POINT OF VIEW

The Olfactory Vector Hypothesis of

Neurodegenerative Disease: Is It Viable?
Richard L. Doty, PhD

Environmental agents, including viruses, prions, and toxins, have been implicated in the cause of a number of neurodegenerative
diseases, most notably Alzheimer’s and Parkinson’s diseases. The presence of smell loss and the pathological involvement of the
olfactory pathways in the formative stages of Alzheimer’s and Parkinson’s diseases, together with evidence that xenobiotics, some
epidemiologically linked to these diseases, can readily enter the brain via the olfactory mucosa, have led to the hypothesis that
Alzheimer’s and Parkinson’s diseases may be caused or catalyzed by agents that enter the brain via this route. Evidence for and
against this concept, the “olfactory vector hypothesis,” is addressed in this review.
Ann Neurol 2008;63:7–15

The causes of Alzheimer’s (AD) and Parkinson’s dis-
eases (PD), the two most common neurodegenerative
disorders, are obscure. Familial concordance, genetic,
and twin studies suggest that, although heritable factors
play a role, environmental factors are prepotent.1 Thus,
despite the fact that numerous genes have been identi-
fied for these two diseases, they usually relate to early-
onset familial forms and account for less than 10% of
all cases. Although largely distinct phenotypically and
pathologically, AD and PD exhibit identical olfactory
dysfunction early in their course,2 are often coex-
pressed,3 share a number of common risk factors (eg,
age, head trauma, the apolipoprotein ε4 gene),1 and
exhibit similar pathologies in brain regions such as the
locus coeruleus.4
Among environmental risk factors reported for AD
and PD are viruses, aerosolized metals, and toxins.1 In-
creased expression of ␤-amyloid (␤A) and indicators of
brain inflammation have been found in the olfactory
bulbs and other olfactory-related brain regions of peo-
ple and dogs exposed to extreme air pollution, likely
reflecting exposures to airborne particulates and aero-
solized metals.5 Previous occupational exposure to her-
bicides, as well as 20 or more years of occupational
exposure to manganese (Mn), have been associated
with 3- to 10-fold increased risks for development of
PD.6,7 Most cases of Mn-related parkinsonism, how-
ever, differ from classic PD on pathological and other
grounds.8
The presence of smell loss and olfactory bulb pathol-
ogy in the formative stages of AD and PD, together
with evidence that airborne xenobiotics viewed as dis-
ease risk factors can enter the brain via the olfactory
mucosa, has led to the hypothesis that these disorders
may be caused or catalyzed by agents that enter the
brain via the nose.9 –12 This review assesses the viability
of this “olfactory vector hypothesis” as a potential
explanation for the induction of some cases of AD
and PD.
Evidence That Xenobiotics Can Enter the Brain
via the Olfactory Mucosa
The anatomy of the nose is well suited for the transfer
of exogenous agents into the brain. Although some xe-
nobiotics, notably viruses, can enter the brain via sev-
eral cranial nerves, the olfactory nerve (cranial nerve I)
is uniquely vulnerable to such penetration (Fig). Thus,
the dendritic knobs and protruding cilia of the 6 to 10
million olfactory receptor cells that make up this nerve
provide an exposed surface area conservatively esti-
mated at 23 cm2.13 These cells are widely distributed
throughout the rostral nasal cavity, embedded in a spe-
cialized neuroepithelium that lines the region of the
cribriform plate, the dorsal septum, and sectors of the
superior and middle turbinates. Unlike other receptor
cells, these cells are also first-order neurons, projecting
axons directly to the brain without an intervening syn-
apse. Although they receive little benefit from the pro-
tection of the blood–brain barrier or the blood–nerve
barrier, they are afforded some protection by secretions

From the Smell and Taste Center and Department of Otorhinolar- Address correspondence to Dr Doty, Smell and Taste Center, Uni-
yngology: Head and Neck Surgery, University of Pennsylvania versity of Pennsylvania School of Medicine, 5 Ravdin Pavilion,
School of Medicine, Philadelphia, PA. 3400 Spruce Street, Philadelphia, PA 19104.
Received Nov 6, 2007, and in revised form Nov 28. Accepted for E-mail: doty@mail.med.upenn.edu
publication Nov 28, 2007.
Published online Jan 30, 2008, in Wiley InterScience
(www.interscience.wiley.com). DOI: 10.1002/ana.21327

