back to Student Projects Index
Home to Taste of Smell

Aging and Alzheimer's Disease: the onset of Anosmia

by James Poppy

Introduction

The human brain is the highest level of biological development. It has the ability to make humans conscience of their surroundings, in conjunction with sensory neurons of the nervous system, causing them to act behaviorally in response to their surroundings. However, what happens when a brain disorder such as Alzheimer's Disease occurs? The disorder disrupts the neurological system that the brain is entirely dependent on for external and internal awareness and control by eliminating synapses the ability of neurons to communicate with one another. The purpose of this paper is to analyze the effect of Alzheimer's Disease on the human brain, but using an unorthodox approach, by means of olfaction. In writing this paper, I hope to determine a correlation between the severity of Alzheimer's Disease and the progressive loss of olfactory perception--anosmia. Can the progression of anosmia be a means of diagnostic assessment of Alzheimer's Disease?

Current Statistics and Research Progress of Alzheimer's Disease

Alzheimer's disease is the most common form of dementia, affecting 4 million men and women non-discriminately in the U.S. alone. It is the 4th leading cause of death in adults after heart disease, cancer, and stroke; costing society approximately $100 billion a year in research, diagnosis, treatment, nursing home care, and medical expenses combined. Due to progressive research, so much more is known about the disease concerning genetic inheritance, diagnosis, and neuronal degeneration. In fact, research has progressed so rapidly that specific chromosomes (21, 19, and 14) have been marked that carry genes expressed in Alzheimer's disease paving the way for development of effective drugs that regulate the counter effects of the genes (Hamill and Pilgrim, 1995; Video, 1994).

What causes Alzheimer's Disease?

The precise mechanisms that cause Alzheimer's disease (AD) are still unknown. Yet, research is actively investigating the onset of AD and its debilitating effect on the brain. The results are showing many similar characteristics such as the presence of amyloid protein precursor (APP) and neurofibrillary tangles which create lesions, and massive reduction of dendritic spines; most of which lead to the same result, loss of synapses and ultimately death of neurons.

Masliah (1995) states that,

Research with beta-amyloid protein has shown that, in excess, the proteins bind together forming long chains that become entangled and are referred to as plaques. These plaques accumulate in areas of the brain related to high cognitive functioning, such as memory and thinking, and initiate necrosis, the 'unnatural' death of a neuron. It is believed that the plaques kill the neurons by depriving the neurons of life supporting nutrients (Video, 1994). Lesioning occurs when numerous neurons of a specific area are killed and amyloid plaques continue to accumulate. The neuron itself, has the ability to self-destruct, a term referred to as apotosis, 'natural', programmed death of a cell. Once neurons of the brain die they are never replaced because they divide before development, hence the seriousness of amyloid plaques and their ability to literally obliterate most, if not all, neurons of a specific region.

The presence of neurofibrillary tangles (NFT's), like that of the beta-amyloid plaques, is a major pathological hallmark for the onset of AD. NFT's, typically found in large neurons but affecting both large and small, have been shown to concentrate on the entorhinal cortex, hippocampus, supra and infra granular layers, basal forebrain cholinergic systems and many other brain regions. In AD victims, NFT's are found more highly concentrated in the medial temporal lobe: amygdala, hippocampus, parahippocampal gyrus, and uncus. The more prominent NFT's in a region, the more severe the neuronal loss and consequently the larger the lesion in that region. So, with respect to the entorhinal cortex and the hippocampus of an AD victim, because NFT's are common in these areas, NFT's are responsible for a majority of pyramidal cell death in the limbic system. As NFT's progress, cytoarchitectural specific remains accumulate, referred to as 'ghosts' or 'tombstones', the amount of accumulation can be used to predict the advancing of AD, and therefore, it can be used to stage AD (Grasby, http://werple.mira.net.au/~dhs/paper1.html).

AD can be staged into two types. Type I, being not as advanced, is a pronounced loss of synapses, while Type II shows a membrane lipid disturbance with a loss of myelin lipids (Svennerholm and Gottfries, 1994). AD advances by spreading of lesions in the "cortex based on the destruction of synapses and finally of whole neurons, and on the impairment of normal neurotransmission" (Zilles, et al, 1995). And though certain components of synaptic loss in AD occur regionally throughout the temporal lobe, most loss occurs in the hippocampus (Honer, et al, 1992).

