Skip to main content
Journal of Neuropathology and Experimental Neurology logoLink to Journal of Neuropathology and Experimental Neurology
. 2022 Jun 25;81(8):643–649. doi: 10.1093/jnen/nlac042

Olfactory Bulb Amyloid-β Correlates With Brain Thal Amyloid Phase and Severity of Cognitive Impairment

Cécilia Tremblay 1,, Geidy E Serrano 2, Anthony J Intorcia 3, Monica R Mariner 4, Lucia I Sue 5, Richard A Arce 6, Alireza Atri 7,8, Charles H Adler 9, Christine M Belden 10, Holly A Shill 11, Erika Driver-Dunckley 12, Shyamal H Mehta 13, Thomas G Beach 14
PMCID: PMC9297096  PMID: 35751438

Abstract

The Alzheimer disease (AD) neuropathological hallmarks amyloid β (Aβ) and tau neurofibrillary (NF) pathology have been reported in the olfactory bulb (OB) in aging and in different neurodegenerative diseases, which coincides with frequently reported olfactory dysfunction in these conditions. To better understand when the OB is affected in relation to the hierarchical progression of Aβ throughout the brain and whether OB pathology might be an indicator of AD severity, we assessed the presence of OB Aβ and tau NF pathology in an autopsy cohort of 158 non demented control and 173 AD dementia cases. OB Aβ was found in less than 5% of cases in lower Thal phases 0 and 1, in 20% of cases in phase 2, in 60% of cases in phase 3 and in more than 80% of cases in higher Thal phases 4 and 5. OB Aβ and tau pathology significantly predicted a Thal phase greater than 3, a Braak NF stage greater than 4, and an MMSE score lower than 24. While OB tau pathology is almost universal in the elderly and therefore is not a good predictor of AD severity, OB Aβ pathology coincides with clinically-manifest AD and might prove to be a useful biomarker of the extent of brain spread of both amyloid and tau pathology.

Keywords: Aging, Alzheimer disease, Amyloid β, Braak stage, Diagnosis, Mini-Mental State Exam (MMSE), Olfaction, Postmortem

INTRODUCTION

The presence of Alzheimer disease (AD) neuropathological hallmarks, such as amyloid β (Aβ) pathology and tau neurofibrillary changes (NF), was reported in olfactory relevant regions, particularly the olfactory bulb (OB), in aging and in different neurodegenerative diseases at postmortem examination. The OB is of particular interest in neurodegenerative diseases because it is affected in early disease stages and has been suggested to be an entry point for potential pathogens to enter and then spread throughout the brain (1–3).

Indeed, we and others have previously reported on the presence in the OB of tau and α-synuclein (αSyn) histopathology at early stages of AD, Lewy body disease (LBD), Parkinson disease (PD) and multiple system atrophy (MSA), as well as the presence of other specific molecular markers in amyotrophic lateral sclerosis, progressive supranuclear palsy, corticobasal degeneration, Pick disease, and Huntington disease (1, 4–17) These changes are consistent with olfactory dysfunction, which has been repeatedly reported to manifest early in neurodegenerative diseases (18). The changes provide a potential model of olfactory-mediated pathogenesis in neurodegenerative disorders, including AD and LBD, and suggest the potential for new olfactory-related diagnostic modalities.

While tau NF pathology was found to be almost universal in older nondemented individuals, the presence of Aβ plaques has been reported less frequently and found to occur in cases with more severe AD pathology suggesting that the presence of Aβ pathology in the OB could be an indicator of the diagnostic levels of AD (4–6, 8, 9, 19, 20). The hierarchical progression of Aβ pathology throughout the brain was described in 5 Thal amyloid phases in which the pathology typically progresses from the neocortex to limbic regions, basal ganglia, brainstem, and finally to the cerebellum (21). Nevertheless, involvement of the OB has not been specifically assessed in relation to these Thal phases. It has previously been demonstrated that Aβ in the OB correlated with whole-brain Thal amyloid phases and Braak NF stages (6). We sought to extend this work by determining the Thal phase at which OB Aβ deposits are most likely to first appear, and how well the presence and densities of OB tau and Aβ deposits might be suitable indicators of AD stage, histopathological severity, and severity of cognitive impairment.

Therefore, this clinicopathological study aimed to investigate the severity of Aβ and tau deposition in the OB in relation to the progression of whole-brain AD pathology and cognitive impairment. We determined the densities of OB Aβ and tau NF pathologies in a large cohort of 331 autopsied cases that were neuropathologically distributed along a continuum of histopathological AD stages using tissue and data from the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND) and Banner Sun Health Research Institute Brain and Body Donation Program (BBDP) (22).

MATERIALS AND METHODS

Database and Subject Selection

All subjects included in this study were selected from the AZSAND/BBDP database (www.brainandbodydonationprogram.org) (22), and all subjects signed informed consents that were ethically approved by designated Banner Sun Health Research Institute Institutional Review Boards. Subjects are all volunteers and most receive standardized research-dedicated clinical assessments including an extensive neuropsychological test battery and cognitive and movement disorders assessments by board-certified subspecialty neurologists. Additional clinical information is periodically gathered from requisitioned private medical records. Test results available included the Mini-Mental State Exam (MMSE) and the Unified Parkinson’s Disease Rating Scale (UPDRS).

