Hey,

That is a really good question. Unfortunately that is not a nice answer for that. It is not known if the Abeta (intra or extracellular) come first or the hyperphosphorilaiton of tau protein. The Abeta plaques exist but nowadays it is thought that the Abeta inside the cell (the monomers and oligomers) are the ones responsible for the neuronal death.

Hope it helps :)

hey samson,i am bit new to the field of neurosciences but as far i am working on prion peptides which have almost same pathogenesis as AD,there are growing evidences that first amyloid beta is aggregated which in turn effects the microtubules and ultimately TAU is aggregated....look at the link below for further reading...

http://www.nature.com/nrn/posters/ad/nrn_ad_posters.pdf

@ Nuno Leal : could you suggest me some papers regarding that which could help me a lot in study and analysis purpose.

A little note on the semantics, though it is an important distinction:

True there are lot of gaps still in our understanding of disease development, nothing we know so far suggests plaques and tangles CAUSE the disease. In fact, if anything, all the work on oligomers and environmental changes, suggests the contrary - that protein aggregates are more likely the CONSEQUENCE of upstream disease mechanisms.

Failed clinical trials were successful in clearing the brain of plaques, but that didn't help the disease severity in patients, though that did make it worse in some cases. That wouldn't have been so if the aggregates were the cause!

Hi Samsun,

I found the following journal article very good at explaining what you have questioned:

Jack Jr, C.R., Knopman, D.S., Jagust, W.J., Petersen, R.C., Weiner, M.W., Aisen, P.S., et al (2013). Tracking pathophysiological processes in Alzheimer’s disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurology, 12, pp.207–216.

I hope this helps!

Amy

Hi Samsun,

 I agree, good suggestion. Also consider this N&V (Yassa, Nature Neuroscience volume 17 | number 2 | february 2014). Also consider that cognitive decline, based on synaptic dysfunction, apparently preceeds plaques and tangles.

Cristina

First, it is impossible to 100% answer such a question as every human being is different and because classifying patients in terms of AD severity is always partly subjective. However, in the entorhinal cortex, one the first region showing neuron loss in AD, evidence suggest that tangles comes before plaques.

All reactions above contain "truth" but not "the entire truth, and nothing but the truth" (allow me the paraphrasing ...).

All AD patients are NOT created equal, and actually as already pointed out: most, and I dare state all AD patients differ in terms of genetic make-up, in epigenetic effects, in environmental exposure and in lifestyle.

Compare it to oncology: all tumours differ. 

The genetic contribution is best illustrated by the ever growing list of genes "contributing" to AD (cfr http://alzforum.org/genetics). Remember the numerous genetic studies revealing very different genes, mostly not confirmed by as many other studies demonstrating other genes of importance.  

The explanation: pending the actual selection and number of AD patients the outcome of each study differs, overcome more recently by very large GWAS studies, in co-laboration.  

Without indulging in historical analysis or comments, the post-mortem definition of AD is clear:  amyloid & tau pathology, eventually including inflammation (cfr Alzheimer, 1907).  

How much of each & where & when is not at all clearly defined, nor is it  possible to define a 'mean' or 'average' or 'median' or "general' for the entire AD-population - it s only possible for individual patients.  

The studies by Braak et al are most relevant but not "zaligmakend" as we say in flemish. Many other pathologists are to be consulted: Brion, Delacourte, Duyckaerts, Dickson, Hyman, Trojanowski, ...  to name only those - my sincere apologies to the many others.

For a chemist (my initial training, too long ago) the continuum of amyloid peptide to plaque, and of tau protein to thread & tangle is evidently containing dimers, oligomers, small and larger aggregates, ... more or less soluble in many different cocktails of acid or base, salts or detergents, water or organic solvents, or any mixture that works - or not. 

The finding of amyloid pathology in normo-cognitve people, of tau-only dementia, of ad-mixture with synuclein-opathy, prion and lewy body disease, vascular dementia, diabetes, ... illustrates the staggering variability of brain defects in old (and younger) people, which is impossible to capture in 2 or 3 categories - as wanted by clinicians for obvious reasons: diagnosis & therapy is otherwise impossible.

I hope this helps - although for sure does not solve the problem!    

kind Samson Nivins,

maybe this small contribution doesn't fit your request, being me a clinical gerontologist - not a neuropathologist; yet, I just had a glance at the paper by Gianluigi Forloni, pasting the following abstract retrieved through ResearchGate.

