Dear Colleagues,

More than 10 years ago, we published a paper (1) that supported the idea that the neurodegenerative changes associated with AD and normal aging were qualitatively different. This was a stereological study in which we compared the pattern of neuron loss in the subregions of the hippocampus. Critical in this argument was the loss of neurons in CA1 of AD patients but not in normal age-matched controls. A few years later, Simic et al. (2) reported no differences in the loss of CA1 neurons in AD and normal aging. Subsequently, we have shown in a different cohort than that used in our original study that there is a significant difference in the loss of CA1 neurons in normal aging and AD. We believe that the normal aging group in the Simic study contained AD material. We believe that there is a difference in the pattern of neuronal loss in the CA1 region in AD and normal aging, and that this constitutes evidence for a difference in the neurodegenerative processes involved in normal aging and AD.

References:
1. West MJ, Coleman PD, Flood DG, Troncoso JC. Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer's disease. Lancet. 1994 Sep 17;344(8925):769-72. Abstract

2. Simic G, Kostovic I, Winblad B, Bogdanovic N. Volume and number of neurons of the human hippocampal formation in normal aging and Alzheimer's disease. J Comp Neurol. 1997 Mar 24;379(4):482-94. Abstract

3. West MJ, Kawas CH, Stewart WF, Rudow GL, Troncoso JC. Hippocampal neurons in pre-clinical Alzheimer's disease. Neurobiol Aging. 2004 Oct 1;25(9):1205-12. Abstract

View all comments by Mark West

The question is a vexed one, since "AD" is not a single disorder. Besides the early onset, dominantly inherited form of AD, and people with increased risk due to ApoE-ε4 or other genetic risk factors, it is probable that the hallmark NFT and NP pathology represent the end-stage of a number of different age-related changes (ARCs) that eventuate in synaptic loss and neuronal death. Since the large majority of elderly individuals will ultimately accumulate varying amounts of the pathologic changes of AD, the issue may be a quantitative one—depending on initial endowment and rate of progression of attrition. One should also not expect a simple, linear relation to age, since failure of "housekeeping" cellular functions must be a threshold phenomenon. So, sporadic AD is obviously dramatically age-related, but neither uniquely nor exclusively related to aging, and depends on many converging entropic factors (see reference below).

References:
Drachman DA. Aging of the brain, entropy and Alzheimer Disease. Neurology,2006;67;1340-1352. Abstract

View all comments by David Drachman

Nobody knows what "normal brain aging" is ("normal" in this context is not a statistical concept). So what about "the extreme end of [its] spectrum"?

View all comments by Jean-François Foncin

To be sure, one may age under normal or non-pathological circumstances; however, it should always be acknowledged that as one ages, AD risk goes up considerably. As previously noted, AD is a syndrome with heterogenetic/environmental complexity not well understood.

Does living into one's eighties or nineties cause the development of Alzheimer's? Certainly not, but on average more amyloidβ acccumulation is usually observed post mortem, indicating risk factors have increased in even otherwise healthy individuals.

References:
Harrisons Principles of Internal Medicine;2005.

View all comments by Jacob Mack