Alzheimer’s Disease Psychosis

Alzheimer’s disease symptoms include hallucinations and delusions, experienced by approximately 30% of patients with Alzheimer’s disease.

Alzheimer’s Disease

Alzheimer’s disease (AD) is the most common form of dementia. Approximately 6 million people in the United States have AD, with this number projected to rise as the elderly population grows.1,2 AD is a neurocognitive disorder, with diagnosis requiring a combination of clinical assessments.1,3 Criteria like the National Institute on Aging and Alzheimer’s Association guidelines may be used to guide clinical diagnosis,4 that can then only be confirmed through autopsy.5 

Alzheimer’s Disease Psychosis

Patients with AD may experience neuropsychological symptoms, including hallucinations and delusions.3 The overall prevalence of these symptoms of psychosis in AD is approximately 30%. While the literature varies based on study setting, the median the prevalence of symptoms are 36% for delusions and 18% for hallucinations.6 Typically, delusions in patients with AD occur earlier than hallucinations and are of the paranoid type, and hallucinations are more often visual than auditory.3,7

In 2020, the International Psychogeriatric Association (IPA) published criteria for Psychosis in Major or Mild Neurocognitive Disorder: hallucinations or delusions occurring after the onset of cognitive decline, present (at least intermittently) for 1 month or longer, and not better explained by delirium, other medical conditions with psychotic features or other medical conditions known to cause hallucinations (e.g., epilepsy, stroke, migraine).3  

The prevalence of psychosis has been shown to increase as cognitive impairment becomes more severe.6 In addition, the presence of delusions and hallucinations predicts a greater likelihood of progression to severe dementia and death in people with incident AD.8

Serotonin Dysfunction in Alzheimer’s Disease Psychosis

There is evidence that suggests symptoms of psychosis in AD dementia are associated with polymorphisms in the serotonergic pathway genes, in particular the 5HTTLPR polymorphism in SLA6A4, which codes for the serotonin transporter.8-10 A recent meta-analysis has also found evidence for an association between polymorphisms of a 5-HT2A receptor gene and psychosis in AD.11There is evidence that suggests symptoms of psychosis in AD are associated with polymorphisms in the serotonergic pathway genes, in particular the 5HTTLPR polymorphism in SLA6A4, which codes for the serotonin transporter.9-11 A recent meta-analysis has also found evidence for an association between polymorphisms of a 5-HT2A receptor gene and psychosis in AD.12 

Proposed Mechanism of Psychosis in AD

Delusions and hallucinations in AD have been associated with atrophy within  specific neocortical regions.13 Delusions have been associated with decreased grey matter density in the left frontal lobe, right frontoparietal cortex and in the left claustrum,14 whereas reduced baseline bilateral supramarginal cortical thickness15 and occipital atrophy16 have been linked with hallucinations.

Serotonin is thought to play a role in CNS disorders by modulating networks that impact a variety of other neurotransmitters (eg, glutamate and dopamine).17-21 Dysfunction in the neural networks involving serotonin receptors has been linked to hallucinations and delusions associated with ADP.17,22,23 

Activation of the 5-HT2A receptors has been associated with altered visual perceptions and altered cortical activity in visuospatial cortices.20 On a cellular level, 5-HT2A receptor modulation of cortical pyramidal glutamate neurons could correspond with excess glutamate signaling to subcortical structures,17,20,24 such as the ventral tegmental area.25,26 Delusions and auditory hallucinations are thought to stem from sustained hyperactive cortical glutamate neurons projecting to the ventral tegmental area and hyperactivating the dopamine mesolimbic pathway.24,26-28 Visual hallucinations are thought to stem from excess signaling via 5-HT2A receptors in the visual cortex with different hyperactive glutamate neurons in the occipital cortex.20,29 These dysfunctional neural networks involving serotonin receptors is thought to be responsive to the modulation of 5-HT2A receptors on cortical glutamate neurons.17-20,25 

References

1. 2021 Alzheimer’s disease facts and figures. Alzheimers Dement. Mar 2021;17(3):327-406. 

2. Rajan KB, Weuve J, Barnes LL, McAninch EA, Wilson RS, Evans DA. Population estimate of people with clinical Alzheimer’s disease and mild cognitive impairment in the United States (2020-2060). Alzheimers Dement. Dec 2021;17(12):1966-1975. 

3. Cummings J, Pinto LC, Cruz M, et al. Criteria for psychosis in major and mild neurocognitive disorders: International Psychogeriatric Association (IPA) consensus clinical and research definition. Am J Geriatr Psychiatry. Dec 2020;28(12):1256-1269. 

4. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology. Jul 1984;34(7):939-44. 

5. Petersen RC. How early can we diagnose Alzheimer disease (and is it sufficient)? The 2017 Wartenberg lecture. Neurology. Aug 28 2018;91(9):395-402. 

6. Ropacki SA, Jeste DV. Epidemiology of and risk factors for psychosis of Alzheimer’s disease: a review of 55 studies published from 1990 to 2003. Am J Psychiatry. Nov 2005;162(11):2022-30. 

7. Jost BC, Grossberg GT. The evolution of psychiatric symptoms in Alzheimer’s disease: a natural history study. J Am Geriatr Soc. Sep 1996;44(9):1078-81. 