Dendritic reduction, though it does not result in neuronal loss, plays a major role in the ability of the neurons to sense a stimulus. If a neuron loses its sensitivity, it is unable to detect a stimulus, if it can not detect a stimulus, it can not react because of it. Therefore, synapses are ultimately lost on account of the inability of the neurons to detect a problem (becoming "blind") and relate it to other neighboring neurons.

Memories, the target of Alzheimer's?

It has been reported that synaptic loss due to AD occurs regionally throughout the brain but becomes more dense in areas of memory and thought processing and specifically in the region of the hippocampus (Video, 1994; Honer, et al, 1992). In order to fully understand the disease in hopes to find effective drugs or possibly a cure, one must ascertain: why does Alzheimer's Dementia manifest itself within the hippocampal region?

The hippocampus is one of 6 structures that compose the Limbic system. This system is referred to as the "seat of emotion" in the brain and basically functions as a hardrive storing and processing information--memories. The hippocampus, along with the amygdala, cigulate gyrus, and the septal area, form the telecephalon. Collectively, the telecephalon and the diencephalon, composed of the anterior portion of the thalamus, and the mammillary body; form the forebrain region of the brain. The hippocampus serves to recall simple, short-term memory stimulated by sensory input such as taste, smell, touch, vision, and sound. The memories recalled by the hippocampus are spatial, i.e. memorizing the location on a map, or remembering to be in class by 8:30 am. Unlike spatial memories, memories that evoke emotion and cause you to cry when you remember a funeral, or smile when you think about your first kiss, are recalled by the amygdala. Any memories associated with emotions are stored here. The amygdala helps to aid the septal area in controlling aggressive behavior. Studies have shown using test monkeys that when portions of the amygdala and septal area were removed, the monkeys became emotionless and extremely aggressive. In separate studies removal of portions of the hippocamus resulted in patients having short term memory failure (Brown and Wallace, 1982; Restak, 1984). These behaviors can be witnessed in AD victims, confirmed by massive lesions in the structures of the Limbic system through autopsy (Zilles, et al, 1995).

The thalamus serves as a "staging center", incoming sensory information is first sent here. The information is then sorted out by the thalamus and sent to the appropriate higher brain centers for further interpretation and integration. This is true for all the senses, however, smell and taste synapse directly to the amygdala and hippocampus as well (Kandell, et al, 1991). This physiological advantage gives smell and taste powerful memory stimulating qualities (Restak, 1984). Initial detection of odors occurs in the nose in the olfactory epithelium. The epithelium contains millions of odor molecule specific neurons that make direct physical contact between the external world and the brain. When a certain odor is detected it causes certain neurons to synapse, these synapses are carried away from the neuron bodies by axons to the olfactory bulb where the synapses are then condensed down by the glomeruli. The olfactory bulb then sends the condensed signal to the olfactory cortex and then on to the Limbic system for further processing and memory recall. It is within the olfactory cortex and the final destination, the Limbic system, that I believe the olfactory signal is disrupted because of synaptic loss brought on by AD.

Normal aging vs. Alzheimer's, the battle for Synapses

In normal aging, memory loss as well as smell loss can still occur. Research based on autopsies of normal aging has shown that amyloid plaques and neurofibrillary tangles do naturally form in the brains of normal elderly throughout the neocortex, hippocampus, and amygdala (Reisberg, 1981). They are responsible for the death of neurons reflected in varying degrees by partial, or sometimes, no loss of memory or smell. It is also important to remember that apoptosis, the natural self- termination of the neurons, is likewise occurring and is also accountable for death of neurons and partial loss of senses. What distinguishes the onset of AD from that of normal aging is the significantly greater accumulation of the amyloid plaques and neurofibrillary tangles. Because there are fewer plaques and tangles in normal aging, fewer neurons are destroyed and the remaining neurons may continue to support synapses due to mechanisms such as axonal sprouting, synaptic enlargement, and/or synaptic ingrowth (Lippa, et al, 1992). Bertoni-Freddari and colleagues (1992) observed that "during physiological aging and senile dementia, the synaptic average area was significantly increased as compared to adult values in both the CNS areas investigated. Conversely, the number of contacts and their total surface area per unit volume of tissue were decreased. ...the increased synaptic size observed in [this] study appears to represent a compensative reaction of old and demented CNS to counteract the reduction in number and in total contact of the synaptic junctions."