© 2008 American Neurological Association 7

Published by Wiley-Liss, Inc., through Wiley Subscription Services

Fig. (A) Sagittal view of the rat brain showing olfactory neu-
roepithelium (OE) receptor cells and their axonal projections
to the olfactory glomeruli (G). In the glomerulus, receptor cell
axons contact the dendrites of periglomerular (PG) and mitral
(M) cells. Mitral cells project to the piriform cortex (PC).
Centrifugal afferent innervation comes from the horizontal
limb of the diagonal band (HLDB), the substantia nigra
(SN), the dorsal raphe (DR), and the locus ceruleus (LC). (B)
The olfactory mucosa includes an epithelial cell layer (OE)
and the lamina propria (LP) separated by the basal lamina
(BL). The OE contains sustentacular (S), basal (B), and re-
ceptor (R) cells. Receptor cells have a dendritic knob (DN)
from which cilia (C) project into the nasal cavity (NC). Un-
like the cilia of the respiratory epithelium (C), these cilia do
not beat in unison, but more or less waft in the mucus, lack-
ing dynein (C) arms to induce motility. Receptor cell axons
fasciculate to form the olfactory nerve (ON) that crosses the
cribriform plate (CP) to enter the central nervous system. The
axon and nerve are surrounded by a perineural sheath that
forms the perineural space (PN). The lamina propria contains
mucus secreting Bowman’s glands (BG), axons of receptor cells,
and numerous blood vessels (BV). Red and green dots depict
possible entry pathways through neurons, glands, and blood
vessels. (C) Respiratory neuroepithelium consists of columnar
ciliated (C), goblet (G), and basal (B) cells, and is highly
vascular (BV). (D) Hematoxylin-and-eosin (H&E)–stained
section illustrating the layers of the OE and LP showing the
numerous blood vessels in the lamina propria. Olfactory
marker protein (OMP) immunostained section showing that
only mature receptor neurons and their axons, not basal or
sustentacular cells, contain OMP. (Reproduced from Baker
and Genter,15 by permission.)
from Bowman’s glands and by neighboring supporting
cells, both of which express chemical metabolizing en-
zymes, including isozymes of cytochrome P450 –depen-
dent monooxygenases, aldehyde dehydrogenase, car-
boxyesterases, epoxide hydrolases, uridine diphosphate-
8 Annals of Neurology Vol 63 No 1 January 2008
glucuronyl transferase, glutathione S-transferase, and
rhodanase.14 Some of these enzymes, for example, the
P450 monooxygenases, are more active within the olfac-
tory mucosa than within the liver, playing a key role in
detoxifying xenobiotics within this vulnerable region.
Other mechanisms that protect the olfactory mucosa
from invasion or chemical damage include intracellular
detoxification factors, ligand-specific binding proteins
that remove agents from the mucosa, immune system
cells, and the ability of the receptor cells to degenerate
and then regenerate from stem cells within the basement
membrane.15 Unfortunately, such protective mecha-
nisms can be overwhelmed, resulting in enhanced levels
of xenobiotics that, in some cases, enter the brain.
The ability of foreign agents to move from the nasal
cavity into the brain was noted as early as the second
century.16 In the early twentieth century, olfactory re-
ceptor cells were identified as a major route of entry of
poliomyelitis virus into the brain, affording an oppor-
tunity for direct neural infection without preliminary
multiplication in nonneural tissue. By 1912, Flexner
and others had shown that this virus could enter the
monkey central nervous system via the olfactory
nerve,17 and by the mid-1930s, it was apparent that
such entry could be prevented by lesioning the olfac-
tory neuroepithelium, bulbs, or tracts.18,19 The pres-
ence of infected olfactory bulbs in children who had
died of the disease implicated the olfactory system in
viral transmission,20 because in monkeys only intrana-
sal, not intracranial, subdural, or intrasciatic, viral in-
oculation induced such bulbar infection.21 The evi-
dence for olfactory nerve transmission of the polio
virus was so strong that, in the late 1930s, Canadian
public health officials chemically cauterized the olfac-
tory epithelia of large numbers of school children dur-
ing polio epidemics in efforts to prevent the disease.22
Since these early studies, a range of viruses in addi-
tion to poliomyelitis virus have been shown capable of
entering the brain via uptake into the olfactory recep-
tor cells (Table 1). Entrance can also occur by penetra-
tion into associated lymphatic channels and into extra-
neural spaces within the nerve bundles that make up
the cranial nerve I fila.23 In some cases, such as that of
the arthropod-borne St. Louis encephalitis virus, brain
entry via the olfactory path eventually occurs even
when the virus is instilled intravenously, subdurally, or
interperitonieally.24 In addition, lectins, dyes, solvents,
metals, amino acids, nanoparticles, and numerous mi-
crobes have been shown capable of entering the brain
via the olfactory mucosa (for review, see Baker and
Genter15). Examples of metals capable of entering the
olfactory receptor cells are listed in Table 2.
Once internalized into the olfactory bulb, some xe-
nobiotics penetrate into higher brain regions, often
along neurotransmitter-specific lines. For example, her-
pes simplex virus type 1, placed intranasally in mice, is
 Table 1. Examples of Major Viruses Capable of Incorporation into Olfactory Receptor Cells from the Nasal Cavity
and, in Some Cases, Transported Transneuronally to Other Brain Regions (Modified from Ref. 15)
Virus Species Method of Receptor Transneuronal Example
Application Cell Transport Reference
Incorporation

