medalphabetМедицинский алфавитMedical alphabet2078-56312949-2807ООО «Альфмед»10.33667/2078-5631-2021-22-7-11medalphabet-2227Research ArticleСтатьиНарушение обоняния при болезни АльцгеймераOlfactory dysfunction in Alzheimer's diseasehttps://orcid.org/0000-0002-2867-1223СтрументоваЕ. С.StrumentovaE. S.

 Струментова Елена Сергеевна, аспирант кафедры неврологии имени акад. С.Н. Давиденкова

 Санкт-Петербург 

Strumentova Elena S., postgraduate student at Dept of Neurology n.a. acad. S.N. Davidenkov

 Saint Petersburg 

lenavmeda@maul.ruhttps://orcid.org/0000-0002-3272-7293ЛобзинС. В.LobzinS. V.

Лобзин Сергей Владимирович, д.м.н., проф., зав. кафедрой и клиникой неврологии имени акад. С.Н. Давиденкова

 Санкт-Петербург 

 Lobzin Sergey V., DM Sci, professor, head of Dept and Clinic of Neurology n.a. acad. S.N. Davidenkov 

 Saint Petersburg 

https://orcid.org/0000-0003-3109-8795ЛобзинВ. Ю.LobzinV. Yu.

Лобзин Владимир Юрьевич, д.м.н., проф. кафедры неврологии имени акад. С.Н. Давиденкова, профессор кафедры нервных болезней, с.н.с. отдела нейроинфекций и органической патологии нервной системы.

 Санкт-Петербург 

Lobzin Vladimir Yu., DM Sci, professor at Dept of Neurology n.a. acad. S.N. Davidenkov, professor at Dept of Nervous Diseases, senior researcher at Dept of Neuroinfections and Organic Pathology of Nervous System

Saint Petersburg

https://orcid.org/0000-0003-3307-0083ЧистоваИ. В.ChistovaI. V.

 Чистова Инга Викторовна, к.м.н., ассистент кафедры неврологии имени акад. С.Н. Давиденкова

 Санкт-Петербург 

Chistova Inga V., PhD Med, assistant at Dept of Neurology n.a. acad. S.N. Davidenkov

 Saint Petersburg 

https://orcid.org/0000-0002-6163-5718ЗуевА. А.ZuevA. A.

Зуев Андрей Александрович, к.м.н., доцент, доцент кафедры неврологии имени акад. С.Н. Давиденкова

 Санкт-Петербург 

 Zuev Andrey A., PhD Med, associate professor, associate professor at Dept of Neurology n.a. acad. S.N. Davidenkov 

 Saint Petersburg 

АлизадеМ. Р.о.AlizadeM. R.о.

Ализаде Мехти Раил оглы, врач-невролог клиники, ст. лаборант кафедры неврологии имени акад. С.Н. Давиденкова

 Санкт-Петербург 

Alizade Mekhti R.o., neurologist of Clinic, senior laboratory assistant at Dept of Neurology n.a. acad. S.N. Davidenkov

 Saint Petersburg 

ЗыряноваА. А.ZyryanovaA. A.

 Зырянова Анна Александровна, ординатор кафедры неврологии имени акад. С.Н. Давиденкова

  Санкт-Петербург 

 Zyryanova Anna A., resident of Dept of Neurology n.a. acad. S.N. Davidenkov 

 Saint Petersburg 

ФГБОУ ВО «Северо-Западный государственный медицинский университет имени И.И. Мечникова» Минздрава РоссииРоссияNorth-Western State Medical University n.a. I.I. MechnikovRussian FederationФГБОУ ВО «Северо-Западный государственный медицинский университет имени И.И. Мечникова» Минздрава России; ФГБВОУ ВО «Военно-медицинская академия имени С.М. Кирова» Минобороны России; ФГБУ «Детский научно-клинический центр инфекционных болезней» ФМБА РоссииРоссияNorth-Western State Medical University n.a. I.I. Mechnikov; Military Medical Academy n.a. S.M. Kirov; Children's Research and Clinical Centre for Infectious DiseasesRussian Federation202128092021022Неврология и психиатрия (3)711Copyright © Струментова Е.С., Лобзин С.В., Лобзин В.Ю., Чистова И.В., Зуев А.А., Ализаде М.Р., Зырянова А.А., 20212021Струментова Е.С., Лобзин С.В., Лобзин В.Ю., Чистова И.В., Зуев А.А., Ализаде М.Р., Зырянова А.А.Strumentova E.S., Lobzin S.V., Lobzin V.Y., Chistova I.V., Zuev A.A., Alizade M.R., Zyryanova A.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.med-alphabet.com/jour/article/view/2227

Болезнь Альцгеймера (БА) является наиболее распространенным нейродегенеративным заболеванием, приводящим к деменции. Нарушение обоняния выявляется на доклиническом этапе развития данного заболевания, что важно для раннего назначения терапии. В процесс идентификации запаха вовлечены обонятельная и орбитофронтальная кора, медиобазальные структуры височной доли, включая энторинальную кору и гиппокамп, что делает его крайне чувствительным к нейродегенерации, в особенности альцгеймерского типа. У пациентов из группы риска развития БА (например, носителей генотипа АПОE 4), пациентов с легкими и умеренными когнитивными нарушениями также присутствует обонятельная дисфункция, усиливающаяся при прогрессировании когнитивного дефицита.

