long as oxidative stress is limited, it is possible to have both plaques and tangles in one’s brain and not have Alzheimer’s disease.

    The key to treating the disease is not to remove plaque and tangles, the key to treating the disease is to reverse (as much as possible) the damage done by nitro-oxidative stress. Compounds that do this include cannabidiol, THC, and terpenes in CBD oil from marijuana; eugenol, geraniol and linalool in rosemary, lemon, orange, and lavender essential oils via aromatherapy, and ferulic acid, syringic acid, maltol, p-coumaric acid, and vanillic acid in panax ginseng.

  • Curiously, it is not mentioned a third simplest (and likeliest) explanation:

    Amyloid plaques and tau tangles have little to do with the cognitive deficits associated with AD.

    Probably because, pretty much every big shot both in industry and academia have made their career on the assumption that plaques and tangles are the culprit of AD, even though evidence keeps mounting against that assumption. And if that is the case, all their academic (and financial) achievements would be put into question

    • Agreed Ralf. I’ve long been skeptical of this theory. Medicine has a longstanding and ongoing problem with correlation being assumed to be causation.
      There is a Turkish proverb that seems applicable. “No matter how far you have gone on the wrong road, turn back.”
      This may not be the wrong road, but it feels like it’s the only one being taken seriously, despite the mounting evidence.

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