At the time of death, a full neuropathological examination is performed, including assignment of the AD Braak NF stage (23), the Thal amyloid phase for Aβ plaque brain distribution (21), the CERAD neuritic plaque density score (24), and αSyn stage according to the Unified Staging System for Lewy Body Disorders (USSLBD) (25). Data also include regional and summary cortical brain density measures for tau NF brain and plaque load (for both, there is a total possible score of 15 based on summary of 0–3 scores in each of 5 regions: frontal association cortex, parietal association cortex, temporal association cortex, hippocampus CA1, and entorhinal/transentorhinal areas). The regional and summary brain load of αSyn pathology is also recorded (total possible score of 40 based on summary of 0–4 scores for each of 10 brain regions).

Cases included were selected to cover the full range of AD pathology and were categorized at their final consensus clinical conference as either controls without dementia or parkinsonism (n = 158) or as AD dementia (n = 173), which was defined as having an “intermediate” or “high” rating on the NIA-Reagan system. Because many of the cases were autopsied prior to the publication of the newer NIA-AA rating system, the NIA-Reagan system was used for all subjects. Some AD subjects presented with additional comorbid neuropathologically diagnosed conditions, including PD (n = 10), DLB (n = 12), vascular dementia (n = 13), and progressive supranuclear palsy (n = 2).

Immunohistochemical Assessment of OB Pathology

For the purpose of this study, additional OB immunohistochemical staining was performed. Tissue samples of the OB were embedded in paraffin, sectioned at 5-μm thickness, and mounted on charged glass slides for histology. Immunohistochemical staining was then performed using the monoclonal antibody clone 6E10 (BioLegend, San Diego, CA) for specific detection of all types of Aβ pathology including neuritic, cored, and diffuse plaques. The primary antibody concentration was 1:1000. Staining for tau pathology was performed with the AT8 antibody to phosphorylated tau (Thermo Fisher Scientific, Waltham, MA), diluted to 1:1000. For both types of staining, the epitope exposure method consisted of 20 minutes in 80% formic acid. Secondary antibodies and signal development were performed with an immunoperoxidase method as previously described (26). The presence of pathology in the OB was semiquantitatively assessed by an experienced neuropathologist (T.G.B), who was blinded to clinical data. The density of Aβ plaques was scored from 0 to 3, as 0 for absent, 1 for sparse, 2 for moderate, and 3 for frequent, based on templates published by CERAD (24). The density of OB tau pathology was graded from 0 to 4, based on our previously published templates (27).

Photomicrographs depicting Aβ and tau pathologies in the OB are shown in Figure 1.

FIGURE 1.

FIGURE 1.

Photomicrographs depicting (A) amyloid β and (B) tau immunohistochemical pathologic inclusions in the OB at low and high magnifications.

Because OB lesions were reported to most frequently and heavily affect the anterior olfactory nucleus (AON), which consists of multipolar medium-sized neurons arranged in small discontinuous groups along the central axis of the OB, we also noted the localization of the lesions in the AON and in the outer layers of the OB (altogether including glomerular, external plexiform, mitral cell, internal plexiform, and granule cell layers), in a subset of 60 cases for each stain (1).

Data Analysis

Statistical analysis was performed using SPSS software (IBM SPSS Statistics 23.0). The link between OB Aβ and tau pathology scores and other clinical and neuropathologic characteristics was assessed using non-parametric univariate Spearman correlations. Non-parametric Mann-Whitney U-test or chi-square tests, as appropriate, were used to compare these measures between sexes and for the differences between OB Aβ-positive cases (cases with the presence of Aβ in the OB) and OB-Aβ negative cases. The relationships between OB Aβ and tau pathology scores with whole-brain Thal amyloid phase, Braak NF stage, and last MMSE score were further investigated using logistic regression models adjusting for age and sex. Receiver operating characteristics (ROC) were analyzed to assess the ability of OB Aβ presence for discrimination between a lower (0–3) and a higher (4–5) Thal phase.

RESULTS

Table 1 depicts basic demographic, clinical, and neuropathological characteristics of the cases studied. The presence of Aβ in the OB was found in less than 5% of cases in lower Thal phases 1 and 2, in 60% of cases in phase 3 and in more than 80% in higher Thal phases 4 and 5. Tau pathology was found in more than 95% of cases and as early as Thal phase 0 (Fig. 2 and Table 2). In most cases, lesions were located in both the AON and the outer layers of the OB but the AON was most frequently and heavily involved. Aβ lesions were located in both the AON and outer layers of the OB in 75% of cases, only in the AON in 17% of cases and only in outer layers in 8% of cases. For tau pathology, they were in both regions in 87% of cases, only in the AON in 8% of cases and only in outer layers in 5% of cases. Localization of pathology was not related to severity of pathology in the bulb.

TABLE 1.

