1. If you don't know the cause, you can't find a cure.2. Make sure you aren't adding to the significant misdiagnosis figures by failing to rule out dementia mimics.

As an other neurodegenerative disease - glaucoma, etc.the best treatment opition will be directed to Neuroprotection, which makes the search of therapy and supposed drugs nonevidence-based. The latest approach

selected sterols could help in the treatment of a host of other human diseases such as cardiomyopathy and neurodegenerative diseases where similar proteins are involved. As more details on the mechanism of action become known, it is possible that such sterol-based drugs could have applications for the treatment of Parkinson’s disease, Alzheimer’s disease and other types of dementia.

If you are interested let me know and I can send you a  Reference for Sterols

Dear Dr.Shahsuvaryan 

Thank you very much for your reply and yes please I would like to read more about sterols.

Much appreciated

Sweilem

Dear Dr.Al Rihani,

This is the Reference

My Best regards

Leah N. Makley1,*,Kathryn A. McMenimen1,Brian T. DeVree3,Joshua W. Goldman2,Brittney N. McGlasson2, Ponni Rajagopal4, et al. Pharmacological chaperone for α-crystallin partially restores transparency in cataract models. Science  06 Nov 2015:Vol. 350, Issue 6261, pp. 674-677

DOI: 10.1126/science.aac9145

Its Difficult to find a cure for AD as the pathophysiology itself has multiple mechanisms ranging from oxidative stress to inflammation to neuronal loss. These pathophysiological sequale is progressive in nature and it worsens as age progresses. It is therefore to target one particular target to improve. To my knowledge, there is no clear animal model for AD, which simulates all clinical AD symptoms and therefore,  multi mechanistic approach might be fruitful. 

Thank you All and yes combination of drugs with different mechanisms might be the solution.

best wishes

 Dear Dr.Mohammad Kamal

Thank you for sharing the link for your publication and I will make sure to read your interesting work.

If you would like to give us a summary from your experience in this field that would be great.

Thanks

Sweilem 

I think main problem: what is initial causes? and what is consequence or accompanying phenomena? Then, we probably can develop some targeted therapy 

Think outside the box and investigate something that is different- find what is the initial or very early underlying molecular mechanisms causing age-dependent cognitive impairment and use that as a therapeutic target.

1. If you don't know the cause, you can't find a cure.2. Make sure you aren't adding to the significant misdiagnosis figures by failing to rule out dementia mimics.

Thanks All for your thoughtful comments

Dear Sweilem,

The majority of cases are sporadic and with unknown cause. This variability among patients makes it very difficult to understand, and complicates treatment. Another issue is the diagnosis and symptoms when more than 25% or neurons are lost at advanced ages when the regeneration capacity of the brain is significantly reduced.

best wishes, Refik

As Irene mentioned above -" If you don't know the cause, you can't find a cure.". Regretably  even those cholinergic drugs mentined by Sweilem  as  acting simptomaticaly have a very  very modest contribution  With respect to Alzheimer's Diasease we are now much far away from its understanding and treatment than we are from that of many cancers....   Why is it so ? Somebody said it is because in this case the brain has to investigate itself...

I suspect I am being repetitive, but this is a cause and effect scenario to me.  There are multiple causes for DRD's that range from ID to poor lifestyle choices to sports related injuries and of course heredity.  And these inputs result in 25 + different kinds of DRD's.  And top it all off, individuals are not getting the individualized attention from PCP's and GP's who are quick to prescribe Aricept, Nemenda, etc.  We need to look at the inputs and individuals more closely to determine the causes of CI and how to develop an appropriate research protocol.  Question #1 in research is "Are we asking the right questions?"  

With respect to the question about asking the wrong questions, I ask indulgence for the length of this response but I feel that there are issues re the dementias and their diagnosis that have to be reconsidered.

As someone who has spent several years assessing persons with various forms of dementia and following most to autopsy, I am becoming more and more alarmed at the scaremongering that fills the media about Alzheimer and other dementias. There are several million people diagnosed as having Alzheimer disease but that does not mean that they actually have the disease. The misdiagnosis rate has been shown to be between 30 and 50 percent. The early onset disease that tragically affects some families, is not, in fact, the same disease as later onset AD. Sir Terry Patchett, who died recently, was an example and though he was known as the poster boy for Alzheimer he actually had posterior cortical atrophy that  causes the progressive disruption of complex visual processing and other features that do not appear in late onset AD. Alzheimer’s first patient, Auguste D, was probably a case of early onset in its late stages. When his original materials were found in Frankfurt in 1995, it was seen that he had concentrated on the superior cortex, which contained multiple plaques and tangles, but ignored the hippocampus and entorhinal areas as well as the posterior brain.  It is heresy to suggest that we may have been following a tangential path for over a hundred years.

 Early onset disease must be seen as the distinct disease that it is requiring very different approaches to assessment and management. In addition, the diagnostic process that currently exists is shameful.  Most people don’t live near highly sophisticated medical centres with SPECT scans, PET, genetic testing etc. and rely on general practitioners for medical care. A GP is not trained in the very complex assessment of Alzheimer and other dementias, performs a few screening tests and makes a diagnosis. Few are aware of the many conditions that mimic dementia, one of the most common being significant hearing loss. Few patients are given a thorough physical examination first in order to rule out such conditions including the many medications and mixtures of medications that can cause the appearance of a dementia of which there are many types.  We hear about a “strategy” to fight Alzheimer disease with, as far as I can tell, few individuals trained and experienced in the nature and presentation of all of them, some familial  and another known as GSSD, almost always omitted from consideration of the genetic, autosomal dominant types. Without individuals who have extensive training and experience in assessment and have followed patients through to specific autopsy of the brain, we are lacking the fundamental essential armaments for the battle.

