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Cited by 146Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsOlfactory and Sensory Function Studies

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Odor identification as a biomarker of preclinical AD in older adults at risk

Open access
Lafaille-Magnan, Marie-Elyse, Poirier, Judes, Etienne, Pierre, Tremblay-Mercier, Jennifer, Frenette, Joanne, Rosa-Neto, Pedro, Breitner, John C.S., For the PREVENT-AD Research Group·2017·Neurology
DOI 10.1212/wnl.0000000000004159PMC PMC5574678
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Abstract

Objective: To assess odor identification (OI) as an indicator of presymptomatic Alzheimer disease (AD) pathogenesis in cognitively normal aging individuals at increased risk of AD dementia. Methods: In 274 members of the PREVENT-AD cohort of healthy aging persons with a parental or multiple-sibling history of AD dementia, we assessed the cross-sectional association of OI with potential indicators of presymptomatic AD. Some 101 participants donated CSF, thus enabling assessment of AD pathology with the biomarkers total tau (t-tau), phospho-tau (P181-tau), and their ratios with β-amyloid (Aβ1-42). Adjusted analyses considered age, cognition, APOE ε4 status, education, and sex as covariates. We measured OI using the University of Pennsylvania Smell Identification Test and cognitive performance using the Repeatable Battery for Assessment of Neuropsychological Status. Standard kits provided assays of the AD biomarkers. Analyses used robust-fit linear regression models. Results: Reduced OI was associated with lower cognitive score and older age, as well as increased ratios of CSF t-tau and P181-tau to Aβ1-42 (all p < 0.02). However, the observed associations of OI with age and cognition were unapparent in adjusted models that restricted observations to CSF donors and included AD biomarkers. OI showed little association with CSF Aβ1-42 alone except in APOE ε4 carriers having lowest-quartile Aβ1-42 levels. Conclusions: These findings from healthy high-risk older individuals suggest that OI reflects degree of preclinical AD pathology, while its relationships with age and cognition result from the association of these latter variables with such pathology. Diminished OI may be a practical and affordable biomarker of AD pathology.

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Crossref · 10.1212/wnl.0000000000004159

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Figure 1 Robust-fit linear regression models of UPSIT error score vs CSF biomarkers of AD (A) CSF t-tau/Aβ1-42 (β = 0.287, p = 0.00494, n = 100). (B) CSF P181-tau/Aβ1-42 (β = 1.77, p = 0.0165, n = 100). (C) CSF t-tau (β = 3.61 ×10−4, p = 0.0257, n = 100). (D) CSF P181-tau (β = 2.10 ×10−3, p = 0.0724, n = 100). (E) CSF Aβ1-42 (β = −7.01 ×10−5, p = 0.359, n = 100) and in individuals with CSF Aβ1-42 levels below the 25th percentile (β = −0.000827, p = 0.0135, n = 25). (F) CSF t-tau/Aβ1-42 in individuals with CSF Aβ1-42 levels below the 25th percentile (β = 0.399, p = 0.00260, n = 25). In panel (E), blue circles represent the top 3 quartiles for Aβ concentrations, while red circles in panels (E) and (F) are data from the lowest quartile of Aβ concentrations (suggesting that they have more advanced preclinical AD). Aβ = β-amyloid; AD = Alzheimer disease; P181-tau = phospho-tau; t-tau = total tau; UPSIT = University of Pennsylvania Smell Identification Test.
Figure 1 Robust-fit linear regression models of UPSIT error score vs CSF biomarkers of AD (A) CSF t-tau/Aβ1-42 (β = 0.287, p = 0.00494, n = 100). (B) CSF P181-tau/Aβ1-42 (β = 1.77, p = 0.0165, n = 100). (C) CSF t-tau (β = 3.61 ×10−4, p = 0.0257, n = 100). (D) CSF P181-tau (β = 2.10 ×10−3, p = 0.0724, n = 100). (E) CSF Aβ1-42 (β = −7.01 ×10−5, p = 0.359, n = 100) and in individuals with CSF Aβ1-42 levels below the 25th percentile (β = −0.000827, p = 0.0135, n = 25). (F) CSF t-tau/Aβ1-42 in individuals with CSF Aβ1-42 levels below the 25th percentile (β = 0.399, p = 0.00260, n = 25). In panel (E), blue circles represent the top 3 quartiles for Aβ concentrations, while red circles in panels (E) and (F) are data from the lowest quartile of Aβ concentrations (suggesting that they have more advanced preclinical AD). Aβ = β-amyloid; AD = Alzheimer disease; P181-tau = phospho-tau; t-tau = total tau; UPSIT = University of Pennsylvania Smell Identification Test.CC BY-NC-ND · PubMed Central
Figure 2 Robust-fit linear regression models of UPSIT error score vs CSF biomarkers, stratified by APOE ε4 status Red circles represent APOE ε4 carriers. Blue circles represent APOE ε4 noncarriers. (A) CSF t-tau/Aβ1-42 in carriers (β = 0.352, p = 0.0158, n = 33) and in noncarriers (β = 0.252, p = 0.131, n = 67). (B) CSF P181-tau/Aβ1-42 in carriers (β = 2.416, p = 0.0270, n = 33) and in noncarriers (β = 0.980, p = 0.408, n = 67). (C) CSF t-tau in carriers (β = 4.68 ×10−4, p = 0.0914, n = 33) and in noncarriers (β = 0.000312, p = 0.144, n = 67). (D) CSF P181-tau in carriers (β = 2.76 ×10−3, p = 0.204, n = 33) and in noncarriers (β = 0.00178, p = 0.218, n = 67). (E) CSF Aβ1-42 in carriers (β = −3.76 ×10−4, p = 0.00841, n = 33) and in noncarriers (β = 4.890e−05, p = 0.598, n = 67). Aβ = β-amyloid; AD = Alzheimer disease; P181-tau = phospho-tau; t-tau = total tau; UPSIT = University of Pennsylvania Smell Identification Test.
Figure 2 Robust-fit linear regression models of UPSIT error score vs CSF biomarkers, stratified by APOE ε4 status Red circles represent APOE ε4 carriers. Blue circles represent APOE ε4 noncarriers. (A) CSF t-tau/Aβ1-42 in carriers (β = 0.352, p = 0.0158, n = 33) and in noncarriers (β = 0.252, p = 0.131, n = 67). (B) CSF P181-tau/Aβ1-42 in carriers (β = 2.416, p = 0.0270, n = 33) and in noncarriers (β = 0.980, p = 0.408, n = 67). (C) CSF t-tau in carriers (β = 4.68 ×10−4, p = 0.0914, n = 33) and in noncarriers (β = 0.000312, p = 0.144, n = 67). (D) CSF P181-tau in carriers (β = 2.76 ×10−3, p = 0.204, n = 33) and in noncarriers (β = 0.00178, p = 0.218, n = 67). (E) CSF Aβ1-42 in carriers (β = −3.76 ×10−4, p = 0.00841, n = 33) and in noncarriers (β = 4.890e−05, p = 0.598, n = 67). Aβ = β-amyloid; AD = Alzheimer disease; P181-tau = phospho-tau; t-tau = total tau; UPSIT = University of Pennsylvania Smell Identification Test.CC BY-NC-ND · PubMed Central