Demographic and Neuropathological Characteristics of Cases

All Cases ADD Controls OB Aβ Positive Cases OB Aβ Negative Cases
Number of cases 331 173 158 174 157
Age 84.6 ± 7.8 82.7 ± 8.6 86.6 ± 6.7 84.1 ± 8.2 84.9 ± 7.7
Sex (M/F) 160/171 87/86 73/85 86/88 74/83
% Apo E genotype 39.4 42.9 35.6 40.8 37.7
MMSE 19.8 ± 10.2 11.6 ± 8.2 28.2±1.5 15.2 ± 9.9 24.97 ± 7.8*
UPDRS 15.4 ± 19.1 31.4 ± 25.0 8.1 ± 8.6 22.1 ± 22.8 10.6 ± 14.0*
OB Aβ density 1.4 ± 1.4 2.2 ± 1.2 0.6 ± 1.1 2.7 ± 0.6 0.0 ± 0.0*
OB tau density 2.2 ± 0.9 2.5 ± 0.8 1.9 ± 0.9 2.6 ± 0.7 1.7 ± 0.9*
Thal phase 3.0 ± 1.8 4.2 ± 1.0 1.7 ± 1.8 4.1 ± 1.1 1.8 ± 1.7*
Braak stage 4.0 ± 1.3 4.7 ± 1.1 3.2 ± 0.9 4.5 ± 1.1 3.4 ± 1.3*
USSLBD stage 1.1 ± 1.4 1.6 ± 1.5 0.6 ± 1.0 1.4 ± 15 0.7 ± 1.2*
NF brain load 7.9 ± 4.5 10.6 ± 4.2 5.0 ± 2.4 9.8 ± 4.2 5.8 ± 3.7*
Plaque brain load 9.0 ± 5.5 12.7 ± 2.1 5.0 ± 5.3 12.5 ± 2.4 5.1 ± 5.4*
αSyn brain load 5.6 ± 9.3 8.9 ± 10.9 2.5 ± 5.9  7.4 ± 10.27 3.8 ± 7.7*

Data are presented as mean ± SDs.

ADD, Alzheimer disease dementia; ApoE, apolipoprotein E genotype; MMSE, last Mini Mental State Examination score; UPDRS, last Unified Parkinson’s Disease Rating Scale motor score (part 3 motor score); USSLBD stage, Unified staging system for Lewy body disorders; Plaque Score and NF Score, summary regional brain density of neurofibrillary tangles and plaques scores with maximum scores of 15; αSyn Score, summary regional brain Lewy-type synucleinopathy density score with a maximum score of 40.

*

Significant differences between OB-Aβ positive cases and OB Aβ-negative case.

FIGURE 2.

FIGURE 2.

Percentage of cases with olfactory bulb Amyloid β immunoreactivity for each Thal Phase.

TABLE 2.

Cases with Olfactory Bulb Amyloid β and Tau Pathology for Thal Phase and Braak NF Stage

(a) Thal Phase
Thal Phase 0 Thal Phase 1 Thal Phase 2 Thal Phase 3 Thal Phase 4 Thal Phase 5
OB Aβ+ cases (%) 2 (3.5) 1 (5.9) 9 (21.4) 47 (61.8) 25 (92.6) 90 (80.4)
OB tau+ cases (%) 53 (93.0) 15 (88.2) 41 (97.6) 75 (98.7) 27 (100) 112 (100)
Total number of cases 57 17 42 76 27 112
(b) Braak NF Stage
Braak NF 1 Braak NF 2 Braak NF 3 Braak NF 4 Braak NF 5 Braak NF 6
OB Aβ+ cases (%) 0 (0) 6 (28.5) 25 (31.6) 54 (51.5) 56 (86.2) 33 (70.2)
OB tau+ cases (%) 10 (71.4) 21 (100) 78 (98.7) 102 (97.1) 65 (100) 47 (100)
Total number of cases 14 21 79 105 65 47

OB Aβ-positive and -negative cases did not differ in age (p = 0.3) or sex (χ2 = 0.1735; p = 0.68), but positive cases had significantly lower last MMSE score; and higher last motor UPDRS scores, OB tau pathology score, Thal phase, Braak NF stage and total brain plaque, tangle and αSyn brain scores (all p < 0.001). Mean age (U = 10292.5, p < 0.001) and Braak stage (U = 11617.0, p = 0.015) were higher overall in females, while no sex differences were observed for OB tau density, Aβ density, Thal phase, or MMSE score (Table 1).

OB Aβ density scores were found to correlate with Thal phases (Rho = 0.616, p < 0.001), Braak NF stages (Rho = 0.449, p < 0.001), total brain plaque score (Rho = 0.641, p < 0.001), total tangles brain score (Rho = 0.491, p < 0.001), and total αSyn brain score (Rho = 0.198, p < 0.001), as well as USSLBD stage (Rho = 0.182, p = 0.001), MMSE score (Rho = −0.534, p < 0.001), and UPDRS motor score (Rho = 0.332, p < 0.001) but did not correlate with age (Rho = −0.035, p = 0.4; Fig. 3).

FIGURE 3.

FIGURE 3.

Correlation between olfactory bulb Amyloid β and MMSE, Thal amyloid phase and Braak NF stage.

OB tau density scores were found to significantly correlate with Thal phases (Rho = 0.439, p < 0.001), Braak NF stages (Rho = 0.511, p < 0.001), total brain plaque score (Rho = 0.482, p < 0.001), total brain tangle score (Rho = 0.550, p < 0.001), and total brain αSyn score (Rho = 0.196, p = 0.001), as well as USSLBD stage (Rho = 0.161, p = 0.003), MMSE score (Rho = −0.360, p < 0.001), UPDRS motor score (Rho = 0.250, p < 0.001), and age (Rho = 0.113, p = 0.04).