В данной обзорной статье представлены предполагаемые механизмы развития гипосмии у пациентов с болезнью Альцгеймера, основные методы ее изучения, такие как обонятельные тесты, обонятельные вызванные потенциалы, МРТ и функциональная МРТ, а также данные популяционных исследований последних лет.

Alzheimer's disease (AD) is the most common neurodegenerative disease that causes dementia. Olfactory dysfunction is detected at preclinical stage of this disease, this is important for the early appointment of therapy. The smell identifcation process involves the olfactory and orbitofrontal cortex, mediobasal structures of the temporal region, including the entorhinal cortex and hippocampus, which makes it extremely sensitive to neurodegeneration, especially of the Alzheimer's type. In patients at risk of developing AD (for example, carriers of the APOE4 genotype), patients with mild cognitive impairment and subjective cognitive decline also have olfactory dysfunction, which increases with the progression of cognitive defcit. This article presents the proposed mechanisms of hyposmia development in patients with Alzheimer's disease, the main methods of its study, such as olfactory tests, evoked olfactory potential, MRI and functional MRI, as well as data from population studies of recent years.

болезнь Альцгеймерагипосмияобоняниекогнитивные нарушенияAlzheimer diseasehyposmiaolfactioncognitive impairmentReferencesAlzheimer’s Disease International. Dementia Statistics. ADI https://www.alzint.org/about/dementia-facts-fgures/dementia-statistics (2017).Alzheimer’s Disease International. Dementia Statistics. ADI https://www.alzint.org/about/dementia-facts-fgures/dementia-statistics (2017).Livingston G, Sommerlad A, Orgeta V, et al. Dementia prevention, intervention, and care. Lancet 2017; 390: 2673–2734.Livingston G, Sommerlad A, Orgeta V, et al. Dementia prevention, intervention, and care. Lancet 2017; 390: 2673–2734.Masters CL, Bateman R, Blennow K, Rowe CC, Sperling RA, Cummings JL. Alzheimer's disease. Nat Rev Dis Primers. 2015; 1: 15056.Masters CL, Bateman R, Blennow K, Rowe CC, Sperling RA, Cummings JL. Alzheimer's disease. Nat Rev Dis Primers. 2015; 1: 15056.Dourlen P, Kilinc D, Malmanche N, Chapuis J, Lambert JC. The new genetic landscape of Alzheimer's disease: from amyloid cascade to genetically driven synaptic failure hypothesis? Acta Neuropathol; 2019.Dourlen P, Kilinc D, Malmanche N, Chapuis J, Lambert JC. The new genetic landscape of Alzheimer's disease: from amyloid cascade to genetically driven synaptic failure hypothesis? Acta Neuropathol; 2019.Genin E, Hannequin D, Wallon D, Sleegers K, Hiltunen M, Combarros O, Bullido MJ, Engelborghs S, De Deyn P, Berr C, et al. АПОE and Alzheimer disease: a major gene with semi-dominant inheritance. Mol Psychiatry. 2011; 16: 903–7.Genin E, Hannequin D, Wallon D, Sleegers K, Hiltunen M, Combarros O, Bullido MJ, Engelborghs S, De Deyn P, Berr C, et al. АПОE and Alzheimer disease: a major gene with semi-dominant inheritance. Mol Psychiatry. 2011; 16: 903–7.Thal DR, Walter J, Saido TC, Fandrich M. Neuropathology and biochemistry of Abeta and its aggregates in Alzheimer's disease. Acta Neuropathol. 2015; 129: 167–82.Thal DR, Walter J, Saido TC, Fandrich M. Neuropathology and biochemistry of Abeta and its aggregates in Alzheimer's disease. Acta Neuropathol. 2015; 129: 167–82.Waldton, S. Clinical observations of impaired cranial nerve function in senile dementia. Acta Psychiat. Scand. 50, 539–547 (1974). https://doi.org/10.1111/j.1600–0447.1974.tb09714.xWaldton, S. Clinical observations of impaired cranial nerve function in senile dementia. Acta Psychiat. Scand. 