Skip to main content
Download PDF
  • Research article
  • Open access
  • Published:

Correlations of apathy with clinical symptoms of Alzheimer’s disease and olfactory dysfunctions: a cross-sectional study

BMC Neurology volume 20, Article number: 416 (2020) Cite this article

Abstract

Background

Apathy is one of the most common symptoms of Alzheimer’s disease (AD), however, correlations of apathy with demographic variables, cognitive functions, neuropsychiatric symptoms, activity of daily living and olfactory functions in AD patients are still lacking comprehensive investigations.

Methods

This is a cross-sectional study. Total 124 typical AD patients were consecutively recruited from April 2014 to April 2017. In 124 AD patients, 47 cases (37.9%) were male and 77 cases were female; patients’ age were 43–93 years with an average of 68 years. Patients were divided into AD with apathy (AD-A) and AD with no apathy (AD-NA) groups according to the score of Modified Apathy Evaluation Scale, then were evaluated cognitive functions, neuropsychiatric symptoms and activity of daily living, and tested olfactory functions. Above variables were compared between AD-A and AD-NA groups. Further correlation analyses and linear regression analysis were performed between apathy and above variables.

Results

Compared with AD-NA group, global cognitive level, verbal memory, verbal fluency and activity of daily living were significantly compromised in AD-A group (P < 0.002); depression and agitation were severely displayed in AD-A group (P < 0.002). Apathy was negatively correlated with global cognitive function, verbal memory, verbal fluency and activity of daily living (P < 0.05). There was no significant difference of olfactory functions between the two groups (P > 0.002), and correlations between apathy and olfactory threshold, olfactory identification and global olfactory function were significant (P < 0.05) but quite weak (|r| < 0.3). Further linear regression analysis showed that only verbal fluency and instrumental activities of daily living were independently associated with apathy.

Conclusions

Independent correlations among apathy, verbal fluency and instrumental activities of daily living in AD patients might be related to the common brain area involved in their pathogeneses.

Peer Review reports

Background

Apathy is characterized by the lack of motivation, decreased initiative, akinesia, and emotional indifference. Apathy has been proposed to be a signal of imminent cognitive decline and future risk for dementia in patients with Alzheimer’s disease (AD) [1]. The prevalence of apathy also increases as dementia severity worsens [2]. It is known that the multiple cognitive domains of AD patients are progressively impaired in the process of disease, however, the specific cognitive domain associated with apathy is rarely reported.

Other neuropsychiatric symptoms, such as depression, anxiety and agitation are also common in patients with mild cognitive impairment (MCI) and dementia due to AD. However, the relation between apathy and other neuropsychiatric symptoms in AD, are barely reported and not clear now.

It was reported that patients with MCI and dementia due to AD exhibited significantly worse performance in olfactory identification (ID) compared with healthy individuals [3]. Furthermore, longitudinal studies showed that olfactory identification ID was able to predict cognitive decline due to neuropathology of AD [4]. Olfactory disorder and apathy both could predict the development of AD, however, the relation between them is not clear now, and the relation between apathy and other domains of olfaction, such as olfactory threshold (THR) and discrimination (DIS), are rarely reported.

In a word, this investigation aims to provide comprehensive investigations on correlations between apathy and cognitive functions, neuropsychiatric symptoms, activity of daily living and olfactory functions in AD patients, which may give better understandings of AD with apathy.

Methods

Subjects

This is a cross-sectional study. Total 124 AD patients who were community dwelling were consecutively recruited from April 2014 to April 2017. All patients were diagnosed with typical AD phenotype according to the International Working Group-2 criteria [5]. Patients with history of sinus surgery or nasal fracture, depression or other major mental health disorders were excluded.