In physiological aging the compensatory mechanisms are capable of maintaining synapses; in AD these compensatory mechanisms can only attempt to salvage what is left of synapses. The tremendous loss of the neurons effectively inhibits the remaining neurons to synapse independently, and therefore, the surviving neurons fail to act as an independent system (Lippa, et al, 1992).

The onset of Anosmia of normal aging and Alzheimer's, possible diagnosis?

With all the research from the past to present, little is known why the loss of olfaction occurs in Alzheimer's victims. What is known is that olfactory loss is prevalent; anosmia and Alzheimer's go hand in hand. Anosmia is currently being studied as a possible diagnosis for Alzheimer's dementia. According to one particular study, 10 patients with probable AD had their Cranial Nerve I examined. It was reported that 90% of the patients showed varying degrees of anosmia (Solomon, 1994). The purpose for examining the Cranial Nerve I is that it is the olfactory nerve; a highway that transmits signals from the olfactory bulb to the olfactory cortex of the brain. In another experiment the smell sensitivity of 80 normal elderly and 80 AD elderly were compared, the AD elderly had significantly poorer smell sensitivity. It was reported, that 74% of the AD elderly claimed to have had normal smell sensitivity after smelling the sample with an average concentration of nine times more than that of the normal elderly; versus 77% of the normal elderly afflicted with varying degrees of smell loss, who claimed to have had normal smell sensitivity after smelling the same sample but at the original concentration (Nordin, et al, 1995). In these studies AD victims were not aware of the onset of anosmia, or the severity of damage and therefore, did not recognize their loss of olfactory sensitivity.

Can anosmia be used to diagnose AD? I would speculate that it would be a reputable means of AD diagnosis. If AD victims reveal a smell sensitivity almost 10% less than that of normal aging, then I propose that careful monitoring of olfactory decline could indicate the onset of AD. Anosmia can be used as a probable indicator of the diagnosis of AD, but anosmia itself cannot be a definite factor. AD is diagnosed by means of exclusion and confirmed only through autopsy. According to Kenneth L. Davis, MD, he only gives a diagnosis of AD when he feels "pretty sure" after he has rigorously eliminated other possibilities, and he reports he has an autopsy confirmation rate of only 85% (Video, 1994). He did not state if he implored olfactory sensitivity tests as part of his eliminating processes.

Conclusion

The nervous system is composed of multiple complexes of dependent functions that must occur in unison in order for a message to be accurately sent to the central processing center. If the synapses are non-synchronous, or independent, then the message that the neurons were sending will be canceled out as "noise" by the brain (Freeman, 1991). With respect to the above statement, I hypothesized how Alzheimer's produces anosmia in its' victims: first, AD destroys most synapses by eliminating neurons (i.e. APP and NFT's) and putting a strain on the neurons that survive (i.e. dendritic reduction). Next, it inhibits compensation mechanisms from taking place between surviving neurons by overwhelming them with NFT's 'ghosts' and APP plaques. The AD victim is unaware of the loss of smell, while the irreparable destruction of neurons of the Limbic system, and/or olfactory cortex, and/or olfactory nerve continues.

Alzheimer's Disease successfully makes its' victim anosmic, not by destroying all the neurons of the olfactory cortex or Limbic system, but rather, by causing neurons to become "blind", giving them no reason to synapse and/or eliminating enough neurons so that they synapse independently and non-synchronously, and their messages are eliminated by the brain as "noise". Therefore, it is extremely plausible that progressive anosmia can be used as a diagnostic tool to assess the onset of Alzheimer's Disease.

References

Works Cited

Bertoni-Freddari, C., Fattoretti, P., Pieroni, M., Meier-Ruge, W., and Ulrich, J. (1992). Enlargement of synaptic size as a compensative reaction in aging and dementia. Pathology, Research & Practice. 188(4-5): 612-5.