I may suggest you to "follow" him; best regards, Mauro Colombo

Neurobiology of aging 10/2014; DOI: 10.1016/j.neurobiolaging.2014.10.027Source: PubMed

ABSTRACT Alzheimer's disease is experimentally modeled in transgenic (Tg) mice overexpressing mutated forms of the human amyloid precursor protein either alone or combined with mutated presenilins and tau. In the present study, we developed a systematic approach to compare double (TASTPM) and triple (APP/PS2/Tau) Tg mice by serial magnetic resonance imaging and spectroscopy analysis from 4 to 26 months of age to define homologous biomarkers between mice and humans. Hippocampal atrophy was found in Tg mice compared with WT. In APP/PS2/Tau the effect was age-dependent, whereas in TASTPM it was detectable from the first investigated time point. Importantly, both mice displayed an age-related entorhinal cortex thinning and robust striatal atrophy, the latter associated with a significant loss of synaptophysin. Hippocampal magnetic resonance spectroscopy revealed lower glutamate levels in both Tg mice and a selective myo-inositol increase in TASTPM. This noninvasive magnetic resonance imaging analysis, revealed common biomarkers between humans and mice, and could, thus, be promoted as a fully translational tool to be adopted in the preclinical investigation of therapeutic approaches.

Copyright © 2014 Elsevier Inc. All rights reserved.

 1 more abstract retrieved from Geneva correspondents in ResearchGate

best regards, Mauro Colombo

Advances in experimental medicine and biology (Impact Factor: 1.83). 01/2015; 821:11-7. DOI: 10.1007/978-3-319-08939-3_6

Source: PubMed

ABSTRACT Neuropathological hallmarks of Alzheimer's disease (AD) include tangles (NFT) and beta amyloid (Aβ) plaques. Despite numerous neuropathological studies that assessed the relationship of cognitive decline with neuropathologic lesions, their correlation still remains unclear. NFTs and Aβ plaques have been widely implicated and described in normal aging. The number of NFTs in the CA1 and the entorhinal cortex seems to be more closely related to cognitive status, compared to the amyloid load whose role still remains controversial in the AD. In this review, we refer to our main studies performed in Geneva during the past two decades attempting to assess the correlation of pathology with clinical expression. The theory of cognitive reserve has been proposed for further understanding of interindividual differences in terms of compensation despite the presence of pathological lesions. The increasing prevalence of the AD, the limitations of actual treatments, as well as the high public cost reflect the imperative need for better therapeutic and early diagnosis strategies in the future.

dear Samson,

few more quotations:

Neurology 2013;80:1378-84 & 1784-91

Neurology 2013;81:1732-40

JAMA Neurology 2013, August; 70 (8); doi: 10.1001/jamaneurol.2013.182. [Knopman DS & Coll]

& the "traditional" paper by Savva & Coll New Engl J Med 2009;360:2302-9

best wishes, Mauro C

The tradition has been the amyloid cascade hypothesis.  Found a paper where they reevaluate the "ACH".  See http://www.hindawi.com/journals/ijad/2011/630865/

Hope this helps!

The ongoing discussion - "reflection" - based on pro & contra elements imported from public sources are the best proof that we don't know "the A to the original Q" - which supports the most likely hypothesis that "it differs in different patients": amyloid or tauopathy or inflammation or vascular or glutamate issues - or even acetylcholine - can come first alone or most likely in combinations,  while they can  engender quite different clinical defects/symptoms - but a similar postmortem pathological signature!

While "allostatic load" is a re-name of "ageing" it is definitely "real" but also different in each of us - and moreover impossible to measure accurately in individuals. The "statistical" analysis of data are of limited use for individuals - which holds for all bio-markers or 'indices' in this area.   

The ACH-based clinical trials (meant is not acetylcholine but amyloid cascade) do not confer nor warrant the greatest confidence in success - nevertheless "TINA" and we must address all options and test all means: from BACE inhibition to ADAM activation, from passive to active vaccination, from amyloid to tau,  ... and accept an eventual negative outcome and move on to the next - different or improved - trial.

Stratification of patients for age and symptoms is proving essential, while we also have to bet on combination therapy - wella ware of the fact that neither is simple to implement: which symptoms or genetic markers? which stage of the disease? which combination? ...

But then again we are facing the most complex problem of the most complex engine in the universe - a daunting task as we we have only "it to understand it" !    

TINA = there is no alternative ... 

the alleged paper by an old Italian neuropathologist problematizes the issue

best regards, Mauro Colombo

Thank you Sir...will check..

dear Samson, in the following abstract by Roser Sala-Llonch [pasted via ResearchGate], one can see once more how pathology trajectories are not linear; see also alleged file [downloaded from Francois Herrmann, through ResearchGate]

best regards, Mauro C.