50, 539–547 (1974). https://doi.org/10.1111/j.1600–0447.1974.tb09714.xSaiz-Sanchez D, Ubeda-Bañon I, de la Rosa-Prieto C, Argandoña-Palacios L, Garcia-Muñozguren S, Insausti R, Martinez-Marcos A. Somatostatin, tau, and beta-amyloid within the anterior olfactory nucleus in Alzheimer disease. Exp Neurol. 2010 Jun; 223 (2):347–50. DOI: 10.1016/j.expneurol.2009.06.010. Epub 2009 Jun 25. PMID: 19559700.Saiz-Sanchez D, Ubeda-Bañon I, de la Rosa-Prieto C, Argandoña-Palacios L, Garcia-Muñozguren S, Insausti R, Martinez-Marcos A. Somatostatin, tau, and beta-amyloid within the anterior olfactory nucleus in Alzheimer disease. Exp Neurol. 2010 Jun; 223 (2):347–50. DOI: 10.1016/j.expneurol.2009.06.010. Epub 2009 Jun 25. PMID: 19559700.Saiz-Sanchez D, De la Rosa-Prieto C, Ubeda-Banon I, Martinez-Marcos A. Interneurons, tau and amyloid-beta in the piriform cortex in Alzheimer's disease. Brain Struct Funct. 2015; 220: 2011–25.Saiz-Sanchez D, De la Rosa-Prieto C, Ubeda-Banon I, Martinez-Marcos A. Interneurons, tau and amyloid-beta in the piriform cortex in Alzheimer's disease. Brain Struct Funct. 2015; 220: 2011–25.Vinters HV. Emerging concepts in Alzheimer's disease. Annu Rev Pathol. 2015; 10: 291–319Vinters HV. Emerging concepts in Alzheimer's disease. Annu Rev Pathol. 2015; 10: 291–319Arnold SE, Lee EB, Moberg PJ, Stutzbach L, Kazi H, Han LY, Lee VM, Trojanowski JQ. Olfactory epithelium amyloid-beta and paired helical flament-tau pathology in Alzheimer disease. Ann Neurol. 2010; 67: 462–9.Arnold SE, Lee EB, Moberg PJ, Stutzbach L, Kazi H, Han LY, Lee VM, Trojanowski JQ. Olfactory epithelium amyloid-beta and paired helical flament-tau pathology in Alzheimer disease. Ann Neurol. 2010; 67: 462–9.Olofsson, J.K., Larsson, M., Roa, C. et al. Interaction Between Odor Identifcation Defcit and APOE4 Predicts 6-Year Cognitive Decline in Elderly Individuals. Behav Genet 50, 3–13 (2020). https://doi.org/10.1007/s10519–019–09980–9.Olofsson, J.K., Larsson, M., Roa, C. et al. Interaction Between Odor Identifcation Defcit and APOE4 Predicts 6-Year Cognitive Decline in Elderly Individuals. Behav Genet 50, 3–13 (2020). https://doi.org/10.1007/s10519–019–09980–9.Zhang J, Hao C, Jiang J, Feng Y, Chen X, Zheng Y, Liu J, Zhang Z, Long C, Yang L. The mechanisms underlying olfactory defcits in apolipoprotein E-defcient mice: focus on olfactory epithelium and olfactory bulb. Neurobiol Aging. 2018 Feb; 62: 20–33. DOI: 10.1016/j.neurobiolaging.2017.09.036. Epub 2017 Oct 10. PMID: 29107844.Zhang J, Hao C, Jiang J, Feng Y, Chen X, Zheng Y, Liu J, Zhang Z, Long C, Yang L. The mechanisms underlying olfactory defcits in apolipoprotein E-defcient mice: focus on olfactory epithelium and olfactory bulb. Neurobiol Aging. 2018 Feb; 62: 20–33. DOI: 10.1016/j.neurobiolaging.2017.09.036. Epub 2017 Oct 10. PMID: 29107844.Murphy C., Jernigan T.L. & Fennema- Notestine C. Left hippocampal volume loss in Alzheimer’s disease is reflected in performance on odor identifcation: a structural MRI study. J. Int. Neuropsychol. Soc. 9, 459–471 (2003).Murphy C., Jernigan T.L. & Fennema- Notestine C. Left hippocampal volume loss in Alzheimer’s disease is reflected in performance on odor identifcation: a structural MRI study. J. Int. Neuropsychol. Soc. 9, 459–471 (2003).Braak H, Braak E. Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol Aging. 1997 Jul-Aug; 18 (4): 351–7. DOI: 10.1016/s0197–4580(97)00056–0.PMID: 9330961.Braak H, Braak E. Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol Aging. 1997 Jul-Aug; 18 (4): 351–7. DOI: 10.1016/s0197–4580(97)00056–0.PMID: 9330961.Growdon ME, Schultz AP, Dagley AS, Amariglio RE, Hedden T, Rentz DM, Johnson KA, Sperling RA, Albers MW, Marshall GA. Odor identifcation and Alzheimer disease biomarkers in clinically normal elderly. Neurology. 