In logistic regression models, OB pathology predicted a higher Thal phase than 3 [χ2(4) = 116.910; p < 0.001; R2 = 0.298], with covariates for sex and age, significant independent predictors were OB Aβ, OB tau, and age. A higher Braak stage than 4 could significantly be predicted [χ2(4) = 109.535; p < 0.001; R2 = 0.282] with significant independent predictors being OB Aβ, OB tau, age, and sex. A lower MMSE score than 24 was also significantly predicted [χ2(4) = 118.990; p < 0.001; R2 = 0.315] with significant independent predictors being OB Aβ, OB tau, and age. Significance, odds ratios, and 95% confidence intervals of each significant independent predictor as well as sensitivity and specificity of whole models are shown in Table 3.

TABLE 3.

Logistic Regression Analyses With Thal Phase, Braak Stage, and Last MMSE Score as the Dependent Variable

Predictors p-Value Odds Ratios 95% CI Specificity Sensitivity
(a) Predicting a higher Thal phase than 3
Equation <0.001 78.6 73.3
OB Aβ <0.001 2.139 1.715, 2. 667
OB tau 0.02 1.846 1.259, 2.708
Age 0.01 0.942 0.909, 0.977
Sex 0.2
(b) Predicting a higher Braak stage than 4
Equation <0.001 82.8 63.1
OB Aβ <0.001 1.683 1.355, 2.090
OB tau <0.001 2.592 1.717, 3.912
Age <0.001 0.909 0.873, 0.945
Sex 0.02 1.979 1.112, 3.520
(c) Predicting a lower MMSE score than 24
Equation <0.001 78.2 78.5
OB Aβ <0.001 2.167 1.746, 2.691
OB tau 0.02 1.543 1.355, 2.090
Age <0.001 0.917 0.881, 0.955
Sex 0.2 1.447 0.826, 2.533

Significant independent predictors in regression models are presented in bold.

To better assess how specifically OB Aβ can predict Thal phases, we computed analysis of ROC curves that showed that Aβ presence in the OB can predict a higher Thal phase than 3 with a sensitivity of 80.2%, a specificity of 63.3%, and an area under the curve of 0.717 (Fig. 4).

FIGURE 4.

FIGURE 4.

ROC curve for the prediction of a higher whole-brain Thal phase greater than 3 by presence or absence of OB Aβ. Sensitivity is 80.2% and specificity is 63.3% with an area under the curve of 0.717.

DISCUSSION

This clinicopathological study evaluates the link between the presence of Aβ and tau pathologies in the OB and the severity of AD pathology in the brain. We show that OB Aβ inclusions, though rare in low amyloid Thal phases, are present in two-thirds of cases in Thal phase 3 and in more than 80% of cases in higher Thal phases 4 and 5. OB Aβ and tau pathology both significantly predicted a Thal phase greater than 3, a Braak NF stage greater than 4, and an MMSE score lower than 24. While tau pathology is almost universal in OBs of older individuals and therefore not useful to stage AD severity, OB Aβ pathology may be a better predictor of diagnostic levels of AD neuropathology and cognitive decline.

This is the first study to specifically assess the appearance of Aβ pathology in the OB in relation to the topographical whole-brain progression of Aβ deposition according to the hierarchical sequence described by Thal and colleagues (21, 28). We report the presence of OB in about 60% of cases in amyloid Thal phase 3 and in more than 80% of cases in higher Thal phases 4 and 5. With regards to Braak NF stages, 50% of cases with Braak NF stage 4 presented OB Aβ pathology and up to 80% of cases in Braak NF stages 5 or 6 presented OB Aβ pathology. Even though the OB is typically suggested to be one of the first regions affected in neurodegenerative diseases and was shown to have tau and αSyn pathology in very early stages of disease, this study along with previous work suggests that Aβ pathology affects the OB only in more advanced AD disease stages (5, 6, 8, 11). Exact mechanisms of Aβ initial deposition or progression are not fully understood, hence it is not yet clear as to why brain regions are involved in a particular sequence (29). It has been demonstrated, however, that the neocortex is first affected, in phase 1, and that later regions are subsequently affected based on their neuroanatomical connections with the neocortex (21, 28, 29). The OB is heavily connected with the amygdala (30) and it is therefore possible that Aβ “spreads” from the amygdala to the OB. According to Thal phases, the amygdala is affected in 88% of cases in Thal phase 3 and in up to 100% of cases in Thal phase 4 while the OB has Aβ deposits in about 60% of Phase 3 cases and 80% of phases 4 and 5. Alternatively, brain regions may simply be differentially affected based on their inherent selective vulnerability.

