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 (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
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