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New clue to Alzheimer's disease
Lane Simonian
Posted: Saturday, September 20, 2014 10:39 AM
Joined: 12/12/2011
Posts: 4854

This study provides a very important clue as to the origins of Alzheimer's disease. 



Using a high-end mass spectrometry, we screened phosphoproteins and phosphopeptides in four types of Alzheimer's disease (AD) mouse models and human AD postmortem brains. We identified commonly changed phosphoproteins in multiple models and also determined phosphoproteins related to initiation of Aβ deposition in the mouse brain. After confirming these proteins were also changed in and human AD brains, we put the proteins on experimentally verified protein-protein interaction databases. Surprisingly most of the core phosphoproteins were directly connected, and they formed a functional network linked to synaptic spine formation. The change of the core network started at a preclinical stage even before histological Aβ deposition. Systems biology analyses suggested phosphorylation of MARCKS by over-activated kinases including PKCs and CaMKs initiates synapse pathology. Two-photon microscopic observation revealed recovery of abnormal spine formation in the AD model mice by targeting a core protein MARCKS or by inhibiting candidate kinases, supporting our hypothesis formulated based on phosphoproteome analysis. 


And a corresponding chart: 




PLC: phospholipase C; PIP2: phosphatidylinositol 4,5 biphosphate, PKC: protein kinase C; Gq: g protein.



High levels of myo-inositol (due to high glucose levels, high sodium levels, or Down syndrome) and/or the oveactivation of protein kinase C (via g protein-coupled receptors, tyrosine receptor kinases, or direct g protein activation) by such factors as stress, air pollutants, various herbicides and pesticides, various chronic bacterial and viral infections, aluminum fluoride, sodium fluoride, high fructose corn syrup, benzodiazepines, and bisphenols in plastitcs can lead to Alzheimer's disease.  The irony is that protein kinase C also activates the neuroprotective phosphatidylinositol 3-kinase/Akt pathway under conditions of non-oxidative or mild oxidative stress. Presenilin gene mutations, bisphosponate osteoporosis drugs, and factors leading to oxidative stress cut off this pathway.  A Mediterranean diet or a diet from India high in spices and herbs and omega 3 fatty acids inhibit the over-activation of protein kinase C and thus delay the onset of Alzheimer's disease. 


 2005 Dec;26 Suppl 1:133-6. Epub 2005 Nov 2.

Prevention of Alzheimer's disease: Omega-3 fatty acid and phenolic anti-oxidant interventions.


Alzheimer's disease (AD) and cardiovascular disease (CVD) are syndromes of aging that share analogous lesions and risk factors, involving lipoproteins, oxidative damage and inflammation. Unlike in CVD, in AD, sensitive biomarkers are unknown, and high-risk groups are understudied. To identify potential prevention strategies in AD, we have focused on pre-clinical models (transgenic and amyloid infusion models), testing dietary/lifestyle factors strongly implicated in reducing risk in epidemiological studies. Initially, we reported the impact of non-steroidal anti-inflammatory drugs (NSAIDs), notably ibuprofen, which reduced amyloid accumulation, but suppressed few inflammatory markers and without reducing oxidative damage. Safety concerns with chronic NSAIDs led to a screen of alternative NSAIDs and identification of the phenolic anti-inflammatory/anti-oxidant compound curcumin, the yellow pigment in turmeric that we found targeted multiple AD pathogenic cascades. The dietary omega-3 fatty acid, docosahexaenoic acid (DHA), also limited amyloid, oxidative damage and synaptic and cognitive deficits in a transgenic mouse model. Both DHA and curcumin have favorable safety profiles, epidemiology and efficacy, and may exert general anti-aging benefits (anti-cancer and cardioprotective.).


In Alzheimer's disease, before there is amyloid there are peroxynitrites (amyloid in the absence of significant amounts of peroxynitrites means no Alzheimer's disease). Currently the best treatment for the disease is methoxyphenol scavengers of peroxynitrites, such as eugenol in various essential oils, ferulic acid and eugenol in lemon balm extract, and ferulic acid, vanillic acid, syringic acid, maltol, and p-coumaric acid in heat-processed ginseng. 