2015 May 26; 84 (21): 2153–60. DOI: 10.1212/WNL.0000000000001614. Epub 2015 May 1. PMID: 25934852; PMCID: PMC4451046.Growdon ME, Schultz AP, Dagley AS, Amariglio RE, Hedden T, Rentz DM, Johnson KA, Sperling RA, Albers MW, Marshall GA. Odor identifcation and Alzheimer disease biomarkers in clinically normal elderly. Neurology. 2015 May 26; 84 (21): 2153–60. DOI: 10.1212/WNL.0000000000001614. Epub 2015 May 1. PMID: 25934852; PMCID: PMC4451046.Mormino EC, Brandel MG, Madison CM, Marks S, Baker SL, Jagust WJ. Aβ Deposition in aging is associated with increases in brain activation during successful memory encoding. Cereb Cortex. 2012 Aug; 22 (8): 1813–23. DOI: 10.1093/cercor/bhr255. Epub 2011 Sep 23. PMID: 21945849; PMCID: PMC3388896.Mormino EC, Brandel MG, Madison CM, Marks S, Baker SL, Jagust WJ. Aβ Deposition in aging is associated with increases in brain activation during successful memory encoding. Cereb Cortex. 2012 Aug; 22 (8): 1813–23. DOI: 10.1093/cercor/bhr255. Epub 2011 Sep 23. PMID: 21945849; PMCID: PMC3388896.Mori I, Goshima F, Ito H, Koide N, Yoshida T, Yokochi T, Kimura Y, Nishiyama Y. The vomeronasal chemosensory system as a route of neuroinvasion by herpes simplex virus. Virology. 2005 Mar 30; 334 (1): 51–8. DOI: 10.1016/j.virol.2005.01.023. PMID: 15749122.Mori I, Goshima F, Ito H, Koide N, Yoshida T, Yokochi T, Kimura Y, Nishiyama Y. The vomeronasal chemosensory system as a route of neuroinvasion by herpes simplex virus. Virology. 2005 Mar 30; 334 (1): 51–8. DOI: 10.1016/j.virol.2005.01.023. PMID: 15749122.Mori I, Nishiyama Y, Yokochi T, Kimura Y. Olfactory transmission of neurotropic viruses. J Neurovirol. 2005 Apr; 11 (2): 129–37. DOI: 10.1080/13550280590922793. PMID: 16036791Mori I, Nishiyama Y, Yokochi T, Kimura Y. Olfactory transmission of neurotropic viruses. J Neurovirol. 2005 Apr; 11 (2): 129–37. DOI: 10.1080/13550280590922793. PMID: 16036791Morales I, Guzmán-Martínez L, Cerda-Troncoso C, Farías GA, Maccioni RB. Neuroinflammation in the pathogenesis of Alzheimer's disease. A rational framework for the search of novel therapeutic approaches. Front Cell Neurosci. 2014 Apr 22; 8: 112. DOI: 10.3389/fncel.2014.00112. PMID: 24795567; PMCID: PMC4001039.Morales I, Guzmán-Martínez L, Cerda-Troncoso C, Farías GA, Maccioni RB. Neuroinflammation in the pathogenesis of Alzheimer's disease. A rational framework for the search of novel therapeutic approaches. Front Cell Neurosci. 2014 Apr 22; 8: 112. DOI: 10.3389/fncel.2014.00112. PMID: 24795567; PMCID: PMC4001039.Kuo YM, Li Z, Jiao Y, Gaborit N, Pani AK, Orrison BM, Bruneau BG, Giasson BI, Smeyne RJ, Gershon MD, Nussbaum RL. Extensive enteric nervous system abnormalities in mice transgenic for artifcial chromosomes containing Parkinson disease-associated alpha-synuclein gene mutations precede central nervous system changes. Hum Mol Genet. 2010 May 1; 19 (9): 1633–50. DOI: 10.1093/hmg/ddq038. Epub 2010 Jan 27. PMID: 20106867; PMCID: PMC2850613.Kuo YM, Li Z, Jiao Y, Gaborit N, Pani AK, Orrison BM, Bruneau BG, Giasson BI, Smeyne RJ, Gershon MD, Nussbaum RL. Extensive enteric nervous system abnormalities in mice transgenic for artifcial chromosomes containing Parkinson disease-associated alpha-synuclein gene mutations precede central nervous system changes. Hum Mol Genet. 2010 May 1; 19 (9): 1633–50. DOI: 10.1093/hmg/ddq038. Epub 2010 Jan 27. PMID: 20106867; PMCID: PMC2850613.Toda T, Noda Y, Ito G, Maeda M, Shimizu T. Presenilin-2 mutation causes early amyloid accumulation and memory impairment in a transgenic mouse model of Alzheimer's disease. J Biomed Biotechnol. 