New England Journal of Medicine, Vol. 313, pages 388-389, 1985

ALZHEIMER’S DISEASE: DOES NEURON PLASTICITY PREDISPOSE TO AXONAL NEUROFIBRILLARY DEGENERATION?

To the Editor: Gajdusek hypothesizes that disruption of neurofilaments is the basis for several dementing diseases (March 14 issue). 1 To explain why some neurons in the brain are affected and not others, he suggests that cells with large axonal trees, because of their great demands for axonal transport, are especially vulnerable to axoskeletal damage. Gajduseks’s hypothesis is attractive but fails to account for the observation that large otor neurons are minimally affected in Alzheimer’s disease.

We suggest that cell plasticity as well as the size of the axonal tree may impose demands on axonal transport. The plasticity of neural cells has been related to a variety of trophic factors,2 some of which involve axonal transport. A pertinent example is the sprouting seen in septal norepinephrine terminals,3 presumably accompanied by a sizable influx of new neurofilaments.

Neurons showing a high degree of plasticity probably form the substrate of memory and learning; both are impaired in Alzheimer’s disease. Norepinephrine pathways have been associated with reward-related learning,4 and the norephinephrine cells of the locus ceruleus are destroyed in some cases of Alzheimer’s disease.5 Alzheimer degeneration also damages the locus of origin of serotonin cells in the midbrain raphe,6 and serotonin has been proposed as the mediator of classic conditioning.7 Acetylcholine pathways projecting from the nucleus basalis of Meynert to the cortex may have the role of latchkey in complex memory storage and retrieval,8.9 and as is well known, Alzheimer’s disease is associated with loss of these cell bodies as well as their enzymes.10 At the cortical level Alzheimer-type deterioration preferentially affects neuron in associative areas, most strikingly the hippocampus and amygdala,11 both of which play a major role in memory.12 Furthermore, neurofibrillary degeneration occurs selectively in neurons with axons connecting the hippocampus with the entorhinal cortex.13 Since neurons from each of these groups form connections associated with encoding of information,14 which requires a high degree of plasticity, their deterioration supports the inference that cells showing considerable plasticity are prone to neurofibrillary disruption.

The disruption of the slow axonal-transport mechanism in neurons with a high degree of plasticity may lead to pervasive memory dysfunction, the core symptom of dementia regardless of the cause. This axonal-filament dysfunction may provide a micropathological basis for the previously postulated link between a microtubular diathesis and Alzheimer-type dementia 15,16 and tie together a sub-class of dementing diseases.

J. Wesson Ashford, M.D., Ph.D.
Lissy Jarvik, M.D., Ph.D.

UCLA Neuropsychiatric Institute
Los Angeles, CA 90024