Patients’ demographic information, including gender, age, disease duration, educational level and smoking condition was collected. Disease duration was based on the retrospective clinical information of the illness timeline. All AD patients were evaluated by Modified Apathy Evaluation Scale (MAES). MAES [6] is an abridged version of an apathy scale designed by Robert Mann [7]. MAES has 14 items, and the score of each item ranges from 0 to 3 (points), representing “not at all”, “slightly”, “some”, and “a lot”, respectively. Thus, the total score of MEAS ranges from 0 to 42 (points), and the higher score indicates more severe apathy. Using a cutoff point of 14 points, the sensitivity and specificity were 66 and 100%, respectively [6]. According to the results of MAES, patients were divided into AD with apathy (AD-A, MAES> 14 points) group and AD with no apathy (AD-NA, MAES ≤14 points) group, respectively.

Assessments of clinical symptoms

Cognitive functions

Patients were evaluated for global cognitive function by Mini-Mental State Examination (MMSE). Score ranges from 0 to 30 (points); lower score indicates more severe cognitive impairment [8]. Individual cognitive domain was assessed by scales as followed:

Memory: Memory was assessed by the Auditory Verbal Learning Test (AVLT) [9]. It includes immediate recall with the score range from 0 to 36 (points), short- delayed recall and long-delayed recall, both with the score range from 0 to 12 (points). Lower score indicates worse memory.

Attention: The Symbol Digit Modalities Test (SDMT) was used to evaluate attention [10] with score range from 0 to 95 (points). Lower score reflects worse attention. The Trail Making Test A (TMT-A) was another scale used for testing attention [11]. Longer time spent in the test (the maximum is 4 min) means worse attention.

Executive function: The Stroop Color-Word Test (SCWT) was used to evaluate executive function [11] with score range from 0 to 50 (points).The lower the score was, the worse the executive function was. The Trail Making Test B (TMT-B) was another scale used for assessing attention [11]. The maximum time used for the test is 4 min. The longer the time consumed, the worse the executive function presented.

Language: The Animal Fluency Test (AFT) was used to assess language [12]. Patients were asked to enumerate animals as more as possible in 1 min. Score was the number of animals enumerated. If the score was lower, the language function was poorer.

Visuospatial ability: The Complex Figure Test (CFT) was used to evaluate visuospatial ability [13] with score range from 0 to 36 (points). Lower score represents worse visuospatial ability.

Neuropsychiatric symptoms

Depression was evaluated by the Hamilton Depression Scale (HAMD)-24 items [14] with scores range from 0 to 80 (points), and score > 8 points implies depression. Anxiety was assessed by the Hamilton Anxiety Scale (HAMA)-14 items [15] with score range from 0 to 56 (points) and score > 8 points indicated anxiety. Agitation was tested by the Cohen-Mansfield Agitation Inventory (CMAI) [16] with score range from 0 to 203 (points), and the higher the CMAI score was, the severer the agitation was.

Activities of daily living (ADL)

The scales established by Lawton and Brody were used to assess ADL of each patient, including Physical Self-maintenance Scale as basic ADL scale (BADL Scale, score ranges from 6 to 24 points) and Instrumental Activities of Daily Living Scale (IADL Scale, score ranges from 8 to 32 points) [17]. The higher the score was, the worse the ADL was.

Test of olfactory functions

Olfactory functions of AD patients were evaluated by Sniffin’ Sticks test, which was from Burghart Messtenik Company, German (product number: LA-13-00005). There were total 112 sticks, among which, 48, 48 and 16 were used for testing olfactory THR, DIS and ID, respectively.

THR: Participants were exposed to n-butyl alcohol from the lowest concentration to the highest one. The score of olfactory THR was the number of Sniffin sticks with the minimal concentration of n-butyl alcohol that participants identified. The lower the score of olfactory THR was, the worse the function of olfactory recognition was.

DIS: Participants were instructed to distinguish the target odor from the other two. The score of olfactory DIS was the number of Sniffin sticks that participants correctly chose. The lower the score of olfactory DIS was, the worse the function of olfactory discrimination was.

ID: Participants were required to identify the odor he (she) smelled among the 4 given answers. The score of olfactory ID was the number of Sniffin sticks that participants correctly answered. The lower the score of olfactory ID was, the worse the function of olfactory identification was.