2011; 2011: 617974. DOI: 10.1155/2011/617974. Epub 2010 Dec 29. PMID: 21234330; PMCID: PMC3018.Toda T, Noda Y, Ito G, Maeda M, Shimizu T. Presenilin-2 mutation causes early amyloid accumulation and memory impairment in a transgenic mouse model of Alzheimer's disease. J Biomed Biotechnol. 2011; 2011: 617974. DOI: 10.1155/2011/617974. Epub 2010 Dec 29. PMID: 21234330; PMCID: PMC3018.Yoo SJ, Lee JH, Kim SY, Son G, Kim JY, Cho B, Yu SW, Chang KA, Suh YH, Moon C. Differential spatial expression of peripheral olfactory neuron-derived BACE1 induces olfactory impairment by region-specifc accumulation of β-amyloid oligomer. Cell Death Dis. 2017 Aug 10; 8 (8): e2977. DOI: 10.1038/cddis.2017.349. PMID: 28796251; PMCID: PMC5596540.662.Yoo SJ, Lee JH, Kim SY, Son G, Kim JY, Cho B, Yu SW, Chang KA, Suh YH, Moon C. Differential spatial expression of peripheral olfactory neuron-derived BACE1 induces olfactory impairment by region-specifc accumulation of β-amyloid oligomer. Cell Death Dis. 2017 Aug 10; 8 (8): e2977. DOI: 10.1038/cddis.2017.349. PMID: 28796251; PMCID: PMC5596540.662.Kim Y.H. et al. Amyloid beta in nasal secretions may be a potential biomarker of Alzheimer’s disease. Sci. Rep. 9, 4966. https://doi.org/10.1038/s4159 8–019–41429–1 (2019).Kim Y.H. et al. Amyloid beta in nasal secretions may be a potential biomarker of Alzheimer’s disease. Sci. Rep. 9, 4966. https://doi.org/10.1038/s4159 8–019–41429–1 (2019).Yoo SJ, Son G, Bae J, Kim SY, Yoo YK, Park D, Baek SY, Chang KA, Suh YH, Lee YB, Hwang KS, Kim Y, Moon C. Longitudinal profling of oligomeric Aβ in human nasal discharge reflecting cognitive decline in probable Alzheimer's disease. Sci Rep. 2020 Jul 8; 10 (1): 11234. DOI: 10.1038/s41598–020–68148–2. PMID: 32641719; PMCID: PMC7343787.Yoo SJ, Son G, Bae J, Kim SY, Yoo YK, Park D, Baek SY, Chang KA, Suh YH, Lee YB, Hwang KS, Kim Y, Moon C. Longitudinal profling of oligomeric Aβ in human nasal discharge reflecting cognitive decline in probable Alzheimer's disease. Sci Rep. 2020 Jul 8; 10 (1): 11234. DOI: 10.1038/s41598–020–68148–2. PMID: 32641719; PMCID: PMC7343787.Lafaille-Magnan ME, Poirier J, Etienne P, Tremblay-Mercier J, Frenette J, Rosa-Neto P, Breitner JCS; PREVENT-AD Research Group. Odor identifcation as a biomarker of preclinical AD in older adults at risk. Neurology. 2017 Jul 25; 89 (4): 327–335. DOI: 10.1212/WNL.0000000000004159. Epub 2017 Jun 28. PMID: 28659431; PMCID: PMC5574678.Lafaille-Magnan ME, Poirier J, Etienne P, Tremblay-Mercier J, Frenette J, Rosa-Neto P, Breitner JCS; PREVENT-AD Research Group. Odor identifcation as a biomarker of preclinical AD in older adults at risk. Neurology. 2017 Jul 25; 89 (4): 327–335. DOI: 10.1212/WNL.0000000000004159. Epub 2017 Jun 28. PMID: 28659431; PMCID: PMC5574678.Wilson RS, Schneider JA, Arnold SE, Tang Y, Boyle PA, Bennett DA. Olfactory identifcation and incidence of mild cognitive impairment in older age. Arch Gen Psychiatry. 2007 Jul; 64 (7): 802–8. DOI: 10.1001/archpsyc.64.7.802. PMID: 17606814.Wilson RS, Schneider JA, Arnold SE, Tang Y, Boyle PA, Bennett DA. Olfactory identifcation and incidence of mild cognitive impairment in older age. Arch Gen Psychiatry. 2007 Jul; 64 (7): 802–8. DOI: 10.1001/archpsyc.64.7.802. PMID: 17606814.Devanand DP, Lee S, Manly J, Andrews H, Schupf N, Doty RL, Stern Y, Zahodne LB, Louis ED, Mayeux R. Olfactory defcits predict cognitive decline and Alzheimer dementia in an urban community. Neurology. 2015 Jan 13; 84 (2): 182–9. DOI: 10.1212/WNL.0000000000001132. Epub 2014 Dec 3. PMID: 25471394; PMCID: PMC4336090.Devanand DP, Lee S, Manly J, Andrews H, Schupf N, Doty RL, Stern Y, Zahodne LB, Louis ED, Mayeux R. Olfactory defcits predict cognitive decline and Alzheimer dementia in an urban community. Neurology. 