Adeno (recombinant) Rat Intranasal Yes Yes 80

Aujeszky’s disease (pseudorabies) Pig Intranasal Yes Yes 81
Borna disease Rat Intranasal Yes Yes 82
Bovine herpes Goat Intranasal Yes Unknown 83
Canine distemper Ferret Intranasal Yes Yes 84
Ectromelia Mouse Intranasal Yes Yes 85
Equine herpes Pig Intranasal Yes Yes 86
Hepatitis Mouse Intranasal Yes Yes 63
Herpes simplex Rat Intranasal Yes Yes 87
Mouse Corneal Yes Yes 88
Mouse Facial skin Yes Limited 88
Influenza A Mouse Intranasal Yes Yes 89
Poliomyelitis Primate Intranasal Yes Yes 17
Rabies Mouse Intranasal Yes Yes 90
St. Louis encephalitis Hamster Intraperitoneal Yes Yes 24
Sendai Mouse Intranasal Yes Limited 91
Semliki forest Mouse Intranasal Yes Age dependent 92
Venezuelan equine encephalitis
virus Mouse Subcutaneous Yes Yes 93
Vesicular stomatitis virus Mouse Intranasal Yes Yes 94

detected in the olfactory bulbs after several days. This
virus subsequently infects cholinergic neurons in the
horizontal limb of the diagonal band, serotonergic neu-
rons in the dorsal and median raphe nuclei, and nor-
adrenergic neurons in the locus coeruleus.25 Ionized
metals (eg, aluminum, cadmium, gold, and Mn) can
be transported to the brain via the olfactory receptor
cell neurons at rates greater than 2mm/hr,26 with
some, such as Mn, subsequently targeting astrocytes
throughout the brain.27 Herbicides, such as the dioxins
and chlorthiamid, are selectively taken up by the olfac-
tory neuroepithelium even when administered system-
ically or to the surface of the cornea28,29 and can dam-
age the olfactory mucosa by causing necrosis of
Bowman’s glands.30 The pathological infectious prion
protein PrPSc is consistently found in the olfactory
cilia, receptor cells, bulbs, tracts, and primary olfactory
cortices of patients with Creutzfeldt–Jakob disease, but
not in the retina, optic nerves, or respiratory mucosa.31
A number of patients with this disease first present to
the clinician with anosmia or complaints of taste and
smell loss.31,32
Although a wide range of xenobiotics can become
incorporated into olfactory receptor cells, including
dyes and amino acids, not all are transported across the
synaptic membrane to neighboring cells. For many that
cross the synapse, including a number of viruses, inter-
nalization into the cell initially occurs via receptor-
mediated endocytosis. The xenobiotic is then trans-
ported within the cell via slow or rapid transport
systems to the transmost saccule of the Golgi appara-
tus, where it is packaged into vesicles bound for axonal
terminals.33 Usually there is minimal involvement of
glial cells, implying limited release into the extracellular
space.15 Agents that are not synaptically transported
but yet enter the cell, such as leucine and horseradish
peroxidase, are taken up by bulk endocytosis and pro-
cessed into protein components of the cell, not the
Golgi saccule.15
Early Olfactory Loss and Progression of
Alzheimer’s Disease– and Parkinson’s Disease–
Related Neuropathology
A key observation in potential accord with the olfac-
tory vector hypothesis is that approximately 90% of
patients with early-stage AD or PD exhibit olfactory