Posted: Saturday, September 20, 2014 11:14 AM
Joined: 9/12/2013
Posts: 3579

Saturday, September 20, 2014

Simple test can help detect Alzheimer's

Alzheimer's Reading Room

York University researchers say a simple test that combines thinking and movement can help to detect heightened risk for developing Alzheimer's disease in a person, even before there are any telltale behavioural signs of dementia.

Faculty of Health Professor Lauren Sergio and PhD candidate Kara Hawkins who led the study asked the participants to complete four increasingly demanding visual-spatial and cognitive-motor tasks, on dual screen laptop computers.

The test aimed at detecting the tendency for Alzheimer's in those whowere having cognitive difficulty even though they were not showing outward signs of the disease.

Test Your Memory for Alzheimer's (5 Best Tests)

We included a task which involved moving a computer mouse in the opposite direction of a visual target on the screen, requiring the person's brain to think before and during their hand movements," says Sergio in the School of Kinesiology & Health Science. "This is where we found the most pronounced difference between those with mild cognitive impairment (MCI) and family history group and the two control groups."
  • Hawkins adds, "We know that really well-learned, stereotyped motor behaviours are preserved until very late in Alzheimer's disease." 
  • These include routine movements, such as walking. The disruption in communication will be evident when movements require the person to think about what it is they are trying to do.

For the test, the participants were divided into three groups – those diagnosed with MCI or had a family history of Alzheimer's disease, and two control groups, young adults and older adults, without a family history of the disease.

The study, Visuomotor Impairments in Older Adults at Increased Alzheimer's Disease Risk, published in the Journal of Alzheimer's Disease, found that 81.8 per cent of the participants that had a family history of Alzheimer's disease and those with MCI displayed difficulties on the most cognitively demanding visual motor task.
"The brain's ability to take in visual and sensory information and transform that into physical movements requires communication between the parietal area at the back of the brain and the frontal regions," explains Sergio. "The impairments observed in the participants at increased risk of Alzheimer's disease may reflect inherent brain alteration or early neuropathology, which is disrupting reciprocal brain communication between hippocampal, parietal and frontal brain regions."
"In terms of being able to categorize the low Alzheimer's disease risk and the high Alzheimer's disease risk, we were able to do that quite well using these kinematic measures," says Hawkins. "This group had slower reaction time and movement time, as well as less accuracy and precision in their movements."
Hawkins says the findings don't predict who will develop Alzheimer's disease, but they do show there is something different in the brains of most of the participants diagnosed with MCI or who had a family history of the disease.

York University is helping to shape the global thinkers and thinking that will define tomorrow. York's unwavering commitment to excellence reflects a rich diversity of perspectives and a strong sense of social responsibility that sets us apart.

Gloria Suhasini, York University Media Relations

Lane Simonian
Posted: Tuesday, September 23, 2014 10:44 AM
Joined: 12/12/2011
Posts: 4854

The tide against Alzheimer's disease is beginning to turn.  New ways of detecting the disease and treating it are being discovered.  More researchers are recognizing that while some forms of amyloid may contribute to Alzheimer's disease, they are not the cause.  Once the transition is fully made to understanding that Alzheimer's disease is driven by oxidation and inflammation, then the sluice gates to its effective treatment will open, as there are a variety of plant compounds that can combat both oxidation and inflammation.

Here is a recent outstanding article by researchers who are closing in on a better understanding of Alzheimer's disease.

“Whenever a theory appears to you as the only possible one, take this as a sign that you have neither understood the theory nor the problem which it was intended to solve.” – Karl Popper
Inconsistencies and controversies surrounding the Amyloid Hypothesis of Alzheimer’s disease
Gary P Morris et al.