Overall olfactory function was assessed by summing up the scores of olfactory THR, DIS and ID, which was abbreviated as TDI. Olfactory dysfunction was identified by the criteria provide by a cross-sectional study in 3282 people [18]. If the age of an individual was between 36 and 55 years old, and male one with TDI score ≤ 24 points, or female one with TDI score ≤ 28 points, was thought to have olfactory dysfunction; if the age of an individual was > 55 years old, a female or male one with TDI score ≤ 19 points was thought to have olfactory dysfunction.

Data analyses

Statistical analyses were performed with SPSS Statistics 20.0 (IBM Corporation, New York, USA). Continuous variables were presented as mean ± standard deviations and compared by 2-tailed t-test if they were normally distributed, and presented as median (quartile) and compared by nonparametric test if they were not normally distributed. Discrete variables were compared by Chi square test. Demographic information, cognitive functions, neuropsychiatric symptoms, olfactory functions and activity of daily life were compared between AD-A and AD-NA groups. Because there were total 25 comparisons between the two groups,Bonferroni correction was performed and the corrected P value was significant when it was less than 0.002(0.05/25 = 0.002). Due to MEAS scores were ordinal data, Spearman correlation analyses were performed between MAES scores and related factors. Further multiple linear regression analysis was performed between apathy and variables that had linear correlations with MAES score. Correlations were considered as significant when P < 0.05 and |r| > 0.3.

Results

In this study, among 124 AD patients, 47 cases (37.9%) were male, and age from 45 to 93 years with an average of 68 years; 77 cases were female and age was 43–88 years with an average of 68 years. Sixty out of 124 (48.4%) AD patients had apathy. The mean apathy score of AD-A group was significantly higher than that of AD-NA group [26.0(18.3 ~ 35.6) vs. 4.5(0.3 ~ 9.0), P < 0.002].

Demographic information, cognitive functions, neuropsychiatric symptoms, ADL and olfactory functions were compared between AD-A and AD-NA groups. The results showed that, gender, age, disease duration, educational level and smoking condition were not significantly different between two groups (P > 0.002) (Table 1).

Table 1 Demographic variables of AD-Aa and AD-NAb groups
Full size table

AD-A group had more serious cognitive dysfunctions, including global cognitive function, immediate recall, short-delayed recall, verbal memory and verbal fluency than AD-NA group (P < 0.002). Depression and agitation were more serious in AD-A group than AD-NA group (P < 0.002). AD-A group also had worse ADL, including BADL and IADL (P < 0.002) (Table 2). Further correlation analyses indicated that apathy was negatively correlated with global cognitive function, immediate recall, short-delayed recall, verbal memory and verbal fluency, and positively correlated with ADL, including BADL and IADL (P < 0.05) (Table 3). There was no significant difference of olfactory functions between two groups (P > 0.05) (Table 4). Correlation analyses implied that apathy was negatively correlated with olfactory THR, ID and TDI (P < 0.05). However, the absolute value of coefficients was less than 0.3 (Table 5). Further linear regression analysis was made between apathy and variables that had linear correlations with it, including MMSE, AVLT, AFT, BADL and IADL (Table 6). The results showed that only the scores of AFT and IADL were independently associated with MAES score (P < 0.05).

Table 2 Clinical Symptoms of AD-Aa and AD-NAb groups
Full size table
Table 3 Spearman correlation analyses between apathy and related factors in Alzheimer disease patients
Full size table
Table 4 Olfactory functions of AD-Aa and AD-NAb groups
Full size table
Table 5 Spearman correlation analyses between apathy and olfactory symptoms in Alzheimer disease patients
Full size table
Table 6 Multiple linear regression analyses between apathy and related factors
Full size table

Discussion

In this investigation, some of participants were with MCI due to AD, which also had apathy. Patients with MCI due to AD and AD dementia had the same pathological changes of AD, therefore, we did not specifically distinguish MCI due to AD from AD dementia. We hope to figure out the common influencing factors of apathy in AD patients. In AD patients recruited in this study, the frequency of apathy reached up to 48.4%. Thus, clinician should pay great attention to this easily ignored symptom of AD patients.