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Metadata

Authors
Lafaille-Magnan, M.-E., Poirier, J., Etienne, P., Tremblay-Mercier, J., Frenette, J., Rosa-Neto, P., Breitner, J. C. S., & For the PREVENT-AD Research Group
Affiliations
  • From the Centre for Studies on Prevention of AD (M.-E.L.-M., J.P., P.E., J.T.-M., J.F., P.R.-N., J.C.S.B.) and McGill Centre for Studies in Aging (P.R.-N.), Douglas Mental Health University Institute, McGill University, Faculty of Medicine, Montreal, Quebec, Canada.
  • Douglas Mental Health University Institute (CA)
ORCID
Venue
Neurology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2017-07-25
Volume
89
Issue
4
Pages
327-335
ISSN
  • 0028-3878 (ISSN-L)
  • 1526-632X
DOI
10.1212/wnl.0000000000004159
PMC
PMC5574678
OpenAlex
W2732607734
Cited by
145
References
38
Citations by year
2026: 6 · 2025: 15 · 2024: 18 · 2023: 16 · 2022: 12 · 2021: 21 · 2020: 20 · 2019: 13 · 2018: 21 · 2017: 3
FWCI
12.81
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Neurology (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • Eli Lilly and Company
  • Pfizer
  • McGill University
  • Weston Brain Institute
  • Consortium canadien en neurodégénérescence associée au vieillissement
  • TauRx Pharmaceuticals
  • Government of Canada
  • Pfizer Canada
  • Canadian Institutes of Health Research
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Sensory Systems › Olfactory and Sensory Function Studies
Keywords
odor identification, smell impairment, preclinical Alzheimer's disease, Alzheimer's disease biomarkers, cerebrospinal fluid tau, phosphorylated tau, amyloid-beta 42, APOE ε4, cognitively normal older adults, high-risk families, olfaction, cognitive aging
MeSH terms
Aged, Aged, 80 and over, Aging, Alzheimer Disease, Cognition, Cross-Sectional Studies, Female, Humans, Male, Middle Aged, Peptide Fragments, Phosphorylation, Risk, Cohort Studies, Biomarkers, Amyloid beta-Peptides, tau Proteins, Recognition, Psychology, Pattern Recognition, Physiological, Apolipoprotein E4, Olfactory Perception, Prodromal Symptoms

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