We found that both Aβ and tau OB pathologies correlated with the severity of whole-brain AD pathology as well as cognitive impairment as measured by the last MMSE. Logistic regression analysis demonstrated that both OB Aβ and tau pathologies significantly predict a higher Thal phase than 3, a higher Braak stage than 4 and a lower MMSE score than 24, when adjusted for age and sex. Odds ratios were higher for OB Aβ than for OB tau pathology to predict a higher Thal phase and a lower MMSE score. Further, independently of tau, the presence of Aβ in the OB can predict a higher Thal phase than 3 with a sensitivity of 80.2%, a specificity of 63.3%. These results support that the appearance of OB Aβ may roughly correspond to the presence of cognitive symptoms and dementia in subjects (21, 31–34). Even though some studies reported that amyloid Thal phase does not appear to be an independent predictor of cognitive changes (35) other demonstrated its linkage with clinical diagnosis and as a predictor of dementia (36). The almost universal presence of tau pathology in OBs of elderly humans with or without AD, appearing as early as Thal phase 0 and Braak NF stage 1, may reduce its usefulness as a binomial marker of disease presence or absence although its density still correlates with brain disease stage severity. Altogether, these results indicate that OB Aβ may prove more useful as a biomarker of the extent of AD disease severity.

Potential techniques that assess the level of Aβ OB pathology may help to clinically confirm a high level of AD pathology in the brain. Thus, tests of olfaction (18, 37–48), as well as OB biopsies or imaging (1, 6, 49–51) or nasal mucosal sampling (52–61) might be diagnostically useful with the additional advantage of also indicating the presence of comorbid neurodegenerative pathologies including LBD, MSA, non-AD tauopathies, and TDP-43. While OB biopsy may be too invasive (50) and would require specialized surgical personnel, the close proximity of primary olfactory sensory neurons in the olfactory mucosa provides a less-invasive substrate, through RT-QuIC or analogous methodology for detecting seed-induced protein aggregation in nasal brushings. This has been successfully demonstrated for prion disease (62–65), and, in preliminary work, for LBD (56, 57, 66, 67). In the future, these highly sensitive methods may also allow minimally invasive fine needle aspiration biopsy of the OB through the existing foramina of the cribriform plate (68). Future studies may also investigate enhanced analyses of olfactory function that may also provide additional disease-stage profiling (38).

We acknowledge some limitations to this study. First, only those cases with an AD clinicopathological diagnosis or control status were evaluated. Future studies should also investigate other neurodegenerative diseases. Moreover, we did not have access to premortem olfactory function of the autopsied cases and therefore could not investigate the link between olfactory performance and the presence of OB Aβ and tau pathologies.

In conclusion, results from this large neuropathological investigation demonstrate that Aβ deposition in the OB correlates with Thal amyloid phase and is observed in two-thirds of subjects in Thal phase 3 and in most cases in Thal phases 4 and 5. Further, OB Aβ and tau pathologies predict diagnostic levels of AD and severity of cognitive impairment emphasizing the promise of olfactory-related diagnostic modalities for staging of AD and potentially other related neurodegenerative diseases.

Acknowledgments

The authors would like to thank the autopsy personnel who helped contribute clinical data and postmortem brains from study subjects. They also thank the donors who were recruited for this study as well as their families.

Contributor Information

Cécilia Tremblay, From the Department of Neuropathology, Banner Sun Health Research Institute, Sun City, Arizona, USA.

Geidy E Serrano, From the Department of Neuropathology, Banner Sun Health Research Institute, Sun City, Arizona, USA.

Anthony J Intorcia, From the Department of Neuropathology, Banner Sun Health Research Institute, Sun City, Arizona, USA.

Monica R Mariner, From the Department of Neuropathology, Banner Sun Health Research Institute, Sun City, Arizona, USA.

Lucia I Sue, From the Department of Neuropathology, Banner Sun Health Research Institute, Sun City, Arizona, USA.

Richard A Arce, From the Department of Neuropathology, Banner Sun Health Research Institute, Sun City, Arizona, USA.

Alireza Atri, From the Department of Neuropathology, Banner Sun Health Research Institute, Sun City, Arizona, USA; Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Charles H Adler, Department of Neurology, Mayo Clinic College of Medicine, Mayo Clinic Arizona, Scottsdale, Arizona, USA.

Christine M Belden, From the Department of Neuropathology, Banner Sun Health Research Institute, Sun City, Arizona, USA.

Holly A Shill, Department of Neurology, Barrow Neurological Institute, Phoenix, Arizona, USA.

Erika Driver-Dunckley, Department of Neurology, Mayo Clinic College of Medicine, Mayo Clinic Arizona, Scottsdale, Arizona, USA.

Shyamal H Mehta, Department of Neurology, Mayo Clinic College of Medicine, Mayo Clinic Arizona, Scottsdale, Arizona, USA.

Thomas G Beach, From the Department of Neuropathology, Banner Sun Health Research Institute, Sun City, Arizona, USA.

The Brain and Body Donation Program has been supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinson’s Disease and Related Disorders), the National Institute on Aging (P30 AG19610 and P30AG072980, Arizona Alzheimer’s Disease Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer’s Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901, and 1001 to the Arizona Parkinson’s Disease Consortium), and the Michael J. Fox Foundation for Parkinson’s Research.

The authors have no duality or conflicts of interest to declare.