The relation between apathy and global cognitive function was investigated in this research. Global cognitive function was significantly impaired in AD-A group than AD-NA group (P < 0.002). The relation between apathy and individual cognitive domains was then explored. Memory was the first one we investigated. The results showed that scores of immediate recall and short-delayed recall were significantly lower in AD-A group than AD-NA group (P < 0.002), and both were negatively correlated with the scores of MAES (P < 0.05). It was reported that one pivotal pathology of apathy in AD was the lack of cholinergic transmitters in the frontal and marginal lobes, especially in the frontal lobe [19]. Interim results from another study suggested that combination of donepezil, an acetylcholinesterase inhibitor, and choline alphoscerate, a cholinergic precursor, alleviated apathy and reduced caregiver distress [20]. Open label studies with cholinesterase inhibitors, including donepezil, rivastigmine and galantamine, showed an improvement in apathy for AD patients [21]. Therefore, the damage of cholinergic function might connect apathy and memory decline in AD patients.

In this research, AFT score was significantly lower in AD-A group than AD-NA group (P < 0.002), and also negatively correlated with MAES score (P < 0.05). AFT is widely used for assessing semantic function of language, which mainly reflects the function of temporal lobe. The database from the Alzheimer Disease Neuroimaging Initiative, a larger study, showed that cortical thinning in temporal cortex was associated with more severe apathy over time after correcting for multiple covariates, such as sex, age, APOE genotype, premorbid intelligence, memory performance, processing speed, antidepressant use, and AD duration [22]. There are extensive projections from temporal lobe to frontal lobe, so the damage in temporal lobe may lead to apathy and problem of verbal fluency at the same time in AD patients.

In this study, AD-A group had more serious depression than AD-NA group (P < 0.002). This might because that apathy and depression are often comorbid. Apathy and depression have similar clinical manifestations, and share some common pathological changes, such as hypoperfusion. However, they also have their unique pathogenic processes [23], which might explain that no significant correlation was found between depression and apathy in this study (P > 0.05). Apathy was specifically correlated with hypometabolism in left orbitofrontal areas while depression was associated with hypometabolism in left dorsolateral prefrontal regions [24]. Apathy score was positively correlated with PIB signal in bilateral frontal and right anterior cingulate cortices, but no correlation was found between PIB and depression [25]. It was reported that apathy but not depression was strongly associated with the transition from MCI to AD [26].

In this study, agitation was more serious in AD-A group than AD-NA group (P < 0.002). Apathy and agitation in AD patients may share common mechanisms. For example, it was reported that the scores of apathy and agitation were both correlated with the elevated level of Aβ1–42 [27] and the decreased volume of anterior cingulate [28]. Therefore, it can be speculated that both apathy and agitation may simultaneously worsened when the common mechanisms they share become serious. However, they also have their own pathogeneses. For example, it was found that apathy was positively correlated to hypofrontality [24] as well as increased gamma-aminobutyric acid level in serum [29], and agitation was connected with the damage of locus coeruleus [30] and positively related to increased brain derived neurotrophic factor level in plasma [31] . The specific pathogeneses may explain why agitation was not significantly correlated with apathy in this study (|r| < 0.3).

We found that apathy was associated with both basic and instrumental ADL in AD patients (P < 0.002). There might be a few potential explanations. First, the presence of apathy was more common in dementia patients with worse ADL; second, patients with reduced ADL were more likely to have aggravated apathy.

In this study, the scores of olfactory THR, DIS, ID and TDI were not significantly different between AD-A and AD-NA groups (P > 0.002), and further correlation analyses showed that MEAS score was positively correlated with the scores of olfactory THR, ID and TDI (P < 0.05). However, the absolute value of coefficient was < 0.3, which meant correlations between apathy and olfactory dysfunctions was quite weak. These contradictory results might be due to limited sample number of 124 patients in this study, which was more likely to cause the result to be false positive. Therefore, further study with larger sample size is much needed. However, other study has reported there was a correlation between apathy and olfactory dysfunctions. An exploration comparing 172 patients with AD dementia, 112 patients with MCI due to AD and 132 controls by using olfactory ID performance showed that the two types of patients were significantly worse in identifying odors, and smell identification deficit was significantly correlated with the degree of apathy, but not depression or other neuropsychiatric symptoms. Importantly, this correlation was observed even after controlling for the severity of dementia [32]. The anatomic proximity of the olfactory network and apathy-related structures might provide a potential explanation for the close correlation between olfaction and apathy [4].