Neurobiology of aging 12/2014; DOI: 10.1016/j.neurobiolaging.2014.12.022

Source: PubMed

ABSTRACT Familial Alzheimer's disease provides the opportunity to investigate brain changes even before the symptoms onset. We performed a structural magnetic resonance imaging (MRI) study in 38 participants from families with presenilin 1 gene mutations: 11 symptomatic mutation carriers, 13 asymptomatic mutation carriers (AMC), with a mean of 16.22 years before the estimated appearance of symptoms, and 14 noncarriers. A subset of subjects was studied longitudinally 2 and 4 years after the first scan. We found decreased cortical thickness (CTh) and volume in cortical and subcortical structures in symptomatic mutation carriers, with progressive loss over time. In AMC, we found increased CTh and volume in temporoparietal regions and in precuneus-posterior cingulate compared with controls at baseline. Longitudinal studies in AMC, by contrast, showed accelerated rates of CTh loss in precuneus-posterior cingulate and superior parietal, right lateral temporal and left orbitofrontal, and middle frontal regions. These findings suggest that brain structure in presenilin 1 mutation carriers follows nonlinear trajectories, with regional increases during the very early presymptomatic period. Initial neuroinflammation and/or accumulation of amyloid species followed by neurodegeneration, or congenital morphometric differences, may explain the observed features.

I understand that the answer to this question can be quite confusing because you have the results from the biomarkers (Abeta and tau in the CSF) and the results from the pathology (plaques and NFTs of tau in the brain), and they differ. So you will have different answers on what comes first from people depending on what they refer to.

- Results from biomarkers: if you look in this article in Lancet Neurology (PMID: 23332364), you will see that changes in Abeta come first in the CSF and are then followed by tau (be careful it can be confusing, the Abeta curve is seen increasing, but Abeta actually decreases in the CSF while tau increases. It's because they plotted the "abnormal changes", not the actual levels).

- Results from brain pathology: now if you look in this seminal article by Braak & Braak (PMID:9330961), you can see that NFTs (stage I & II, clinically silent) come first: Abeta deposits start around 40 year of age, while NFTs are already present in 20% of the population age 20-30. NFTs stage III to VI (from MCI to full blown AD) come after the Abeta deposits.

Why the discrepancy? Plaques are extracellular and when they start to recruit Abeta, it has the immediate effect of depleting the peptide in the CSF. NFTs are intraneuronal and they accumulate for a VERY long time before the neurons start dying. Once the neurons die, tau is freed in the extracellular environment and passes in the CSF.

So the 2 results are not mutually exclusive, they are complementary. In the brain, tau starts accumulating first, but stays at stages I and II, which are clinically silent. Then Abeta starts to accumulate in the brain (and decrease in the CSF), which pushes tau pathology to stages III and beyond, causing neuronal death and then tau increases in the CSF.

You can read this article to see a graph showing the evolution of Abeta and tau on the same graph and a discussion about it (PMID:18688094).

A Culture–Brain Link: Negative Age Stereotypes Predict Alzheimer’s Disease Biomarkers.Levy, Becca R.; Ferrucci, Luigi; Zonderman, Alan B.; Slade, Martin D.; Troncoso, Juan; Resnick, Susan M.

Psychology and Aging, Dec 7 , 2015, No Pagination Specified. http://dx.doi.org/10.1037/pag0000062

Abstract

Although negative age stereotypes have been found to predict adverse outcomes among older individuals, it was unknown whether the influence of stereotypes extends to brain changes associated with Alzheimer’s disease. To consider this possibility, we drew on dementia-free participants, in the Baltimore Longitudinal Study of Aging, whose age stereotypes were assessed decades before yearly magnetic resonance images and brain autopsies were performed. Those holding more-negative age stereotypes earlier in life had significantly steeper hippocampal-volume loss and significantly greater accumulation of neurofibrillary tangles and amyloid plaques, adjusting for relevant covariates. These findings suggest a new pathway to identifying mechanisms and potential interventions related to the pathology of Alzheimer’s disease. (PsycINFO Database Record (c) 2015 APA, all rights reserved)

Scientists find tau protein as better marker of Alzheimer's disease 

A buildup of plaque and dysfunctional proteins in the brain are hallmarks of Alzheimer's disease. While much Alzheimer's research has focused on accumulation of the protein amyloid beta, researchers have begun to pay closer attention to another protein, tau, long associated with this disease but not studied as thoroughly, in part, because scientists only recently have developed effective ways to image tau.