REFERENCES

  • 1. Beach TG, White CL III, Hladik CL, et al. ; Arizona Parkinson’s Disease Consortium. Olfactory bulb α-synucleinopathy has high specificity and sensitivity for Lewy body disorders. Acta Neuropathol  2009;117:169–74 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2. Rey NL, Wesson DW, Brundin P.  The olfactory bulb as the entry site for prion-like propagation in neurodegenerative diseases. Neurobiol Dis  2018;109:226–48 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3. Braak H, Rub U, Gai WP, et al.  Idiopathic Parkinson’s disease: Possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen. J Neural Transm (Vienna)  2003;110:517–36 [DOI] [PubMed] [Google Scholar]
  • 4. Attems J, Lintner F, Jellinger KA.  Olfactory involvement in aging and Alzheimer’s disease: An autopsy study. J Alzheimers Dis  2005;7:149–57; discussion 73–80. [DOI] [PubMed] [Google Scholar]
  • 5. Attems J, Jellinger KA.  Olfactory tau pathology in Alzheimer disease and mild cognitive impairment. Clin Neuropathol  2006;25:265–71 [PubMed] [Google Scholar]
  • 6. Attems J, Walker L, Jellinger KA.  Olfactory bulb involvement in neurodegenerative diseases. Acta Neuropathol  2014;127:459–75 [DOI] [PubMed] [Google Scholar]
  • 7. Christen-Zaech S, Kraftsik R, Pillevuit O, et al.  Early olfactory involvement in Alzheimer’s disease. Can J Neurol Sci  2003;30:20–5 [DOI] [PubMed] [Google Scholar]
  • 8. Kovács T, Cairns NJ, Lantos PL. βamyloid deposition and neurofibrillary tangle formation in the olfactory bulb in ageing and Alzheimer’s disease. Neuropathol Appl Neurobiol  1999;25:481–91 [DOI] [PubMed] [Google Scholar]
  • 9. Kovács T, Cairns NJ, Lantos PL.  Olfactory centres in Alzheimer’s disease: Olfactory bulb is involved in early Braak’s stages. Neuroreport  2001;12:285–8 [DOI] [PubMed] [Google Scholar]
  • 10. Pearce RK, Hawkes CH, Daniel SE.  The anterior olfactory nucleus in Parkinson’s disease. Mov Disord  1995;10:283–7 [DOI] [PubMed] [Google Scholar]
  • 11. Tsuboi Y, Wszolek ZK, Graff-Radford NR, et al.  Tau pathology in the olfactory bulb correlates with Braak stage, Lewy body pathology and apolipoprotein epsilon4. Neuropathol Appl Neurobiol  2003;29:503–10 [DOI] [PubMed] [Google Scholar]
  • 12. Sengoku R, Saito Y, Ikemura M, et al.  Incidence and extent of Lewy body-related α-synucleinopathy in aging human olfactory bulb. J Neuropathol Exp Neurol  2008;67:1072–83 [DOI] [PubMed] [Google Scholar]
  • 13. Takeda T, Iijima M, Uchihara T, et al.  TDP-43 pathology progression along the olfactory pathway as a possible substrate for olfactory impairment in amyotrophic lateral sclerosis. J Neuropathol Exp Neurol  2015;74:547–56 [DOI] [PubMed] [Google Scholar]
  • 14. Kovács T, Papp MI, Cairns NJ, et al.  Olfactory bulb in multiple system atrophy. Mov Disord  2003;18:938–42 [DOI] [PubMed] [Google Scholar]
  • 15. Yoshimura N.  Olfactory bulb involvement in Pick’s disease. Acta Neuropathol  1988;77:202–5 [DOI] [PubMed] [Google Scholar]
  • 16. Highet B, Dieriks BV, Murray HC, et al.  Huntingtin aggregates in the olfactory bulb in Huntington’s disease. Front Aging Neurosci  2020;12:261. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17. Kasanuki K, Ross OA, DeTure MA, et al.  Relationships between Lewy and tau pathologies in 375 consecutive non-Alzheimer’s olfactory bulbs. Mov Disord  2018;33:333–4 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18. Doty RL.  Olfactory dysfunction in neurodegenerative diseases: Is there a common pathological substrate?  Lancet Neurol  2017;16:478–88 [DOI] [PubMed] [Google Scholar]
  • 19. Kovács I, Török I, Zombori J, Kása P.  Neuropathologic changes in the olfactory bulb in Alzheimer’s disease. Neurobiology (Bp)  1996;4:123–6 [PubMed] [Google Scholar]
  • 20. Tremblay C, Serrano GE, Intorcia AJ, et al.  Effect of olfactory bulb pathology on olfactory function in normal aging. Brain Pathol  2022;e13075. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21. Thal DR, Rüb U, Orantes M, et al.  Phases of Aβ-deposition in the human brain and its relevance for the development of AD. Neurology  2002;58:1791–800 [DOI] [PubMed] [Google Scholar]
  • 22. Beach TG, Adler CH, Sue LI, et al.  Arizona study of aging and neurodegenerative disorders and brain and body donation program. Neuropathology  2015;35:354–89 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23. Braak H, Alafuzoff I, Arzberger T, et al.  Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol  2006;112:389–404 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24. Mirra SS, Heyman A, McKeel D, et al.  The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology  1991;41:479–86 [DOI] [PubMed] [Google Scholar]
