Ability to Remove Alzheimer’s Disease Protein From the Brain Slows With Age

The greatest risk factor for Alzheimer’s disease is advancing age. After 65, the risk doubles every five years, and 40 percent or more of people 85 and older are estimated to be living with the devastating condition.

Researchers at Washington University School of Medicine in St. Louis have identified some of the key changes in the aging brain that lead to the increased risk. The changes center on amyloid beta 42, a main ingredient of Alzheimer’s brain plaques. The protein, a natural byproduct of brain activity, normally is cleared from the brain before it can clump together into plaques. Scientists long have suspected it is a primary driver of the disease.

“We found that people in their 30s typically take about four hours to clear half the amyloid beta 42 from the brain,” said senior author Randall J. Bateman, MD, the Charles F. and Joanne Knight Distinguished Professor of Neurology. “In this new study, we show that at over 80 years old, it takes more than 10 hours.”

The slowdown in clearance results in rising levels of amyloid beta 42 in the brain. Higher levels of the protein increase the chances that it will clump together to form Alzheimer’s plaques.

The results appear online in the Annals of Neurology.

For the study, the researchers tested 100 volunteers ages 60 to 87. Half had clinical signs of Alzheimer’s disease, such as memory problems. Plaques had begun to form in the brains of 62 participants.

The subjects were given detailed mental and physical evaluations, including brain scans to check for the presence of plaques. The researchers also studied participants’ cerebrospinal fluids using a technology developed by Bateman and co-author David Holtzman, MD, the Andrew B. and Gretchen P. Jones Professor and head of the Department of Neurology at Washington University. The technology — known as stable isotope-linked kinetics (SILK) — allowed the researchers to monitor the body’s production and clearance of amyloid beta 42 and other proteins.

In patients with evidence of plaques, the researchers observed that amyloid beta 42 appears to be more likely to drop out of the fluid that bathes the brain and clump together into plaques. Reduced clearance rates of amyloid beta 42, such as those seen in older participants, were associated with clinical symptoms of Alzheimer’s disease, such as memory loss, dementia and personality changes.

This shows a amyloid plaques in the brain.
A new study reveals that the brain’s ability to clear the main ingredient of Alzheimer’s plaques slows with age (the plaques are red in this image). The findings could help explain why risk of the disease increases with age. Image credit: John Cirrilto.

Scientists believe the brain disposes of amyloid beta in four ways: by moving it into the spine, pushing it across the blood-brain barrier, breaking it down or absorbing it with other proteins, or depositing it into plaques.

“Through additional studies like this, we’re hoping to identify which of the first three channels for amyloid beta disposal are slowing down as the brain ages,” Bateman said. “That may help us in our efforts to develop new treatments.”

About this Alzheimer’s disease research

Funding: This research was supported by the National Institutes of Health (NIH), grants R01NS065667, K23AG030946, P50 AG05681, P01 AG03991, UL1 RR024992, P30 DK056341, P41 GM103422 and P30 DK020579; the Adler Foundation; and by philanthropic gifts from Edwin and Barbara Shifrin and Jeff Roschman.

Source: Michael C. Purdy – WUSTL
Image Credit: The image is credited to John Cirrilto
Original Research: Abstract for “Age and amyloid effects on human central nervous system amyloid-beta kinetics” by Bruce W. Patterson, Donald L. Elbert, Kwasi G. Mawuenyega, Tom Kasten, Vitaliy Ovod, Shengmei Ma, Chengjie Xiong, Robert Chott, Kevin Yarasheski, Wendy Sigurdson, Lily Zhang, Alison Goate, Tammie Benzinger, John C. Morris, David Holtzman and Randall J. Bateman in Annals of Neurology. Published online July 20 2015 doi:10.1002/ana.24454


Abstract

Age and amyloid effects on human central nervous system amyloid-beta kinetics

Objective
Age is the single greatest risk factor for Alzheimer’s disease (AD), with the incidence doubling every 5 years after age 65. However, our understanding of the mechanistic relationship between increasing age and the risk for AD is currently limited. We therefore sought to determine the relationship between age, amyloidosis, and amyloid-beta (Aβ) kinetics in the central nervous system (CNS) of humans.

Methods
Aβ kinetics were analyzed in 112 participants and compared to the ages of participants and the amount of amyloid deposition.

Results
We found a highly significant correlation between increasing age and slowed Aβ turnover rates (2.5-fold longer half-life over five decades of age). In addition, we found independent effects on Aβ42 kinetics specifically in participants with amyloid deposition. Amyloidosis was associated with a higher (>50%) irreversible loss of soluble Aβ42 and a 10-fold higher Aβ42 reversible exchange rate.

Interpretation
These findings reveal a mechanistic link between human aging and the risk of amyloidosis, which may be owing to a dramatic slowing of Aβ turnover, increasing the likelihood of protein misfolding that leads to deposition. Alterations in Aβ kinetics associated with aging and amyloidosis suggest opportunities for diagnostic and therapeutic strategies. More generally, this study provides an example of how changes in protein turnover kinetics can be used to detect physiological and pathophysiological changes and may be applicable to other proteinopathies.