In this research, a linear regression analysis was made between MAES score and variables that had linear correlations with apathy, including MMSE, AVLT, AFT, BADL and IADL. The results showed that only the scores of AFT and IADL were independently associated with MAES score (P < 0.05). AFT is widely used to test verbal fluency, which reflects semantic function as well as executive function. IADL involves ability of planning and executive function. Executive dysfunction is closely connected with hypofrontality, which also participates in the pathogenesis of apathy. Therefore, we speculate that hypofrontality may be the connection of apathy, verbal fluency and IADL.

The strength of this research is total 11 scales and Sniffin’ Sticks test were used to comprehensively evaluate the clinical symptoms of AD. This investigation also has deficiencies. The sample size was relatively insufficient, and healthy people as control were not included. We did not consider contextual factors that could impact on motivation, such as whether patients were provided with activities that might interest them, and whether the patients’ background was enriched to avoid social isolation. These deficiencies are needed to be avoided in the future study.

Conclusions

In summary, apathy is a very common symptom of AD. It is independently correlated with the impairments of verbal fluency and IADL, which may reflect the association of brain area involved in their pathogeneses.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

AD:

Alzheimer disease

AD-A:

Alzheimer disease with apathy

AD-NA:

Alzheimer disease with no apathy

MCI:

mild cognitive impairment

MAES:

Modified Apathy Evaluation Scale

MMSE:

Mini-Mental State Examination

AVLT:

Auditory Verbal Learning Test

SDMT:

Symbol Digit Modalities Test

TMT:

Trail Making Test

SCWT:

Stroop Color-Word Test

AFT:

Animal Fluency Test

CFT:

Complex Figure Test

HAMD:

Hamilton Depression Scale

HAMA:

Hamilton Anxiety Scale

CMAI:

Cohen-Mansfield Agitation Inventory

BADL:

Basic Activities of Daily Living

IADL:

Instrumental Activities of Daily Living

THR:

Olfactory Threshold

DIS:

Olfactory Discrimination

ID:

Olfactory Identification

TDI:

Sum of Olfactory Threshold, Discrimination and Identification

References

  1. Onyike CU, Sheppard JM, Tschanz JT, Norton MC, Green RC, Steinberg M, et al. Epidemiology of apathy in older adults: the Cache County study. Am J Geriatr Psychiatry. 2007;15(5):365–75. https://doi.org/10.1097/01.JGP.0000235689.42910.0d.

    Article  PubMed  Google Scholar 

  2. Mega MS, Cummings JL, Fiorello T, Gornbein J. The spectrum of behavioral changes in Alzheimer's disease. Neurology. 1996;46(1):130–5.

    Article  CAS  Google Scholar 

  3. Wesson DW, Wilson DA, Nixon RA. Should olfactory dysfunction be used as a biomarker of Alzheimer's disease? Expert Rev Neurother. 2010;10(5):633–5. https://doi.org/10.1586/ern.10.33.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Wilson RS, Arnold SE, Schneider JA, Boyle PA, Buchman AS, Bennett DA. Olfactory impairment in presymptomatic Alzheimer’s disease. Ann N Y Acad Sci. 2009;1170:730–5. https://doi.org/10.1111/j.1749-6632.2009.04013.x.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Dubois B, Feldman HH, Jacova C, Hampel H, Molinuevo JL, Blennow K, et al. Advancing research diagnostic criteria for Alzheimer's disease: the IWG-2 criteria. Lancet Neurol. 2014;13(6):614–29. https://doi.org/10.1016/S1474-4422(14)70090-0.

    Article  PubMed  Google Scholar 

  6. Starkstein SE, Mayberg HS, Preziosi TJ, Andrezejewski P, Leiguarda R, Robinson RG. Reliability, validity, and clinical correlates of apathy in Parkinson's disease. J Neuropsychiatr Clin Neurosci. 1992;4(2):134–9. https://doi.org/10.1176/jnp.4.2.134.