  • 25. Beach TG, Adler CH, Lue L, et al. ; Arizona Parkinson’s Disease Consortium. Unified staging system for Lewy body disorders: Correlation with nigrostriatal degeneration, cognitive impairment and motor dysfunction. Acta Neuropathol  2009;117:613–34 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26. Serrano GE, Intorcia A, Carew J, et al.  Feasibility study: Comparison of frontal cortex needle core versus open biopsy for detection of characteristic proteinopathies of neurodegenerative diseases. J Neuropathol Exp Neurol  2015;74:934–42 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27. Tremblay C, Serrano GE, Intorcia AJ, et al.  Hemispheric asymmetry and atypical lobar progression of Alzheimer-type tauopathy. J Neuropathol Exp Neurol  2022;81:158–71 [DOI] [PubMed] [Google Scholar]
  • 28. Thal DR, Walter J, Saido TC, et al.  Neuropathology and biochemistry of Aβ and its aggregates in Alzheimer’s disease. Acta Neuropathol  2015;129:167–82 [DOI] [PubMed] [Google Scholar]
  • 29. Nath S, Agholme L, Kurudenkandy FR, et al.  Spreading of neurodegenerative pathology via neuron-to-neuron transmission of β-amyloid. J Neurosci  2012;32:8767–77 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30. Cleland TA, Linster C.  Central olfactory structures. In: Doty RL, ed. Handbook of Clinical Neurology. Amsterdam, Netherlands: Elsevier 2019:79–96 [DOI] [PubMed] [Google Scholar]
  • 31. Trejo-Lopez JA, Yachnis AT, Prokop S.  Neuropathology of Alzheimer’s disease. Neurotherapeutics  2022;19:173–185 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32. Montine TJ, Phelps CH, Beach TG, et al. ; Alzheimer’s Association. National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: A practical approach. Acta Neuropathol  2012;123:1–11 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33. Hyman BT, Phelps CH, Beach TG, et al.  National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimers Dement  2012;8:1–13 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34. Nelson PT, Alafuzoff I, Bigio EH, et al.  Correlation of Alzheimer disease neuropathologic changes with cognitive status: A review of the literature. J Neuropathol Exp Neurol  2012;71:362–81 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35. Serrano-Pozo A, Qian J, Muzikansky A, et al.  Thal amyloid stages do not significantly impact the correlation between neuropathological change and cognition in the Alzheimer Disease Continuum. J Neuropathol Exp Neurol  2016;75:516–26 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36. Boluda S, Toledo JB, Irwin DJ, et al.  A comparison of Aβ amyloid pathology staging systems and correlation with clinical diagnosis. Acta Neuropathol  2014;128:543–50 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37. Beach TG, Adler CH, Zhang N, et al.  Severe hyposmia distinguishes neuropathologically confirmed dementia with Lewy bodies from Alzheimer’s disease dementia. PLoS One  2020;15:e0231720. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38. Gerkin RC, Adler CH, Hentz JG, et al.  Improved diagnosis of Parkinson’s disease from a detailed olfactory phenotype. Ann Clin Transl Neurol  2017;4:714–21 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39. Driver-Dunckley E, Adler CH, Hentz JG, et al.  Olfactory dysfunction in incidental Lewy body disease and Parkinson’s disease. Parkinsonism Relat Disord  2014;20:1260–2 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40. Chou KL, Bohnen NI.  Performance on an Alzheimer-selective odor identification test in patients with Parkinson’s disease and its relationship with cerebral dopamine transporter activity. Parkinsonism Relat Disord  2009;15:640–3 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41. McKinnon J, Evidente V, Driver-Dunckley E, et al.  Olfaction in the elderly: A cross-sectional analysis comparing Parkinson’s disease with controls and other disorders. Int J Neurosci  2010;120:36–9 [DOI] [PubMed] [Google Scholar]
  • 42. Hawkes CH, Shephard BC, Daniel SE.  Olfactory dysfunction in Parkinson’s disease. J Neurol Neurosurg Psychiatry  1997;62:436–46 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43. Tremblay C, Durand Martel P, Frasnelli J.  Trigeminal system in Parkinson’s disease: A potential avenue to detect Parkinson-specific olfactory dysfunction. Parkinsonism Relat Disord  2017;44:85–90 [DOI] [PubMed] [Google Scholar]
  • 44. Woodward MR, Hafeez MU, Qi Q, et al. ; Texas Alzheimer’s Research and Care Consortium. Odorant item specific olfactory identification deficit may differentiate Alzheimer disease from aging. Am J Geriatr Psychiatry  2018;26:835–46 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45. Doty RL.  The olfactory system and its disorders. Semin Neurol  2009;29:74–81 [DOI] [PubMed] [Google Scholar]
