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SAGE KE Bulletin Board

Alzheimer�s disease revisited: Q & A on some basic issues

9 September 2002

George M. Martin

I thank Ming Chen for posting her views on the pathogenesis of late-onset dementias of the Alzheimer type (DAT) on our Bulletin Board. I like her use of the dialogue methodology as a way to highlight contrasting opinions. It is a time-honored technique, one that was used extensively by one of the founders of modern science, Galileo Galilei. For some delightful quotes from these dialogues, read Galileo�s Daughter (1). Let us hope that Dr. Chen�s dialogue will stimulate many responses.

Although Dr.Chen touches upon many issues, one major thesis appears to be a dichotomization of pathogenetic mechanisms responsible for various structural and functional aberrations (diseases) in �young� human subjects with those responsible for superficially similar pathologies as they occur in �old� human subjects. The former, she argues, are due to various �pathogens�, both extrinsic (e.g., infectious agents) and intrinsic (e.g., constitutional gene mutations). The latter, and in particular late-onset DAT, are considered to have, as their primary pathogenetic agents, phenomena related to basic mechanisms of aging. Although the age cut-offs for �young� and �old� are not precisely defined, most investigators of DAT generally define late-onset DAT as those with beginning expressions at around age 60 or 65 years. As an aficionado of the evolutionary biological theory of aging, however, I suggest that a useful operational distinction would be the age range at which the force of natural selection is no longer operative. While this decline in the force of natural selection is gradual, it essentially disappears, in humans, by around ages 40-45 years (reviewed in 2). Many patients with �early onset� familial, mutational forms of the disease develop their signs and symptoms within or later than that age range. We therefore cannot rule out a role for aging processes in the expression of even �early onset� DAT. The incidence and prevalence of the most common forms of the disorder, however, increase exponentially with age after around age 65. These forms regularly escape the force of natural selection. Fundamental processes of aging are almost surely setting the stage for the pathologies. We therefore require comparatively greater research efforts on these underlying mechanisms of aging in order to unravel the pathogenesis and devise rational preventive regimes.

I do not believe that Dr. Chen�s arguments rule out a role for infectious agents in some forms of late-onset DAT, nor do they falsify the hypothesis that a given pathogenetic mechanism, as revealed by early acting mutations, may also play some role in at least some forms of �late-onset� DAT. My use of the term DAT as opposed to AD is quite deliberate, as it suggests the possibility that we may be dealing with a pathogenetically heterogeneous group of disorders. The brain has only a rather limited repertoire for how it reacts to injury. Beta amyloidosis (vascular and non-vascular; intracellular and extracellular), neurofibrillary tangles, hippocampal granulovacuolar degeneration, synaptic loss and predominantly medial temporal lobe neuronal loss may be the result of different initiating and precipitating events, perhaps all of which share some downstream pathways.

Dr. Chen seems to be puzzled by the variations in expression of late-onset degenerative phenotypes. Given the fact that there are potential roles for numerous environmental, stochastic and genetic variables, this is not at all surprising.

References:
1. Sobel, Dava. Galileo�s Daughter, Walker & Company, New York (1997).
2. Martin, G.M. Genetic analysis of ageing: role of oxidative damage and environmental stresses. Nat. Genet. 13, 25-34 (1996).


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