    Article  CAS  Google Scholar 

  7. Marin RS. Differential diagnosis and classification of apathy. Am J Psychiatry. 1990;147(1):22–30. https://doi.org/10.1176/ajp.147.1.22.

    Article  PubMed  CAS  Google Scholar 

  8. Cockrell JR, Folstein MF. Mini-mental state examination (MMSE). Psychopharmacol Bull. 1988;24(4):689–92.

    PubMed  CAS  Google Scholar 

  9. Guo Q, Zhao Q, Chen M, Ding D, Hong Z. A comparison study of mild cognitive impairment with 3 memory tests among Chinese individuals. Alzheimer Dis Assoc Disord. 2009;23(3):253–9. https://doi.org/10.1097/WAD.0b013e3181999e92.

    Article  PubMed  Google Scholar 

  10. A S. Symbol digits modalities test: manual. Los Angeles: Western Psychological Services; 1982.

    Google Scholar 

  11. Guo QHSY, Yuan J, Hong Z, Lu CZ. Application of eight executive tests in participants at Shanghai communities. Chin J Behavioral Med Sci. 2007;16:4.

    Google Scholar 

  12. Sebaldt R, Dalziel W, Massoud F, Tanguay A, Ward R, Thabane L, et al. Detection of cognitive impairment and dementia using the animal fluency test: the DECIDE study. Can J Neurol Sci. 2009;36(5):599–604. https://doi.org/10.1017/s0317167100008106.

    Article  PubMed  Google Scholar 

  13. Guo QLC, Hong Z. Application of Rey-Osterrieth complex figure test in Chinese normal old people. Chin J Clin Psychol. 2000;8:3.

    Google Scholar 

  14. Whisman MA, Strosahl K, Fruzzetti AE, Schmaling KB, Jacobson NS, Miller DM. A structured interview version of the Hamilton rating scale for depression: reliability and validity. Psychol Assess. 1989;1(3):238–41.

    Article  Google Scholar 

  15. Guy W. HAMA Hamilton anxiety scale. ECDEU Assessment Manual. 1976;5.

  16. Lin LC, Kao CC, Tzeng YL, Lin YJ. Equivalence of Chinese version of the Cohen-Mansfield agitation inventory. J Adv Nurs. 2007;59(2):178–85. https://doi.org/10.1111/j.1365-2648.2007.04303.x.

    Article  PubMed  Google Scholar 

  17. Katz S, Ford AB, Moskowitz RW, Jackson BA, Jaffe MW. Studies of illness in the aged. The index of Adl: a standardized measure of biological and psychosocial function. JAMA. 1963;185:914–9. https://doi.org/10.1001/jama.1963.03060120024016.

    Article  PubMed  CAS  Google Scholar 

  18. Hummel T, Kobal G, Gudziol H, Mackay-Sim A. Normative data for the “Sniffin’ sticks” including tests of odor identification, odor discrimination, and olfactory thresholds: an upgrade based on a group of more than 3,000 subjects. Eur Arch Otorhinolaryngol. 2007;264(3):237–43. https://doi.org/10.1007/s00405-006-0173-0.

    Article  PubMed  CAS  Google Scholar 

  19. Boyle PA, Malloy PF. Treating apathy in Alzheime’s disease. Dement Geriatr Cogn Disord. 2004;17(1–2):91–9. https://doi.org/10.1159/000074280.

    Article  PubMed  Google Scholar 

  20. Rea R, Carotenuto A, Traini E, Fasanaro AM, Manzo V, Amenta F. Apathy treatment in Alzheimer's disease: interim results of the ASCOMALVA trial. J Alzheimers Dis. 2015;48(2):377–83. https://doi.org/10.3233/JAD-141983.

    Article  PubMed  CAS  Google Scholar 

  21. Cohen-Mansfield J, Golander H, Cohen R. Rethinking psychosis in dementia: an analysis of antecedents and explanations. Am J Alzheimers Dis Other Dement. 2017;32(5):265–71. https://doi.org/10.1177/1533317517703478.