With respect to the question on pain in advanced disease, I would offer this:

Sir William Osler, a Canadian often called the “Father of Modern Medicine” created the first residency program for specialty training of physicians, and he was the first to bring medical students out of the lecture hall for bedside clinical training . He wrote the following around the early 1900s: “There are, in truth, no specialties in medicine, since to know fully many of the most important diseases a man must be familiar with their manifestations in many organs.”

You have right Irene - very few primary care physicians, who are probably those who cope with early cases of cognitive decline have the necessary preparation. Moreover they are even less prepared to provide proper care and support to the patients and their families along the long years of this deteriorating disease.As for the diagnostic  aspects i am not sure if easy access to sophysticated neuroimaging devices is the key to substantially contribute to this problem.  As for the proper research question - one such could be to what extent does the  distribution of histological findings in different regions of the brain reflect a different disease ?Another approach not much explored is to focus on nonagenarians with preserved cognitive function  and try to find out what gave them this " protection ". 

Arthur

I didn’t mean to imply that SPECT, PET etc. were necessary or even useful in the diagnosis of dementia but that there seems to be a growing conviction that they are.  My point is that, given the many studies over the past thirty years that have shown evidence of multiple plaques and tangles as well as marked brain atrophy in normal very elderly, we have perhaps been following the wrong path. It may be more useful to search for what is missing in the cognitively impaired brain than what is present. And have we really studied the glia adequately?

There is an interesting article by Russell Swerdlow that warrants a read, I think. Brain aging, Alzheimer's disease, and mitochondria.Russell H. Swerdlow. Biochimica et Biophysica Acta 1812 (2011) 1630–1639

Thank you - i will read that article . ( interesting author name )

Thank you very much Dear doctors as you made the discussion very fruitful and It's a great opportunity for me to learn from you.

highly appreciated 

I wonder whether we have to rethink about the amyloid theory for Alzheimer's disease. For almost 20 years the beta amyloid cascade theory has dominated thinking and research efforts in the developing of new pharmacological treatments. Beta amyloid antibodies are now in clinical trails, but the results do not appear so exiting, because often to the clerance of plaques doesn't correspond an improvement in cognitive functions.

Probably the early diagnosis may allow an early pharmacological treatment, and the drugs already avaliable or those that will arrive might give better results.

I think there is an underlying cause to Alzheimer's, which could also link to PD and other Lewy body diseases. My hunch is that this category of diseases share a common cause, most probably genetic, which then propagate due to different mechanism of actions which cause these different diseases. There is also probably a link to different regions of alpha-synuclein aggregation in the brain. All these are just based on what I have read and understand, but not sure if any studies have been done further to validate this,

Thank you Daniela and yes I totally agree with you early diagnosis and finding reliable biomarkers will help a lot

Isobel that's what makes it that much complicated since many factors and pathophysiological causes might be involved i guess.

thanks

Basically, diagnosis is based on clinic-pathological correlation, as Alzheimer did. Most likely, his case was a "juvenile" case. The term AD was coined soon afterwards by his department head Kraepelin in 1910, referring to it as presenile dementia. Between the world wars, and afterwards, there were other problems, so sound reevaluation, and the definition as major cause of senile dementia came from Blessed, Tomlinson, and Roth only in the 60s and 70s. Later on, it was thought, that AD consists mainly of degeneration of the Ncl basalis of Meynert, which is cholinergic, leading to the development of treatments we rely on actually. The was proven inaccurate by Braak in the late80s and early 90s, who pointed out that his classification stages may take some decades to advance into manifest AD, and nearly invariably affects the entorhinal and perirhinal cortex first.

There has always been some buzz about amyloid, the correlation of neurofibrillary tangles was always a little bit better than that of neuritic plaques. Diffuse plaques seem rather to correlate which age than cognition.

Consequently, the research was hampered in a complex disease, which may begin much earlier (at least as neuropathology is concerned) than it manifests clinically. So research criteria were developed allowing for definition of biological asymptomatic disease. Now we wait what happens....

one of the main reasons for which drug production did not increase

was the fact that many of concepts were based mostly on Amyloid Cascade theory..

Aparently are some negative stagnations from top 10 pharma which seems to not analyse all the concepts regards this affection

recently at Toronto Conf on Alzheimer July 2016 officially was presented the failure of one new drug-made by "tau-st"promoters...

it is more than evident that folowing this pathway the future does not look bright at all..

New and more efficenct mechanisms need to be explored

both amyloid and tau protein exerts neuroprotective actions

also prion protein is neuroprotective!!

A total reshape of our understanding for Alzheimer need to happen!!

Indeed the total research concept should be reevaluated and started from the beginning. New theories should be elaborated and tackled. The lack of a proper animal model is also a problem. And perhaps as some say it is complicated because this is the case when the brain has to explore itself  / ( himself ? ) ...

Arthur

I agree, Alzheimer's two patients appear to have been in the advanced stages of early onset disease, a completely different disorder from late /sporadic onset. We may have been traipsing down the wrong path for over 100 years. 

yes I fully agree and I add to the current "darkness"about new potential drugs the fact that so many neuropathological aspects of  Alzheimer are so so close to prion pathology. at same time is not yet the time to clearly accept that AD is a prion-disease.even so much abundant studies done by renowned scientists are pushing in to that direction.

by reanalisyng in full depth the early stages of neurodegenerative process in AD but also in PD(the huuge role of alpha-synuclein) we might develop new pathways for drug treatment for coming epidemics of AD.

thank you all for making this discussion fruitful.

Best wishes 

Sweilem