Brown, Thomas S., and Wallace, Pactricia M. (1980). Physiological Psychology . New York : Academic Press Inc. pgs. 54-60. ISBN: 0-12-136660-X.

Freeman, Walter J. (1991). The Physiology of Perception. Scientific American. Vol. 264, (2) pgs. 78-85.

Grasby, Devika Chin. Pathological Hallmarks of Alzheimer's Disease. pgs. 1-4. Netscape http://werple.mira.net.au/~dhs/paper1.html.

Hamill, Robert W., MD, and Pilgrim, David M., MD. (1995). Advances in Alzheimer's Disease. Contemporary Internal Medicine . Vol. 7, num. 7, pgs. 46-58.

Honer, W.G., Dickson, D.W., Gleeson, J., and Davies, P. (1992). Regional Synaptic Pathology in Alzheimer's Disease. Neurobiology of Aging. 13(3): 375-82.

Kandell, Eric J., Schwartz, James H., and Jessel, Thomas M. (1991). Principles of Neural Science, III ed. New York: Elsevier Science Pub. Co., Inc. pg. 517 (diagram). ISBN: 0-444-01562-0.

Lippa, C.F., Hamos, J.E., Pulaski-Salo, D., DeGennaro, L.J., and Drachman, D.A. (1992). Alzheimer's Disease and aging: effects on perforant pathway perikarya and synapses. Neurobiology of Aging. 13(3):405-11.

Masliah, E. (1995). Mechanisms of synaptic dysfunction in Alzheimer's disease [Review]. Histology & Histopathology. 10(2): 509-19.

Nordin, S., Monsch, A.U., and Murphy, C. (1995). Unawareness of smell loss in normal and Alzheimer's disease: discrepancy between self-reported and diagnosed smell sensitivity" Journal of Gerontology. Series B, Psychological Sciences & Social Sciences. 50(4):187-92.

Reisberg, Barry, MD. (1981). Brain Failure: An Introduction to Current Concepts of Senility. New York: The Free Press. pgs. 12-37. ISBN: 0-02-926260-7.

Restak, Richard M, MD. (1984). The Brain. New York: Bantam Books. pgs. 205-15. ISBN: 0-553-05047-8.

Svennerholm, L., and Gottfries, CG. (1994). Membrane lipids, selectively diminished in Alzheimer brains, suggest synapse loss as a primary event in early-onset form (type I) and demyelination in late-onset form (type II). Journal of Neurochemistry. 62(3):1039-47.

Solomon, G.S. (1994). Anosmia in Alzheimer Disease. Perceptual and Motor Skills. 79(3 pt 1): 1249-50.

(Video)Alzheimer's Disease . . . A Wilderness Explored. (1994). Distributor, Glaxo. A 30 min. documentary on current research of Alzheimer's Disease. With Kenneth L. Davis, MD and Dennis J. Selkoe, MD. Produced by Vision.

Zilles K., Qu, M., Schleicher, A., Schroeter, M., Kraemer, M., and Witte, O.W. (1995). Plasticity and neurotransmitter receptor changes in Alzheimer's disease and experimental cortical infarcts. Arzneimittel-Forschung. 45(3A): 361-6.

Works Consulted

Axel, Richard. (1995). The Molecular Logic of Smell. Scientific American. Oct. pgs. 154-159.

Campbell, Neil A. (1993). Biology, III ed. New York: Benjamin/Cummings Pub. Comp., Inc. ISBN: 0-8053-1880-1.

Coen, Clive W., editor. (1985). Functions of the brain. Oxford: Clarendon Press. ISBN: 0-19-857212-3.

DiCara, Leo V. (1974). Limbic and Autonomic Nervous System Research . New York: Plenum Press. ISBN: 0-306-30786-3.

Isaacson, Robert L. (1982). The Limbic System, II ed. New York: Plenum Press. ISBN: 0-306-40874-0.

Isaacson, Robert L., and Pribam, Karl H., editors. (1975). The Hippocampus, vol. 2: Neurophysiology and Behavior. New York: Plenum Press. ISBN: 0-306-37536-2 (v. 2).