    Article  Google Scholar 

  22. Porsteinsson AP, Drye LT, Pollock BG, Devanand DP, Frangakis C, Ismail Z, et al. Effect of citalopram on agitation in Alzheimer disease: the CitAD randomized clinical trial. JAMA. 2014;311(7):682–91. https://doi.org/10.1001/jama.2014.93.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Li XL, Hu N, Tan MS, Yu JT, Tan L. Behavioral and psychological symptoms in Alzheimer's disease. Biomed Res Int. 2014;2014:927804. https://doi.org/10.1155/2014/927804.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Holthoff VA, Beuthien-Baumann B, Kalbe E, Ludecke S, Lenz O, Zundorf G, et al. Regional cerebral metabolism in early Alzheimer’s disease with clinically significant apathy or depression. Biol Psychiatry. 2005;57(4):412–21. https://doi.org/10.1016/j.biopsych.2004.11.035.

    Article  PubMed  CAS  Google Scholar 

  25. Husebo BS, Ballard C, Sandvik R, Nilsen OB, Aarsland D. Efficacy of treating pain to reduce behavioural disturbances in residents of nursing homes with dementia: cluster randomised clinical trial. BMJ. 2011;343:d4065. https://doi.org/10.1136/bmj.d4065.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Guercio BJ, Donovan NJ, Munro CE, Aghjayan SL, Wigman SE, Locascio JJ, et al. The apathy evaluation scale: a comparison of subject, informant, and clinician report in cognitively Normal elderly and mild cognitive impairment. J Alzheimers Dis. 2015;47(2):421–32. https://doi.org/10.3233/JAD-150146.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Kurz A, Thone-Otto A, Cramer B, Egert S, Frolich L, Gertz HJ, et al. CORDIAL: cognitive rehabilitation and cognitive-behavioral treatment for early dementia in Alzheimer disease: a multicenter, randomized, controlled trial. Alzheimer Dis Assoc Disord. 2012;26(3):246–53. https://doi.org/10.1097/WAD.0b013e318231e46e.

    Article  PubMed  Google Scholar 

  28. Nowrangi MA. Neuropsychiatric aspects of Alzheimer dementia: from mechanism to treatment. Psychiatr Clin North Am. 2020;43(2):383–97. https://doi.org/10.1016/j.psc.2020.02.012.

    Article  PubMed  Google Scholar 

  29. Lanctot KL, Herrmann N, Rothenburg L, Eryavec G. Behavioral correlates of GABAergic disruption in Alzheimer's disease. Int Psychogeriatr. 2007;19(1):151–8. https://doi.org/10.1017/S1041610206003899.

    Article  PubMed  Google Scholar 

  30. Matthews KL, Chen CP, Esiri MM, Keene J, Minger SL, Francis PT. Noradrenergic changes, aggressive behavior, and cognition in patients with dementia. Biol Psychiatry. 2002;51(5):407–16. https://doi.org/10.1016/s0006-3223(01)01235-5.

    Article  PubMed  CAS  Google Scholar 

  31. Nagata T, Kobayashi N, Shinagawa S, Yamada H, Kondo K, Nakayama K. Plasma BDNF levels are correlated with aggressiveness in patients with amnestic mild cognitive impairment or Alzheimer disease. J Neural Transm (Vienna). 2014;121(4):433–41. https://doi.org/10.1007/s00702-013-1121-y.

    Article  CAS  Google Scholar 

  32. Seligman SC, Kamath V, Giovannetti T, Arnold SE, Moberg PJ. Olfaction and apathy in Alzheimer’s disease, mild cognitive impairment, and healthy older adults. Aging Ment Health. 2013;17(5):564–70. https://doi.org/10.1080/13607863.2013.768208.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We express sincere thanks to professor Gai-fen Liu of China National Clinical Research Center for Neurological Disease, Beijing Tiantan Hospital, Capital Medical University, for providing the valuable advice for statistical analyses.