Controversies and Inconsistencies within the current amyloid hypothesis. 1. Aβ deposition occurs in cognitively normal individuals (Aβ deposition occurs in cognitively normal individuals); 2. There is a weak correlation between plaque load and cognition (The rise of the soluble Aβ hypothesis); 3. The biochemical nature and presence of Aβ oligomeric assemblies in vivo is unclear (Uncertainty surrounding the presence of Aβ oligomers in vivo); 4. Pre-clinical AD models based on EOAD-linked mutations are biased toward the amyloid hypothesis (Pre-clinical AD models are not representative of human disease); 5. Pathological heterogeneity and comorbidities are unexplained by the amyloid hypothesis (AD symptoms and pathology are heterogeneous); 6. Aβ has a normal physiological role and targeting Aβ may disrupt these roles over the long term (Pre-clinical AD models are not representative of human disease); 7. Genetic factors linked to AD can be interpreted independently of amyloid (A complex picture indeed); 8. APP cleavage and biology is more complex than solely the production of Aβ, indicating other APP family members may play a role in disease progression (Understanding the complexity of APP biology independently of Aβ is important to understanding AD pathogenesis); 9. The triggers of synapse loss, neuronal loss and neuroinflammation in AD are still unclear (Redefining ‘neuroinflammation’ through viewing the synapse as a complex multicellular structure is important in future AD research); 10. The relationship between Aβ and tau pathologies is unclear (The inflammatory hypothesis of AD is a valid alternative to the amyloid hypothesis); 11. The onset of dementia in Down’s Syndrome is highly variable, despite the presence of fibrillar plaques in 100% of Down’s individuals by the fifth decade (Aβ deposition occurs in cognitively normal individuals); 12. The APOE4 genotype has numerous functional effects, rather than solely relating to reduced Aβ clearance, including links to enhanced inflammatory phenotypes (APOE4 dysfunction is also related to inflammation).

Lane Simonian
Posted: Tuesday, September 23, 2014 6:52 PM
Joined: 12/12/2011
Posts: 4854

It keeps getting better: 



According to reports published in the New England Journal of Medicine, the phase 3 clinical trials of two high-profile Alzheimer’s disease (AD) antibodies against the aggregation-prone peptide amyloid beta (Aβ), bapineuzumab and solanezumab, have failed to improve clinical outcomes in patients with late onset AD [1-3]. Along with their predecessors, these treatments have been informed by the long-standing amyloid hypothesis, and are the latest examples in a long list of unsuccessful attempts to treat AD with anti-amyloid therapies. Along with a chorus of others, we have previously argued against the assumption that Aβ accumulation is the primary early pathogenic trigger of AD [4-8]. An unintended consequence of that assumption, which contributes to the continued failure of anti-amyloid clinical trials, is that affirmative diagnosis of AD-type dementia can only occur when the presence of Aβ accumulation in the brain is confirmed. However, recent imaging studies confirm previous observations of Aβ accumulation in a significant proportion of non-demented individuals [4,9,10]. Conversely, a sizable proportion of patients clinically diagnosed with AD do not display Aβ accumulation-even though neurodegeneration is in progress [4,11]. Remarkably, rather than concluding that Aβ status is not a reliable marker for the early stages of clinical AD, a consensus has been reached in which clinically diagnosed AD patients without Aβ are classified as not suffering from AD. This line of thought is not scientifically warranted, as there is no evidence to assume that clinical AD cases with and without Aβ accumulation are etiologically different. Nevertheless, it has been used, in the EXPEDITION 3 phase of the ongoing solanezumab trial, to justify the exclusion of approximately 25% of patients in the study-all of whom were clinically diagnosed with mild AD, but whose imaging data showed no Aβ accumulation [1,3].
In that regard, several hypotheses that are not amyloid-centric have been proposed, although few have gained significant traction [6,31-35]. Unlike in the past, however, numerous independent researchers have now gathered sufficient information to strongly support a reworked conceptualization of late onset AD. Our recently proposed Adaptive Response Hypothesis synthesizes this work, proposing that Aβ may accumulate as part of an adaptive response to chronic brain stress stimuli [6]. These stress stimuli constitute the bona fide pathogenic triggers of late onset AD and, therefore, would be suitable candidates for therapeutic intervention [5-7,32,36]. In this model, illustrated in Figure 1B, the total population (Figure 1B, 1) can be affected by chronic stress stimuli (Figure 1B, 2) which may include, but are not limited to, oxidative stress, metabolic dysregulation (cholesterol homeostasis, insulin resistance, etc.), genetic factors, and inflammatory response [7,36]. Each of these stimuli is capable of eliciting a response in which Aβ is produced, and the nature of that response (not the total amount of Aβ that may accumulate in parallel) determines progression into clinical AD [5,6]. 

