[extropy-chat] Alzheimer breakthru?

[Rafal Smigrodzki]

Hal Finney wrote:

>Damien Broderick forwards:
>  
>
>>http://www.theaustralian.news.com.au/printpage/0,5942,10922717,00.html
>>Alzheimer's breakthrough 'excites' scientists
>>    
>>
>
>This was a good article but it seemed to be edited badly and stopped in
>the middle of a thought.  I found the abstract for the conference presentation
>at http://www.asbmb.org.au/combio2004/abstracts/edited/VERDILE-20040713212913.rtf.
>
>After menopause, estrogen levels fall, and this causes other hormone
>levels to rise.  The key sentence is, "We now report that high LH levels,
>rather than the decrease in oestrogen per se, are associated with lower
>cognitive performance (assessed by CAMCOG scores) in elderly women
>without dementia."  LH, luteinizing hormone, is of a class of hormones
>known as gonadatropins, part of the many hormone groups related to the
>female reproductive cycle.  The new results show biological evidence
>that LH affects the processing of the proteins which are precursors to
>Alzheimer's plaques.  Based on this, the abstract concludes,
>
>"Taken together, these results suggest the marked increases in
>serum LH following menopause/andropause as a physiologically relevant
>signal that could promote A-beta secretion and deposition in the aging
>brain. Suppression of the age related increase in serum gonadotropins
>using gonadotropin releasing hormone agonists/antagonists may represent
>a novel therapeutic strategy for AD [Alzheimer's Disease]."
>
>  
>
### I sincerely doubt this. Every theory of Alzheimer's (and there are 
dozens) that fails to address the issue of what is the material 
substrate of the clock which sets AD in motion at age 55 or 85 but not 
at age 2, 20 or 45, is merely sliding on the surface of the complexity 
that is human aging.

There is a clock (or rather, a number of clocks), molecules which are 
capable of accumulating change with time - a material record of events, 
such as impingement of background radioactivity, or radicals, to cause 
chemical bond breakage or formation. To act as a clock capable of 
running for decades, a molecule must be either long-lived, or be 
replicated with preservation of accumulated change. The only one type of 
such molecules is DNA, both nuclear and mitochondrial.  Then there are 
molecular species which do not accumulate information over long periods 
of time - proteins, lipids, hormones - all those species which have fast 
turnover and are incapable (except for very unusual situations) of 
storing information and transferring it to their newly synthesized 
replacements.

If you look carefully, the whole A-beta story is getting more and more 
shaky, and even people like Dennis Selkoe start hedging their bets and 
admitting that A-beta could be just a secondary, or tertiary phenomenon. 
Fuzzy hypothesizing about hormone levels does not even make the cut for 
serious discussion among the hardcore AD researchers. For really 
cutting-edge explanations of AD look to this article:

Med Hypotheses. 2004;63(1):8-20.
  
    A "mitochondrial cascade hypothesis" for sporadic Alzheimer's disease.

    Swerdlow RH, Khan SM.

    Department of Neurology, McKim Hall, University of Virginia Health 
System, PO Box 800394, 1 Hospital Drive, Charlottesville, VA, USA. 
rhs7e at virginia.edu

    Alzheimer's disease (AD) includes etiologically heterogeneous 
disorders characterized by senile or presenile dementia, extracellular 
amyloid protein aggregations containing an insoluble amyloid precursor 
protein derivative, and intracytoplasmic tau protein aggregations. 
Recent studies also show excess neuronal aneuploidy, programmed cell 
death (PCD), and mitochondrial dysfunction. The leading AD molecular 
paradigm, the "amyloid cascade hypothesis", is based on studies of rare 
autosomal dominant variants and does not specify what initiates the 
common late-onset, sporadic form. We propose for late-onset, sporadic AD 
a "mitochondrial cascade hypothesis" that comprehensively reconciles 
seemingly disparate histopathologic and pathophysiologic features. In 
our model, the inherited, gene-determined make-up of an individual's 
electron transport chain sets basal rates of reactive oxygen species 
(ROS) production, which determines the pace at which acquired 
mitochondrial damage accumulates. Oxidative mitochondrial DNA, RNA, 
lipid, and protein damage amplifies ROS production and triggers three 
events: (1) a reset response in which cells respond to elevated ROS by 
generating the beta-sheet protein, beta amyloid, which further perturbs 
mitochondrial function, (2) a removal response in which compromised 
cells are purged via PCD mechanisms, and (3) a replace response in which 
neuronal progenitors unsuccessfully attempt to re-enter the cell cycle, 
with resultant aneuploidy, tau phosphorylation, and neurofibrillary 
tangle formation. In addition to defining a role for aging in AD 
pathogenesis, the mitochondrial cascade hypothesis also allows and 
accounts for histopathologic overlap between the sporadic, late-onset 
and autosomal dominant, early onset forms of the disease.

(DISCLOSURE - I personally know, like and admire both authors).

As you may find, the authors specify the molecular substrate of the 
clock, mainly mtDNA, and the primary influence on the clock speed 
setting (the rate of accumulation of change, determined by genetically 
determined ROS production rates), and tie this in with the secondary, 
both adaptive and maladaptive phenomena, such as A-beta accumulation, 
tangle formation, and others.

Rafal