Doty: Olfactory Vector Hypothesis 9

 Table 2. Examples of Metals Shown to Be Capable of Incorporation into Olfactory Receptor Cells from the Nasal
Cavity and, in Some Cases, Transported Transneuronally to Other Brain Regions (Modified from Ref. 15)
Metal Species Method of Receptor Cell Transneuronal Example
Application Incorporation Transport Reference

Aluminum lactate Rabbit Intranasal Yes Indirect 95

pathological
evidence
Aluminum silicate Rabbit Bedding Yes No 96
Aluminum acetylacetonate Rat Inhalation Yes Yes 97
Cadmium Rat Intranasal Yes No 98
Pike Intranasal Yes No 99
Cadmium chloride Rat Intranasal Yes No 100
Cadmium oxide Rat Aerosol Yes No 101
Cobalt Rat Intranasal Yes Yes 102
Salmon Intranasal Yes Possible 103
Gold Squirrel Intranasal Yes Yes 104
Monkey
Rabbit Mucosal Yes No 105
Iron oxide (Fe2O3) Mouse Intranasal Yes Yes 106
Manganese Pike Intranasal Yes Yes 107
Rat Intranasal Yes Yes 108
Mercury Rat and pike Intranasal Yes No 109
Nickel Rat and pike Intranasal Yes Yes 110
Zinc Rat and pike Intranasal Yes Yes 111

dysfunction, as measured by psychophysical and elec-
trophysiological tests.4 In well-documented PD, the
dysfunction is unrelated to disease stage or the use of
anti-PD medications (eg, L-dopa, dopamine agonists,
anticholinergic compounds)34 and rivals or exceeds the
prevalence rate of the defining motor signs of the dis-
order. Longitudinal studies suggest that, in both AD
and PD, the olfactory deficit precedes the classic clin-
ical signs by several years, serving as a “preclinical”
marker.4 For example, in a study of 1,604 nonde-
mented older adults, women with anosmia who pos-
sessed at least 1 apolipoprotein ε4 allele had an odds
ratio of 9.71 for development of cognitive decline over
the ensuing 2 years, compared with an odds ratio of
1.90 for women with no olfactory dysfunction and at
least 1 such allele.35 In another study, 361 asymptom-
atic relatives of PD patients were administered olfac-
tory tests. Those with olfactory test scores in the top
and bottom 10% of the group underwent single-
photon emission computed tomography (SPECT)
with 2␤-carboxymethoxy-3␤ (4-iodophenyl)tropane
(␤-CIT) labeled with iodine 123, a dopamine trans-
porter measure of the health of this motor control
brain region.36 At the 2-year follow-up, 4 of the 40
relatives with olfactory test scores in the bottom 10%,
all of whom exhibited substantial reduction in trans-
porter uptake at baseline, had experienced development
of clinically defined PD, whereas none of the 38 rela-
tives with test scores in the top 10% did. The remain-
ing individuals in the bottom 10%, although not yet
experiencing parkinsonian symptoms, exhibited signif-
icant declines in transporter uptake across the two
tests, implying PD-related neuropathology was devel-
oping.
Congruent with the early olfactory loss of AD and
PD is the early pathological involvement of the olfac-
tory bulb and anterior olfactory nucleus, where marked
cell loss and the presence of disease-related pathology
(eg, neuritic plaques, neurofibrillary tangles, or Lewy
bodies) are present.37,38 In AD, tau-related pathology
within these structures correlates with disease severity,
cortical Lewy body counts, and apolipoprotein 4 car-
rier status.39,40 Superoxide dismutases, enzymes that
defend against reactive oxygen species, are abundant in
the olfactory bulb, anterior olfactory nucleus, and neu-
roepithelium of patients with AD, where they are over-
expressed relative to control subjects.41 Increases in
other indices of oxidative damage within the olfactory
neuroepithelium of patients with AD have also been