2015 Jan 13; 84 (2): 182–9. DOI: 10.1212/WNL.0000000000001132. Epub 2014 Dec 3. PMID: 25471394; PMCID: PMC4336090.Wang Q, Chen B, Zhong X, Zhou H, Zhang M, Mai N, Wu Z, Huang X, Haehner A, Chen X, Auber LA, Peng Q, Hummel T, Ning Y. Olfactory Dysfunction Is Already Present with Subjective Cognitive Decline and Deepens with Disease Severity in the Alzheimer's Disease Spectrum. J Alzheimers Dis. 2021; 79 (2): 585–595. DOI: 10.3233/JAD-201168. PMID: 33361601.Wang Q, Chen B, Zhong X, Zhou H, Zhang M, Mai N, Wu Z, Huang X, Haehner A, Chen X, Auber LA, Peng Q, Hummel T, Ning Y. Olfactory Dysfunction Is Already Present with Subjective Cognitive Decline and Deepens with Disease Severity in the Alzheimer's Disease Spectrum. J Alzheimers Dis. 2021; 79 (2): 585–595. DOI: 10.3233/JAD-201168. PMID: 33361601.Fischer ME, Cruickshanks KJ, Schubert CR, Pinto AA, Carlsson CM, Klein BE, Klein R, Tweed TS. Age-Related Sensory Impairments and Risk of Cognitive Impairment. J Am Geriatr Soc. 2016 Oct; 64 (10): 1981–1987. DOI: 10.1111/jgs.14308. Epub 2016 Sep 9. PMID: 27611845; PMCID: PMC5073029.Fischer ME, Cruickshanks KJ, Schubert CR, Pinto AA, Carlsson CM, Klein BE, Klein R, Tweed TS. Age-Related Sensory Impairments and Risk of Cognitive Impairment. J Am Geriatr Soc. 2016 Oct; 64 (10): 1981–1987. DOI: 10.1111/jgs.14308. Epub 2016 Sep 9. PMID: 27611845; PMCID: PMC5073029.McEvoy LK, Fennema-Notestine C, Roddey JC, Hagler DJ Jr, Holland D, Karow DS, Pung CJ, Brewer JB, Dale AM; Alzheimer's Disease Neuroimaging Initiative. Alzheimer disease: quantitative structural neuroimaging for detection and prediction of clinical and structural changes in mild cognitive impairment. Radiology. 2009 Apr; 251 (1): 195–205. DOI: 10.1148/radiol.2511080924. Epub 2009 Feb 6. PMID: 19201945; PMCID: PMC2663582.McEvoy LK, Fennema-Notestine C, Roddey JC, Hagler DJ Jr, Holland D, Karow DS, Pung CJ, Brewer JB, Dale AM; Alzheimer's Disease Neuroimaging Initiative. Alzheimer disease: quantitative structural neuroimaging for detection and prediction of clinical and structural changes in mild cognitive impairment. Radiology. 2009 Apr; 251 (1): 195–205. DOI: 10.1148/radiol.2511080924. Epub 2009 Feb 6. PMID: 19201945; PMCID: PMC2663582.Rahayel S., Frasnelli J. & Joubert S. The effect of Alzheimer’s disease and Parkinson’s disease on olfaction: a meta- analysis. Behav. Brain Res. 231, 60–74 (2012).Rahayel S., Frasnelli J. & Joubert S. The effect of Alzheimer’s disease and Parkinson’s disease on olfaction: a meta- analysis. Behav. Brain Res. 231, 60–74 (2012).Roalf D.R. et al. A quantitative meta-analysis of olfactory dysfunction in mild cognitive impairment. J. Neurol. Neurosurg. Psychiatry 88, 226–232 (2017).Roalf D.R. et al. A quantitative meta-analysis of olfactory dysfunction in mild cognitive impairment. J. Neurol. Neurosurg. Psychiatry 88, 226–232 (2017).Kobal G., Klimek L., Wolfensberger M., Gudziol H., Temmel A., Owen CM., Seeber H., Pauli E., Hummel T. (2000). Multicenter investigation of 1.036 subjects using a standardized method for the assessment of olfactory function combining tests of odor identifcation, odor discrimination and olfactory thresholds. European Archives of Oto-Rhino-Laryngology, Vol. 257, No.4, pp. 205–211.Kobal G., Klimek L., Wolfensberger M., Gudziol H., Temmel A., Owen CM., Seeber H., Pauli E., Hummel T. (2000). Multicenter investigation of 1.036 subjects using a standardized method for the assessment of olfactory function combining tests of odor identifcation, odor discrimination and olfactory thresholds. European Archives of Oto-Rhino-Laryngology, Vol. 257, No.4, pp. 205–211.Simmen D., Briner HR. & Hess K. (1999). Screeningtest des Geruchssinnes mit Riechdiskette. Laryngorhinootologie, Vol.78, No. 3, (march), pp.125–130.Simmen D., Briner HR. & Hess K. (1999). Screeningtest des Geruchssinnes mit Riechdiskette. Laryngorhinootologie, Vol.78, No. 3, (march), pp.125–130.Hummel T, Sekinger B, Wolf SR, Pauli E, Kobal G. 