Funding

The following programs provided financially support to the conduct of this research, including the study design, collection, analysis, interpretation of data and writing manuscript: The National Key Research and Development Program of China (2016YFC1306300, 2016YFC1306000); The National Key R&D Program of China-European Commission Horizon 2020 (2017YFE0118800–779238); The National Natural Science Foundation of China (81970992, 81571229, 81071015, 30770745); The Key Technology R&D Program of Beijing Municipal Education Commission (kz201610025030); The Key Project of Natural Science Foundation of Beijing, China (4161004); The Natural Science Foundation of Beijing, China (7082032); Project of Scientific and Technological Development of Traditional Chinese Medicine in Beijing (JJ2018–48); Capital Clinical Characteristic Application Research (Z121107001012161); High Level Technical Personnel Training Project of Beijing Health System, China (2009-3-26); Project of Beijing Institute for Brain Disorders (BIBD-PXM2013_014226_07_000084); Excellent Personnel Training Project of Beijing, China (20071D0300400076); Important National Science & Technology Specific Projects (2011ZX09102–003-01); National Key Technology Research and Development Program of the Ministry of Science and Technology of China (2013BAI09B03); Project of Construction of Innovative Teams and Teacher Career Development for Universities and Colleges Under Beijing Municipality (IDHT20140514); Beijing Healthcare Research Project, China (JING-15-2); Basic-Clinical Research Cooperation Funding of Capital Medical University, China (2015-JL-PT-X04, 10JL49, 14JL15); Natural Science Foundation of Capital Medical University, Beijing, China (PYZ2018077); Youth Research Funding, Beijing Tiantan Hospital, Capital Medical University, China (2015-YQN-14, 2015-YQN-15, 2015-YQN-17).

Author information

Authors and Affiliations

  1. Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China

    Shu-yang Yu, Teng-hong Lian, Peng Guo, Du-yu Ding, Dan-ning Li, Yang Hu, Li-jun Zuo, Jun-hua Gao, Qiu-jin Yu, Zhao Jin, Rui-dan Wang, Rong-yan Zhu & Wei Zhang

  2. Department of General Internal Medicine, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China

    Li-xia Li, Li Liu & Hui Zhao

  3. Department of Physiology, Capital Medical University, Beijing, 100069, China

    Xiao-min Wang

  4. China National Clinical Research Center for Neurological Disease, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China

    Wei Zhang

  5. Center of Parkinson’s Disease, Beijing Institute for Brain Disorders, Beijing, 100053, China

    Wei Zhang

  6. Beijing Key Laboratory on Parkinson Disease, Beijing, 100053, China

    Wei Zhang

Authors
  1. Shu-yang Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Teng-hong Lian
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Peng Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Li-xia Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Du-yu Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Dan-ning Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Li Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hui Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yang Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Li-jun Zuo
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jun-hua Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Qiu-jin Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Zhao Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Rui-dan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Rong-yan Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Xiao-min Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Wei Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization, WZ and XW; Methodology, WZ; Investigation, SY, TL, PG, LL, DD, DL LL, HZ, YH, LZ, JG, QY, ZJ, RW and RZ; Formal Analysis, SY; Writing-Original Draft Preparation, SY; Revising the manuscript: TL, PG, LL, DD, DL LL, HZ, YH, LZ, JG, QY, ZJ, RW, RZ and WZ. All authors have read and approved the final version of this manuscript.

Corresponding author

Correspondence to Wei Zhang.

Ethics declarations

Ethics approval and consent to participate

All subjects, or their legal representatives if patients were not capable of providing ethical consent for their participation due to cognitive decline, gave their written informed consent for inclusion before participating in the study. The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Beijing Tiantan Hospital review board (KY2013–003-02).

Consent for publication

All authors have seen and agreed with the contents of the manuscript.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yu, Sy., Lian, Th., Guo, P. et al. Correlations of apathy with clinical symptoms of Alzheimer’s disease and olfactory dysfunctions: a cross-sectional study. BMC Neurol 20, 416 (2020). https://doi.org/10.1186/s12883-020-01978-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12883-020-01978-9

Keywords

BMC Neurology

ISSN: 1471-2377

Contact us