  • 46. Morley JF, Cohen A, Silveira-Moriyama L, et al.  Optimizing olfactory testing for the diagnosis of Parkinson’s disease: Item analysis of the University of Pennsylvania smell identification test. NPJ Parkinsons Dis  2018;4:1–7 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47. Wilson RS, Arnold SE, Schneider JA, et al.  Olfactory impairment in presymptomatic Alzheimer’s disease. Ann N Y Acad Sci  2009;1170:730–5 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48. Shill HA, Zhang N, Driver-Dunckley E, et al.  Olfaction in neuropathologically defined progressive supranuclear palsy. Mov Disord  2021;36:1700–4 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49. Daniel S, Hawkes C.  Preliminary diagnosis of Parkinson’s disease by olfactory bulb pathology. Lancet  1992;340:186. [DOI] [PubMed] [Google Scholar]
  • 50. Parkkinen L, Silveira-Moriyama L, Holton JL, et al.  Can olfactory bulb biopsy be justified for the diagnosis of Parkinson’s disease? Comments on “olfactory bulb α-synucleinopathy has high specificity and sensitivity for Lewy body disorders”. Acta Neuropathol  2009;117:213. [DOI] [PubMed] [Google Scholar]
  • 51. Tremblay C, Mei J, Frasnelli J.  Olfactory bulb surroundings can help to distinguish Parkinson’s disease from non-Parkinsonian olfactory dysfunction. Neuroimage Clin  2020;28:102457. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52. Arnold SE, Lee EB, Moberg PJ, et al.  Olfactory epithelium amyloid-β and paired helical filament-tau pathology in Alzheimer disease. Ann Neurol  2010;67:462–9 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53. Funabe S, Takao M, Saito Y, et al.  Neuropathologic analysis of Lewy-related α-synucleinopathy in olfactory mucosa. Neuropathology  2013;33:47–58 [DOI] [PubMed] [Google Scholar]
  • 54. Duda JE, Shah U, Arnold SE, et al.  The expression of α-, β-, and γ-synucleins in olfactory mucosa from patients with and without neurodegenerative diseases. Exp Neurol  1999;160:515–22 [DOI] [PubMed] [Google Scholar]
  • 55. Witt M, Bormann K, Gudziol V, et al.  Biopsies of olfactory epithelium in patients with Parkinson’s disease. Mov Disord  2009;24:906–14 [DOI] [PubMed] [Google Scholar]
  • 56. Bargar C, De Luca CMG, Devigili G, et al.  Discrimination of MSA-P and MSA-C by RT-QuIC analysis of olfactory mucosa: The first assessment of assay reproducibility between two specialized laboratories. Mol Neurodegener  2021;16:82. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57. De Luca CMG, Elia AE, Portaleone SM, et al.  Efficient RT-QuIC seeding activity for α-synuclein in olfactory mucosa samples of patients with Parkinson’s disease and multiple system atrophy. Transl Neurodegener  2019;8:24. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58. Brozzetti L, Sacchetto L, Cecchini MP, et al.  Neurodegeneration-associated proteins in human olfactory neurons collected by nasal brushing. Front Neurosci  2020;14:145. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59. Talamo BR, Feng WH, Perez-Cruet M, et al.  Pathologic changes in olfactory neurons in Alzheimer’s disease. Ann N Y Acad Sci  1991;640:1–7 [DOI] [PubMed] [Google Scholar]
  • 60. Crino PB, Martin JA, Hill WD, et al. β-Amyloid peptide and amyloid precursor proteins in olfactory mucosa of patients with Alzheimer’s disease, Parkinson’s disease, and down syndrome. Ann Otol Rhinol Laryngol  1995;104:655–61 [DOI] [PubMed] [Google Scholar]
  • 61. Lee JH, Goedert M, Hill WD, et al.  Tau proteins are abnormally expressed in olfactory epithelium of Alzheimer patients and developmentally regulated in human fetal spinal cord. Exp Neurol  1993;121:93–105 [DOI] [PubMed] [Google Scholar]
  • 62. Orru CD, Bongianni M, Tonoli G, et al.  A test for Creutzfeldt-Jakob disease using nasal brushings. N Engl J Med  2014;371:519–29 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63. Orru CD, Groveman BR, Foutz A, et al.  Ring trial of 2nd generation RT-QuIC diagnostic tests for sporadic CJD. Ann Clin Transl Neurol  2020;7:2262–71 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64. Redaelli V, Bistaffa E, Zanusso G, et al.  Detection of prion seeding activity in the olfactory mucosa of patients with Fatal Familial Insomnia. Sci Rep  2017;7:46269. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 65. Zanusso G, Ferrari S, Benedetti D, et al.  Different prion conformers target the olfactory pathway in sporadic Creutzfeldt-Jakob disease. Ann N Y Acad Sci  2009;1170:637–43 [DOI] [PubMed] [Google Scholar]
  • 66. Perra D, Bongianni M, Novi G, et al.  α-Synuclein seeds in olfactory mucosa and cerebrospinal fluid of patients with dementia with Lewy bodies. Brain Commun  2021;3:fcab045. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 67. Stefani A, Iranzo A, Holzknecht E, et al. ; SINBAR (Sleep Innsbruck Barcelona) Group. α-Synuclein seeds in olfactory mucosa of patients with isolated REM sleep behaviour disorder. Brain  2021;144:1118–26 [DOI] [PubMed] [Google Scholar]
  • 68. Kalmey JK, Thewissen JG, Dluzen DE.  Age-related size reduction of foramina in the cribriform plate. Anat Rec  1998;251:326–9 [DOI] [PubMed] [Google Scholar]

Articles from Journal of Neuropathology and Experimental Neurology are provided here courtesy of Oxford University Press

RESOURCES