'Sniffn' sticks': olfactory performance assessed by the combined testing of odor identifcation, odor discrimination and olfactory threshold. Chem Senses. 1997 Feb; 22 (1): 39–52. DOI: 10.1093/chemse/22.1.39. PMID: 9056084.Hummel T, Sekinger B, Wolf SR, Pauli E, Kobal G. 'Sniffn' sticks': olfactory performance assessed by the combined testing of odor identifcation, odor discrimination and olfactory threshold. Chem Senses. 1997 Feb; 22 (1): 39–52. DOI: 10.1093/chemse/22.1.39. PMID: 9056084.Toyota B., Kitamura T. & Takagi SF. (1978). Olfactory disorders- Olfactometry and therapy. Tokyo: Igaku-Shoin, 1978.Toyota B., Kitamura T. & Takagi SF. (1978). Olfactory disorders- Olfactometry and therapy. Tokyo: Igaku-Shoin, 1978.Morgan CD, Murphy C. Olfactory event-related potentials in Alzheimer's disease. J Int Neuropsychol Soc. 2002 Sep; 8 (6): 753–63. DOI: 10.1017/s1355617702860039. PMID: 12240739.Morgan CD, Murphy C. Olfactory event-related potentials in Alzheimer's disease. J Int Neuropsychol Soc. 2002 Sep; 8 (6): 753–63. DOI: 10.1017/s1355617702860039. PMID: 12240739.Morgan CD, Murphy C. Individuals at risk for Alzheimer's disease show differential patterns of ERP brain activation during odor identifcation. Behav Brain Funct. 2012 Jul 31; 8: 37. DOI: 10.1186/1744–9081–8–37. PMID: 22849610; PMCID: PMC3542023.Morgan CD, Murphy C. Individuals at risk for Alzheimer's disease show differential patterns of ERP brain activation during odor identifcation. Behav Brain Funct. 2012 Jul 31; 8: 37. DOI: 10.1186/1744–9081–8–37. PMID: 22849610; PMCID: PMC3542023.Murphy C, Solomon ES, Haase L, Wang M, Morgan CD. Olfaction in aging and Alzheimer's disease: event-related potentials to a cross-modal odor-recognition memory task discriminate ApoE epsilon4+ and ApoE epsilon 4- individuals. Ann N Y Acad Sci. 2009 Jul; 1170: 647–57. DOI: 10.1111/j.1749–6632.2009.04486.x. PMID: 19686207; PMCID: PMC4575288.Murphy C, Solomon ES, Haase L, Wang M, Morgan CD. Olfaction in aging and Alzheimer's disease: event-related potentials to a cross-modal odor-recognition memory task discriminate ApoE epsilon4+ and ApoE epsilon 4- individuals. Ann N Y Acad Sci. 2009 Jul; 1170: 647–57. DOI: 10.1111/j.1749–6632.2009.04486.x. PMID: 19686207; PMCID: PMC4575288.Kjelvik G, Saltvedt I, White LR, et al. The brain structural and cognitive basis of odor identifcation defcits in mild cognitive impairment and Alzheimer’s disease. BMC Neurol 2014; 14: 168.Kjelvik G, Saltvedt I, White LR, et al. The brain structural and cognitive basis of odor identifcation defcits in mild cognitive impairment and Alzheimer’s disease. BMC Neurol 2014; 14: 168.Majed Al-Otaibi, Melissa Lessard-Beaudoin, Christian-Alexandre Castellano, Denis Gris, Stephen C. Cunnane and Rona K. Graham*, “Volumetric MRI Demonstrates Atrophy of the Olfactory Cortex in AD”, Current Alzheimer Research (2020) 17: 904. https://doi.org/10.2174/1567205017666201215120909Majed Al-Otaibi, Melissa Lessard-Beaudoin, Christian-Alexandre Castellano, Denis Gris, Stephen C. Cunnane and Rona K. Graham*, “Volumetric MRI Demonstrates Atrophy of the Olfactory Cortex in AD”, Current Alzheimer Research (2020) 17: 904. https://doi.org/10.2174/1567205017666201215120909Thomann PA, Dos Santos V, Toro P, Schonknecht P, Essig M, Schroder J. Reduced olfactory bulb and tract volume in early Alzheimer's disease – a MRI study. Neurobiol Aging. 