10 Annals of Neurology Vol 63 No 1 January 2008

reported, including heme oxygenase-1, a stress response
protein.42
In PD, Braak and colleagues43 present evidence that
the neuropathology, notably Lewy bodies and neurites,
begins within the olfactory bulb, anterior olfactory nu-
cleus, and dorsal motor nucleus of the vagus nerve
(dmX) and then advances rostrally through susceptible
regions of the medulla oblongata, pontine tegmentum,
midbrain, and basal forebrain. In part because the an-
terior olfactory structures have fewer connections than
the dmX with brain regions that subsequently exhibit
the next proposed stage of pathology, these authors ini-
tially believed that the dmX is the most likely starting
point. According to this concept, an unknown patho-
gen may enter the central nervous system from the
stomach via the enteric nerves. However, the dmX in-
volvement could be secondary to olfactory system in-
volvement because connections exist between the olfac-
tory bulb and this structure via several routes, for
example, the amygdala and stria terminalis. Impor-
tantly, direct connections are present between central
olfactory structures and the substantia nigra. Thus,
horseradish peroxidase injected into the olfactory tu-
bercle results in anterograde labeling of the substantia
nigra, ipsilateral ventral tegmental area, pars reticulata,
and ventral pallidum, as well as retrograde labeling of
the ipsilateral olfactory bulb, anterior olfactory nucleus,
and other olfactory areas.44 Recently, Hawkes,45 in col-
laboration with Braak and colleagues, has proposed a
“dual hit” hypothesis in which both the olfactory and
vagus nerves become involved simultaneously, perhaps
from a pathogen that enters the nose and becomes
swallowed with the nasal secretions, passing the stom-
ach wall into Auerbach’s and Meissner’s plexuses.
If a pathogen related to PD enters the nose and in-
duces smell loss, one might hypothesize that such a
pathogen, injected into the bloodstream, would be less
likely to damage the olfactory system. In support of
this concept, the parkinsonism induced by the intrave-
nous injection of a designer drug that inadvertently
contained the proneurotoxin, 1-methyl 4-phenyl
1,2,3,6-tetrahydropyridine (MPTP), is not associated
with significant olfactory loss.46 The brains of three of
these cases who have gone to autopsy lacked Lewy bod-
ies, PD-related structures that are present within the
olfactory bulb and anterior olfactory nucleus that are
believed to be associated with olfactory dysfunc-
tion.47,48 Interestingly, rats administered MPTP intra-
nasally exhibit progressive impairments in olfactory,
cognitive and motor function which appear to follow
the sequence of neuropathological events proposed by
Braak et al., although the olfactory deficit reverses itself
over time.49 Rats are relatively insensitive to the effects
of systemically introduced MPTP.50,51
Evidence against the Olfactory
Vector Hypothesis
Although xenobiotics can enter the brain via the olfac-
tory nerve, evidence that they initiate or cause AD or
PD is circumstantial. Potential opposition to the olfac-
tory vector hypothesis comes from several sources, in-
cluding: (1) the existence of genetic and familial forms
of AD and PD52; (2) the lack of smell dysfunction in
some AD and PD patients; and (3) a case report of a
65-year-old anosmic nondemented woman with AD-
related neuropathology, an imperforate cribriform
plate, rudimentary olfactory bulbs/tracts, and sulcal ab-
normalities of the orbitofrontal region.53 In addition,
unlike PD, it is less clear whether the pathology of AD
first appears within the peripheral olfactory system or
in more central olfaction-related brain regions. Accord-
ing to Braak and colleagues,54 tau-related neurofibril-
lary tangles occur initially in the transentorhinal region
between the hippocampus and the entorhinal cortex,
not in the olfactory bulb or anterior olfactory nucleus.
Others suggest the initial pathology may first appear in
peripheral olfactory structures.40,55 The lower density
of plaques and tangles in the olfactory bulb and tract
than in the amygdala and hippocampus has been
interpreted as central to peripheral movement of
pathology.56
For a number of reasons, such observations do not
disprove the olfactory vector hypothesis. First, this hy-
pothesis does not preclude other causes of AD and PD.
Second, the mode of entry of pathogens into the brain
need not be viewed as exclusive from genetic or other