In summary, millions of research dollars, both private and public, are annually expended on anti-Aβ therapies that do not work and are based on a logically flawed hypothesis. At this point in time it is no longer unreasonable to suggest that further iterations of anti-Aβ therapies may not be in the best interest of late onset AD patients. Clinicians and researchers should instead direct their attention toward better understanding of the biological function of Aβ in the healthy brain, and the ways in which chronic stress over decades can negatively affect the brain. 

Amyloid is not the cause of Alzheimer's disease. 

Factors leading to oxidative stress (psychological stress, environmental toxins, high glucose levels, high sodium levels, smoking, excessive alcohol consumption, various medications, etc.) provide potential triggers for Alzheimer's disease. 

Whether early onset or late onset; whether at the early stages or the late stages of the disease, Alzheimer's disease can be effectively treated with the appropriate antioxidants. 

Lane Simonian
Posted: Wednesday, September 24, 2014 10:42 PM
Joined: 12/12/2011
Posts: 4854

Here really is the whole key to understanding Alzheimer's disease: pathways that protect the brain under normal circumstances destroy the brain when over-activated by factors leading to oxidative stress.

However, the responses of AMPK activation are dependent on stimulation and the extent of activating stress. Evidently, AMPK signaling can repress and delay the appearance of AD pathology but later on, with increasing neuronal stress, it can trigger detrimental effects that augment AD pathogenesis. We will outline the potential role of AMPK function in respect to various aspects affecting AD pathogenesis.

Posted: Friday, September 26, 2014 5:41 AM
Joined: 4/24/2012
Posts: 484

Lane, you have put together some very convincing evidence! Thank you. What you are arguing for here, from what I have researched, is very likely. Here are a couple of quotes from above that particularly hit home for me:


"the onset of dementia in Down’s Syndrome is highly variable, despite the presence of fibrillar plaques in 100% of Down’s individuals by the fifth decade (Aβ deposition occurs in cognitively normal individuals); 12. The APOE4 genotype has numerous functional effects, rather than solely relating to reduced Aβ clearance, including links to enhanced inflammatory phenotypes (APOE4 dysfunction is also related to inflammation)"


"In this model, illustrated in Figure 1B, the total population (Figure 1B, 1) can be affected by chronic stress stimuli (Figure 1B, 2) which may include, but are not limited to, oxidative stress, metabolic dysregulation (cholesterol homeostasis, insulin resistance, etc.), genetic factors, and inflammatory response [7,36]."


Leukine, which has been shown to remove amyloid, did not cure my mother. However, it did help, and that may be due to it's other immune system functions in reducing inflamation, oxidative stress, or cholesterol homeostasis.


I think we tend to discount simple thinigs like diet, exercise and stress as real causes of AD in favor of more exotic, devious and powerful dysfunctions. What we don't realize is that these "simple things" can be very powerful causes of dysfunction, like chronic inflammation.

Lane Simonian
Posted: Friday, September 26, 2014 10:24 AM
Joined: 12/12/2011
Posts: 4854

Beautifully and wisely said, Serenoa.  And all of it, I believe is true.

There are multiple factors that can lead to Alzheimer's disease, but some are very simple and common which likely explains the majority of cases of people with Alzheimer's disease.  Many of our diets have become loaded with substances that produce oxidation and inflammation with few countervailing antioxidants, we have become increasingly sedentary, and increasingly stressed.  We may be living longer but not necessarily better.