“Age and amyloid effects on human central nervous system amyloid-beta kinetics” by Bruce W. Patterson, Donald L. Elbert, Kwasi G. Mawuenyega, Tom Kasten, Vitaliy Ovod, Shengmei Ma, Chengjie Xiong, Robert Chott, Kevin Yarasheski, Wendy Sigurdson, Lily Zhang, Alison Goate, Tammie Benzinger, John C. Morris, David Holtzman and Randall J. Bateman in Annals of Neurology. Published online July 20 2015 doi:10.1002/ana.24454

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  1. Continuing :

    Using the logic,we can observe that the disorders that happens Upstreams and too during the Glymphatic disfunctions, are the high peroxinitrites accumulation,the mitochondrial dysfunctions,the brain energy disorders,neuroinflammation,that in a sequence and in a vicious circle,preceeds in years and leads to the glymphatic dysfunction,once a Central Nervous System with such disorders,as energy deprivation,can Not have enough energy to improves the glymphatic function.

    Then even giving specific drugs that enhances “downstreams” the glymphatic function or works as betamyloid “cleaners”(as diosmin),without to treat simultaneously the “upstreams” brain energy disorders , the neurons will still suffer apoptosis or necrosis by energy “starvation”.

    As a metaphor,if the Owner of a house has health problems that are deprivating his brain and body energy,disabling him to clean his own home,if someone gets some people to assist the homeowner in cleansing,they can even keeps the house more clean,however the homeowner wiil still continue with his health problems (still without energy to do what he usually did before to be weak.)

    But over the years,even with some help to “drain the wastes” of his house(his brain),the lack of physical and mental energy, can leads the homeowner to die slowly due energy deprivation.

    The logic shows that the brain needs help to clean up it own mess “(cell debris) by hiring assistants (diosmin),but mainly needs too drugs and/or supplements to treat the disorders that happens upstreams (peroxinitrites accumulation, mitochondrial dysfuernction, brain energy disorders, neuroinflammation, etc) that are the actual disorders that are leaving the own of the house (the brain) without enough energy to clear his house or , even to have a good quality of life , or to survive.

    Giving peroxinitrites scavengers, enhancing mitochondrial function , giving alternative fuel neurons , as glucuronolactone , ALCAR , Carnosine,and Diosmin ,all in small doses , and a healthy lifestyle,maybe,can works in dementias …

  2. THE FLAVONOID DIOSMIN CAN IMPROVES THE GLYMPHATIC SYSTEM FUNCTION (the lymphatic system specific to the Central Nervous System , CNS) LEADING TO LOWERS BETAMYLOID EXCESS IN THE BRAIN. AND DIOSMIN IS A NATURAL GSK-3 INHIBITOR, LOWERING IN A DIRECT WAY THE BETAMYLOID ACCUMULATION IN THE CNS.

    In any part or any organs of the human bodies , the oxygen and sugar are transported from the blood vessels to nourish the cells via the another system of “pipes” called Lymphatic System.
    Likewise, wastes from the cells,carbon dioxide, lactic acid and metabolites, are carried back (clearance) to the bloodstream through the fluid in the pipes” of the Lymphatic System (LS) .

    “The lymphatic system is as essential to body function as the bloodstream . But protective complements,through diet, stress reduction, exercise and deep breathing, improves it cleansing function” (quote of dr. Gerald M. Lemole, M.D.).

    Otherwise ,the GLYMPHATIC SYSTEM (or glymphatic clearance pathway) is a functional waste clearance pathway specific to the CENTRAL NERVOUS SYSTEM (CNS ).

    The Glymphatic System (GS) does the clearance of betamyloid and tau accumulation , between others wastes of cells in the CNS, and that looks to fits to the article above.
    But betamyloid and tau are the lasts steps and do Not cause AD ,but are consequence of upstreams disorders.

    DIOSMIN is a flavonoid present in oranges and others fruits, etc., and is a nutraceutical supplement that has a DOUBLE PROTECTIVE FUNCTION :

    1) DIOSMIN, increasing the noradrenaline effects in the venous and lymphatic vessels, works improving the “cleanser and drainage” function of the Lymphatic system ( in whole body) , and improves the GLYMPHATIC SYSTEM function, in the CNS, lowering betamyloid excess in the brain , etc.

    2) DIOSMIN is a natural GSK-3 INHIBITOR, that leads to,lowers betamyloid accumulation in the brain.
    Article : “Flavonoid-Mediated Presenilin-1 Phosphorylation Reduces Alzheimer’s Disease Betamyloid Production” , authors Kavon Rezai-Zadeh ,Terrence Town and colleagues from the, Department of Psychiatry & Behavioral Medicine, University of South Florida,USA , published in the Journal of Cellular and Molecular Medicine .

    3) Researchers can uses DIOSMIN as a safe and very effective biochemical and pharmacological basis to develops others substances with a higher effectiviness.