determinants of neurodegenerative disease. One would
assume that most such putative agents would work in
concert with genetic substrates. Third, the pattern of
pathology may not show the direction of movement of
a xenobiotic. Thus, some cell types may be more vul-
nerable to the pathogen than others, and not all patho-
logical agents that enter the brain via the olfactory sys-
tem need to induce olfactory system damage en
passant.57 In some cases, a pathogen could reactivate
latent viruses within central structures,58 potentially
producing a central-to-peripheral propagation of dam-
age. In other cases, the olfactory pathway could incur
damage from the disease process initiated by the patho-
gen. Fourth, one cannot rule out, even in familial
cases, a breakdown in protective processes within the
olfactory mucosa at some point before phenotypic dis-
ease expression, opening the door to pathogen inva-
sion. It is known, for example, that a mutation in the
P450 cytochrome CYP2D6-debrisoquine hydroxylase
gene increases the risk for development of PD.59 Fifth,
not all familial cases of PD exhibit smell loss, including
some with LRRK2-associated PD.60 Sixth, aside from
interactions between environmental factors and genetic
determinants, the heterogeneity of smell loss observed
in AD and PD could reflect the following circumstances:
Doty: Olfactory Vector Hypothesis 11
(1) clinical misdiagnoses (more than 10% of AD and
PD patients are misdiagnosed),61,62 (2) individual differ-
ences in susceptibility of the olfactory pathways to dam-
age from a pathogen or from subsequent disease induc-
tion, and (3) differences in the virulence of pathogens to
induce damage to the olfactory system. Specificity of
damage to central structures from viruses that enter the
olfactory pathway is well documented. For example,
when Barnett and colleagues63 tracked the spread of two
viruses inoculated into the olfactory bulb, herpes simplex
virus type 1 and mouse hepatitis virus strain JHM, only
herpes simplex type 1 infected the noradrenergic neu-
rons in the locus ceruleus; however, both infected dopa-
minergic neurons in the ventral tegmental area. Finally,
aside from the possibility of multiple causes, the olfac-
tory vector hypothesis is not disproved by a single case
report of a woman with an imperforate cribriform plate
who exhibited AD-related pathological lesions. Because
the foramina of the cribriform plate close off from ap-
positional bone growth in a significant number of peo-
ple as they age,64 a pathogenic agent could have entered
the brain via the olfactory fila before such occlusion.
An argument can be made that damage to the affer-
ent olfactory pathways per se may predispose geneti-
cally or otherwise susceptible individuals to AD or PD,
regardless of the cause of the olfactory damage. In
other words, it is the damage to the olfactory system,
rather than a xenobiotic agent that enters the brain,
that initiates neurodegeneration in susceptible individ-
uals. If this “olfactory damage” hypothesis is correct,
then individuals with smell dysfunction due to any one
or combination of a number of causes (exposure to
toxic agents, head trauma, advanced age) would be
more likely to acquire AD or PD than individuals
without olfactory system compromise. It may be more
than coincidental that major nongenetic risk factors for
AD and PD, such as advanced age, head trauma, vi-
ruses, and exposure to heavy metals or extreme air pol-
lution, are themselves directly related to olfactory sys-
tem damage. The smell loss associated with the most
salient of such risk factors, advanced age, is likely sec-
ondary to the aforementioned occlusion of the foram-
ina of the cribriform plate by appositional bone growth
and to cumulative damage to the olfactory neuroepi-
thelium from bacteria, viruses, and other xenobiotic
agents.65
In potential accord with the “olfactory damage” hy-
pothesis for AD is the finding that removal of the ol-
factory bulbs of both rats and mice leads to decreased
performance on cognitive tasks not dependent on ol-
faction,66 an effect attributed, in part, to degenerative
disruption of interconnections with higher brain re-
gions, such as those between the olfactory and septo-
hippocampal systems.67 Although olfactory bulbectomy
is a severe insult to a rodent, inducing a wide range of
behavioral, hormonal, neurochemical, and anatomic
12 Annals of Neurology Vol 63 No 1 January 2008