2009; 30: 838–41.Thomann PA, Dos Santos V, Toro P, Schonknecht P, Essig M, Schroder J. Reduced olfactory bulb and tract volume in early Alzheimer's disease – a MRI study. Neurobiol Aging. 2009; 30: 838–41.Thomann PA, Dos Santos V, Seidl U, Toro P, Essig M, Schröder J. MRI-derived atrophy of the olfactory bulb and tract in mild cognitive impairment and Alzheimer's disease. J Alzheimers Dis. 2009; 17 (1): 213–21. DOI: 10.3233/JAD-2009–1036. PMID: 19494444.Thomann PA, Dos Santos V, Seidl U, Toro P, Essig M, Schröder J. MRI-derived atrophy of the olfactory bulb and tract in mild cognitive impairment and Alzheimer's disease. J Alzheimers Dis. 2009; 17 (1): 213–21. DOI: 10.3233/JAD-2009–1036. PMID: 19494444.Lian TH, Zhu WL, Li SW, Liu YO, Guo P, Zuo LJ, Hu Y, Yu SY, Li LX, Jin Z, Yu QJ, Wang RD, Zhang W. Clinical, Structural, and Neuropathological Features of Olfactory Dysfunction in Patients with Alzheimer's Disease. J Alzheimers Dis. 2019; 70 (2): 413–423. DOI: 10.3233/JAD-181217. PMID: 31177212.Lian TH, Zhu WL, Li SW, Liu YO, Guo P, Zuo LJ, Hu Y, Yu SY, Li LX, Jin Z, Yu QJ, Wang RD, Zhang W. Clinical, Structural, and Neuropathological Features of Olfactory Dysfunction in Patients with Alzheimer's Disease. J Alzheimers Dis. 2019; 70 (2): 413–423. DOI: 10.3233/JAD-181217. PMID: 31177212.Vasavada MM, Martinez B, Wang J, Eslinger PJ, Gill DJ, Sun X, Karunanayaka P, Yang QX. Central Olfactory Dysfunction in Alzheimer's Disease and Mild Cognitive Impairment: A Functional MRI Study. J Alzheimers Dis. 2017; 59 (1): 359–368. DOI: 10.3233/JAD-170310. PMID: 28671131.Vasavada MM, Martinez B, Wang J, Eslinger PJ, Gill DJ, Sun X, Karunanayaka P, Yang QX. Central Olfactory Dysfunction in Alzheimer's Disease and Mild Cognitive Impairment: A Functional MRI Study. J Alzheimers Dis. 2017; 59 (1): 359–368. DOI: 10.3233/JAD-170310. PMID: 28671131.Kjelvik G, Evensmoen HR, Hummel T, Engedal K, Selbæk G, Saltvedt I, Håberg AK. The Human Brain Representation of Odor Identifcation in Amnestic Mild Cognitive Impairment and Alzheimer's Dementia of Mild Degree. Front Neurol. 2021 Jan 13; 11: 607566. DOI: 10.3389/fneur.2020.607566. PMID: 33519686; PMCID: PMC7838677.Kjelvik G, Evensmoen HR, Hummel T, Engedal K, Selbæk G, Saltvedt I, Håberg AK. The Human Brain Representation of Odor Identifcation in Amnestic Mild Cognitive Impairment and Alzheimer's Dementia of Mild Degree. Front Neurol. 2021 Jan 13; 11: 607566. DOI: 10.3389/fneur.2020.607566. PMID: 33519686; PMCID: PMC7838677.Vasavada MM, Wang J, Eslinger PJ, Gill DJ, Sun X, Karunanayaka P, Yang QX. Olfactory cortex degeneration in Alzheimer's disease and mild cognitive impairment. J Alzheimers Dis. 2015; 45 (3): 947–58. DOI: 10.3233/JAD-141947. PMID: 25633674.Vasavada MM, Wang J, Eslinger PJ, Gill DJ, Sun X, Karunanayaka P, Yang QX. Olfactory cortex degeneration in Alzheimer's disease and mild cognitive impairment. J Alzheimers Dis. 2015; 45 (3): 947–58. DOI: 10.3233/JAD-141947. PMID: 25633674.Haase L, Wang M, Green E, Murphy C. Functional connectivity during recognition memory in individuals genetically at risk for Alzheimer's disease. Hum Brain Mapp. 2013 Mar; 34 (3): 530–42. DOI: 10.1002/hbm.21451. Epub 2011 Nov 18. PMID: 22102296; PMCID: PMC3566346.Haase L, Wang M, Green E, Murphy C. Functional connectivity during recognition memory in individuals genetically at risk for Alzheimer's disease. Hum Brain Mapp. 2013 Mar; 34 (3): 530–42. DOI: 10.1002/hbm.21451. Epub 2011 Nov 18. PMID: 22102296; PMCID: PMC3566346.

The authors declare that there are no conflicts of interest present.