    As the flavonoid DIOSMIN in capsules is used to treat lymphedemas and venous stasis in the legs, and as the doses for such treatments are a little high once they target a short and faster treatment to relieve capillary impairment and venous and lymphatic insufficiency of the lower limb, and for hemorrhoids, as a hypothesis , maybe , in chronic use , the SAFER IS TO USE VERY SMALL DOSES , FIVE TO SIX TIMES LOWER than the usual doses for hemorrhoids ,for example, to be safer for elders.(only under physician prescription).

    Remembering that another reason to use very LOW doses in chronic use of diosmin in ELDERS , is that as all antioxidants and all flavonoids, such supplements can have synergistic effects with antiplatelets drugs as aspirin and as xarelto, and synergistic effects with anticoagulants as coumarin (Warfarin) , etc.

    THE MECHANISM OF ACTION OF DIOSMIN IS BY AN INCREASE IN THE NORADRENALINE EFFECTS in the functions of venous, lymphatic and glymphatic vessels, improving the function of such vessels.
    Then DIOSMIN, used in HIGH DOSES ,by an increasing in noradrenaline levels and in the righ atrial pression , can leads to WORSENS temporaly patients with chronic atrial fibrillation .

    Then for CHRONIC USE BY ELDERS ,during long periods of time , the safest are the very very small doses, and ONLY under physician prescription.

    Researchers can uses DIOSMIN as a safe and very effective biochemical and pharmacological basis to develops others substances with a higher effectiviness.

    But using the logic , or the Rational Thinking , we can observe that the disorders that happens upstreams to the glymphatic disfunctions, as the high peroxinitrites accumulation, the mitochondrial dysfunctions, the brain energy disorders ,neuroinflammation , that in a sequence and in a vicious circle , preceeds in years and leads to the glynphatic dysfunction , once a Central Nervous System with such disorders , can Not have enough energy to improves glymphatic function.

    Then even giving specific drugs that enhances “downstreams” the glymphatic function or works as abeta “cleaners”, without to treat “upstreams” the brain energy disorders ,without to supply the neurons with enough energy , the neurons will still suffer apoptosis or necrosis if we dol Not prevent and treat the main brain disorders (peroxinitrites accumulation, mitochondrial dysfunction, brain energy disorders, neuroinflammation) that preceeds , and leads , years later to the glymphatic disorders.

    To use a “combo” of substances that have synergistic effects to treat the main and “upstreams” disorders , as to givves supplements or drugs that are peroxinitrites scavengers , mitochondrial function improvers, alternative fuels to the neurons,etc., can enable the brain to “clean” by it self the wastes of cells, and more than this , to improves the brain functions.
    ALCAR , CARNOSINE , GLUCURONOLACTONE , are a good sources to researchers find effective treatments to neurodegenerative diseases, as DIOSMIN (in very small doses) and HESPERIDINE are too.

    1. Continuing :

      Using the logic,we can observe that the disorders that happens Upstreams and too during the Glymphatic disfunctions, are the high peroxinitrites accumulation,the mitochondrial dysfunctions,the brain energy disorders,neuroinflammation,that in a sequence and in a vicious circle,preceeds in years and leads to the glymphatic dysfunction,once a Central Nervous System with such disorders,as energy deprivation,can Not have enough energy to improves the glymphatic function.

      Then even giving specific drugs that enhances “downstreams” the glymphatic function or works as betamyloid “cleaners”(as diosmin),without to treat simultaneously the “upstreams” brain energy disorders , the neurons will still suffer apoptosis or necrosis by energy “starvation”.

      As a metaphor,if the Owner of a house has health problems that are deprivating his brain and body energy,disabling him to clean his own home,if someone gets some people to assist the homeowner in cleansing,they can even keeps the house more clean,however the homeowner wiil still continue with his health problems (still without energy to do what he usually did before to be weak.)

      But over the years,even with some help to “drain the wastes” of his house(his brain),the lack of physical and mental energy, can leads the homeowner to die slowly due energy deprivation.

      The logic shows that the brain needs help to clean up it own mess “(cell debris) by hiring assistants (diosmin),but mainly needs too drugs and/or supplements to treat the disorders that happens upstreams (peroxinitrites accumulation, mitochondrial dysfuernction, brain energy disorders, neuroinflammation, etc) that are the actual disorders that are leaving the own of the house (the brain) without enough energy to clear his house or , even to have a good quality of life , or to survive.

      Giving peroxinitrites scavengers, enhancing mitochondrial function , giving alternative fuel neurons , as glucuronolactone , ALCAR , Carnosine,and Diosmin ,all in small doses , and a healthy lifestyle,maybe,can works in dementias …

  3. Okay, there’s a relationship between age and Alzheimer’s risk, but WHY? And why is it that this seems to have increased so significantly in the last 150 years? Is there something in our culture or environment that has changed faster then human evolution?

    Can’t all this be tied to the invention of artificial lights, especially those in our electronics and energy-saving lightbulbs that use the blue spectrum 400-500nm and interfere with melatonin production? Can’t this be tied to dysrhytmias in economics and society that causes both parents to work, to work longer (always-connected), and in work environments that reward workaholism and devalue sleep? Is it not a coincidence that we sleep about 2 hours LESS today then before Thomas Edison’s lightbulb? Let’s see more articles on the effect sleep has on brain health, and overall health and performance.

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