changes including the rewiring of synaptic assemblies
and rebalancing of neurochemical systems,68,69 a num-
ber of these changes mimic key elements of AD-related
neuropathology. Thus, bulbectomy results in degener-
ation within regions of the temporal cortex, hippocam-
pus, and raphe nucleus; decreased density of cholin-
ergic neurons within basal structures of the forebrain;
and increased levels of ␤A within the hippocampus and
other limbic structures.68 –70 The increase in ␤A in-
duced by bulbectomy in nontransgenic mice is compa-
rable with the level of ␤A found in the early stage of
plaque formation of transgenic mice expressing the
mutated human ␤A precursor protein gene.71 Bulbec-
tomy may, in fact, focus trauma-related injury into sus-
ceptible brain regions in a process analogous to that
observed in diffuse brain injury, where long-term accu-
mulation of ␤A and tau occurs within the damaged
axons.72
It is unknown whether damage to the olfactory neu-
roepithelium per se can induce, in either humans or
rodents, elements of the complex cascade of brain
changes observed after bulbectomy. Axotomy or
ZnSO4 irrigation of the olfactory neuroepithelium does
lead to a 33 to 75% decrease of bulb weight in rats
after a month,73–75 largely reflecting degenerative
changes within the glomerular and external plexiform
layers of the bulb. In humans, decreased olfactory bulb
volumes determined using magnetic resonance imaging
have been reported secondary to age,76 head trauma,77
upper respiratory infections that induce epithelial dam-
age,78 and schizophrenia.79 Volume decrements of ap-
proximately 23% were reported for both older persons
and those with schizophrenia.76,79 In light of a finding
of a ⫺0.86 correlation between olfactory threshold sen-
sitivity and magnetic resonance imaging–determined
olfactory bulb volumes in 22 normal subjects,79 appar-
ently olfactory bulb volume is a strong correlate of ol-
factory sensitivity. Research is sorely needed to deter-
mine whether the degeneration-produced decrements
in olfactory bulb volume, particularly in individuals at
risk for neurodegenerative disease such as the elderly,
are associated with the induction of altered central neu-
ropathology, transmitter function, and immunity.
Conclusion
Despite the intuitive appeal of the olfactory vector hy-
pothesis, it remains to be determined whether it ex-
plains the cause of any case of AD or PD. To date, the
evidence for this hypothesis, albeit compelling, is cir-
cumstantial. It is clear that viruses, bacteria, prions,
and a range of airborne toxicants directly or indirectly
implicated as risk factors for these diseases can enter
the brain via the peripheral olfactory system and, in
some instances, spread to brain regions classically asso-
ciated with disease pathology. It is also clear that smell
loss is among the first clinical signs of both AD and
PD, occurring during their “preclinical phase” and dis-
proportionately in persons at risk for the development
of these disorders. However, what is unclear is whether
the pathology of these diseases can be initiated by
agents that specifically enter the brain via the olfactory
pathways. Moreover, numerous basic questions remain
unanswered. Is the olfactory dysfunction a product of
the degenerative disease process or caused by agents
that enter the brain via the olfactory fila? Does this
differ from disease to disease? Can both occur? Are ge-
netic and age-related substrates involved? Can damage
to the olfactory system per se initiate disease pathology
in genetically susceptible individuals, independent of
the cause of such damage? Does damage to the olfac-
tory system induce alterations in cytokines and other
immune system mediators in susceptible persons that
potentially regulate the induction of disease pathology?
The answers to these and related questions will ulti-
mately determine the viability of the olfactory vector
hypothesis and whether novel prophylactic treatments
involving the olfactory mucosa can be developed.
Disclosure
R.L.D. is a major shareholder in Sensonics, Inc., a
manufacturer of tests of taste and smell.
This work was supported by the NIH (National Institute of Envi-
ronmental Health Sciences, 1 P30 ES013508-02). I thank Leslie
Cameron, John A. King, Bert Menco, Muhammad Shah, James B.
Snow, Jr., Isabelle Tourbier, and Özüm Saygi for their constructive
comments on an earlier version of the manuscript.
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