8. Peters ME, Schwartz S, Han D, et al. Neuropsychiatric symptoms as predictors of progression to severe Alzheimer’s dementia and death: the Cache County Dementia Progression Study. Am J Psychiatry. May 2015;172(5):460-5. 

9. DeMichele-Sweet MA, Sweet RA. Genetics of psychosis in Alzheimer’s disease: a review. J Alzheimers Dis. 2010;19(3):761-80. 

10. Quaranta D, Bizzarro A, Marra C, et al. Psychotic symptoms in Alzheimer’s disease and 5-HTTLPR polymorphism of the serotonin transporter gene: evidence for an association. J Alzheimers Dis. 2009;16(1):173-80. 

11. Sweet RA, Pollock BG, Sukonick DL, et al. The 5-HTTPR polymorphism confers liability to a combined phenotype of psychotic and aggressive behavior in Alzheimer disease. Int Psychogeriatr. Dec 2001;13(4):401-9. 

12. Tang L, Wang Y, Chen Y, et al. The association between 5HT2A T102C and behavioral and psychological symptoms of dementia in Alzheimer’s disease: a meta-analysis. Biomed Res Int. 2017;2017:5320135. 

13. Rafii MS, Taylor CS, Kim HT, et al. Neuropsychiatric symptoms and regional neocortical atrophy in mild cognitive impairment and Alzheimer’s disease. Am J Alzheimers Dis Other Demen. Mar 2014;29(2):159-65. 

14. Bruen PD, McGeown WJ, Shanks MF, Venneri A. Neuroanatomical correlates of neuropsychiatric symptoms in Alzheimer’s disease. Brain. Sep 2008;131(Pt 9):2455-63. 

15. Donovan NJ, Wadsworth LP, Lorius N, et al. Regional cortical thinning predicts worsening apathy and hallucinations across the Alzheimer disease spectrum. Am J Geriatr Psychiatry. Nov 2014;22(11):1168-79. 

16. Holroyd S, Shepherd ML, Downs JH, 3rd. Occipital atrophy is associated with visual hallucinations in Alzheimer’s disease. J Neuropsychiatry Clin Neurosci. Winter 2000;12(1):25-8. 

17. Cheng AV, Ferrier IN, Morris CM, et al. Cortical serotonin-S2 receptor binding in Lewy body dementia, Alzheimer’s and Parkinson’s diseases. J Neurol Sci. Nov 1991;106(1):50-5. 

18. Assal F, Alarcón M, Solomon EC, Masterman D, Geschwind DH, Cummings JL. Association of the serotonin transporter and receptor gene polymorphisms in neuropsychiatric symptoms in Alzheimer disease. Arch Neurol. Aug 2004;61(8):1249-53. 

19. García-Bea A, Miranda-Azpiazu P, Muguruza C, et al. Serotonin 5-HT2A receptor expression and functionality in postmortem frontal cortex of subjects with schizophrenia: Selective biased agonism via G(αi1)-proteins. Eur Neuropsychopharmacol. Dec 2019;29(12):1453-1463. 

20. Kometer M, Schmidt A, Jäncke L, Vollenweider FX. Activation of serotonin 2A receptors underlies the psilocybin-induced effects on α oscillations, N170 visual-evoked potentials, and visual hallucinations. J Neurosci. Jun 19 2013;33(25):10544-51. 

21. Elliott MS, Ballard CG, Kalaria RN, Perry R, Hortobágyi T, Francis PT. Increased binding to 5-HT1A and 5-HT2A receptors is associated with large vessel infarction and relative preservation of cognition. Brain. Jul 2009;132(Pt 7):1858-65. 

22. Davies RR, Hodges JR, Kril JJ, Patterson K, Halliday GM, Xuereb JH. The pathological basis of semantic dementia. Brain. Sep 2005;128(Pt 9):1984-95. 

23. Lahti AC, Holcomb HH, Medoff DR, Tamminga CA. Ketamine activates psychosis and alters limbic blood flow in schizophrenia. Neuroreport. Apr 19 1995;6(6):869-72. 

24. McKetin R, Baker AL, Dawe S, Voce A, Lubman DI. Differences in the symptom profile of methamphetamine-related psychosis and primary psychotic disorders. Psychiatry Res. May 2017;251:349-354. 

25. Karreman M, Moghaddam B. The prefrontal cortex regulates the basal release of dopamine in the limbic striatum: an effect mediated by ventral tegmental area. J Neurochem. Feb 1996;66(2):589-98. 

26. Nakazawa K, Zsiros V, Jiang Z, et al. GABAergic interneuron origin of schizophrenia pathophysiology. Neuropharmacology. Mar 2012;62(3):1574-83. 

27. Sesack SR, Pickel VM. Prefrontal cortical efferents in the rat synapse on unlabeled neuronal targets of catecholamine terminals in the nucleus accumbens septi and on dopamine neurons in the ventral tegmental area. J Comp Neurol. Jun 8 1992;320(2):145-60. 

28. Watanabe T, Morimoto K, Nakamura M, Suwaki H. Modification of behavioral responses induced by electrical stimulation of the ventral tegmental area in rats. Behav Brain Res. Jun 1998;93(1-2):119-29. 

29. Huot P, Johnston TH, Darr T, et al. Increased 5-HT2A receptors in the temporal cortex of parkinsonian patients with visual hallucinations. Mov Disord. Jul 30 2010;25(10):1399-408.