Capgras Syndrome as the Core Manifestation of Early-Onset Alzheimer’s Disease

Abstract

Capgras syndrome (CS) was usually considered a symptom of a functional disorder in the young, most commonly schizophrenia, or an organic disorder in the elderly. The occurrence of CS among early-onset Alzheimer’s disease (EOAD) is extremely rare. We describe a case in which the unrecognition of CS as part of EOAD resulted in a wrong psychiatric diagnosis and inappropriate treatment. This paper aims to acknowledge CS as an early or core manifestation and highlight EOAD as a differential diagnosis of mental disorders in young people, even without a remarkable family history.

Keywords

Alzheimer’s disease biomarkers capgras syndrome early-onset dementia mental disorders

INTRODUCTION

Alzheimer’s disease (AD) is the first common type of dementia in the elderly, typically manifest memory loss that disrupts daily life [1]. AD with the onset of symptoms before age 65 is defined as early-onset Alzheimer’s disease (EOAD), which comprises about 5-10% of all AD cases. CS, which is characterized by the delusion that another person, usually a close relative, has been replaced by a double or an impostor, was usually considered a symptom of a functional disorder in young, most commonly schizophrenia, or an organic disorder in the elderly [2].

The pathology in CS is associated with cognitive impairment and neuropsychological disturbance, including reduced affective responsivity to familiar faces, impaired belief evaluation, disconnection of the face recognition system from the autonomic nervous system, and damage to a specific region of the right frontal lobe [3]. Moreover, recent evidence suggests that fronto-parietal or right hemisphere dysfunction and functional connectivity of the parieto-occipital cortex decline in EOAD [4, 5]. Here we reported CS in a 43-year-old male with EOAD and the treatment with memantine and olanzapine was effective. To our knowledge, this is the youngest AD patient with CS. The findings would further expand our knowledge on the disease spectrum of mental disorders in young people and the therapeutic methods on CS caused by EOAD.

In the case study, we summarized the features and diagnosis strategy of all the reported EOAD cases that onset with psychiatric symptoms and illustrated how it induced the wrong or delayed diagnosis and management. This paper aims to highlight EOAD as a differential diagnosis of mental disorders in young, and call attention to the issue for both psychiatrists and neurologists. Written informed consent was obtained from the individual for the publication of any potentially identifiable images or data included in this article.

CASE DESCRIPTION

The patient was a 43-year-old man, a right-handed lawyer with high education (16 years). He had mental and behavioral abnormalities, with progressive cognitive impairment, for 18 months. His past history was unremarkable. He denied a family history of genetic disease or a similar medical history as well.

When he came to our neurology clinic, the patient had the belief that she has been replaced by a double whose appearance or other characteristics is the same as hers. Whenever he met his wife, he always required her to send text messages to prove that she was his wife. Only after confirming that it was the message sent by his wife’s number, would he be willing to talk with her. This similar situation had bothered his family for more than a month. Interestingly the patient did not misidentify neighbors and other members of the family.

Approximately 18 months before this evaluation, the patient became depressed, unwilling to greet colleagues and friends, and even had the short thought of suicide. He also experienced episodic memory impairment, leading him to forget the appointment with important customers. Then, the patient had a delusion that thought his father-in-law was monitoring his movements, and a hallucination that heard his father-in-law verbally attack him, such as “you are weak and useless” and commanding him to “run away from home”. His family found that he often shouted “shut up” suddenly without any explanation of who he was shouting at.

The patient was once diagnosed with “schizophrenia” in a psychiatric hospital 3 months after the onset of the symptom. He has taken risperidone and quetiapine and received Electroconvulsive treatment (ECT), but the psychosis did not relive instead worsen, and memory loss progressively decline. The patient gradually developed the problem with recent and past events. He couldn’t remember his birthday and relatives’ names, meanwhile, he became irritable, impulsive, and often had dirty words. Over time, the patient was gradually unable to perform activities of daily living autonomously. He often repetitive speech and had difficulty in coping with the work, completing the previously familiar tasks, and managing finance. Subsequently, he had to give up the original work due to the illness.

CLINICAL ASSESSMENT AND RESULT

His neurologic physical examination revealed cranial nerve, reflection, motor, and sensory functions were normal, abnormalities only found in cortical functions which showed memory, orientation, calculative and executive functions, and visuospatial ability deficits. Results of complete blood count and coagulation, biochemistry, renal, liver, and thyroid function tests, vitamin B12 levels, folate levels, inflammation factors, autoimmune antibodies, serology for syphilis and anti-HIV, CSF profile, and abdominal ultrasonography were all within normal limits. MRI demonstrated atrophy of bilateral parietal and medial temporal lobe and without space-occupying lesions or significant atrophy of the hippocampus.

We conducted a neuropsychological assessment for AD on the patient, including Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Clock Drawing Task (CDT), Boston Naming Test (BNT), digital span test(DST), auditory verbal learning test (AVLT), Geriatric Depression Scale(GDS), Neuropsychiatric Inventory (NPI), Activities of daily living(ADL), and Clinical Dementia Rating (CDR).

He scored 12/30 on the MMSE, and 9/30 on the MoCA. The patient performed poorly in attention, visuospatial, and memory functions. He had a score of 5/10 for forwards and 0/8 for backward on DST in the attention domain, and 1/3 on CDT in the visuospatial domain. In the memory domain, he scored 5/15 for word delayed recall and 0/15 for word long-delayed recognition on AVLT. Results of BNT, NPI, GDS, ADL were all beyond the normal limits. The global CDR of the patient was rated as 2.

Due to the abnormal result, we tested the AD biomarkers of the patient. CSF analysis showed p-tau and t-tau levels were normal (t-Tau: 155.34 pg/ml, p-tau: 33.80pg/ml), while Aβ_1–42 level and Aβ_1–42/Aβ_1–40 were reduced (Aβ_1–42: 389.96 pg/ml, Aβ_1–40: 6808.09 pg/ml, Aβ_1–42/Aβ_1–40: 0.06). ¹⁸F-fluorodeoxyglucose positron emission tomography (¹⁸F-FDG PET) showed low signal intensities in the frontal, parietal, and posterior temporal lobe (Fig. 1A). PET imaging with the ¹¹C-labelled Pittsburgh Compound-B (¹¹C-PIB-PET) showed amyloid deposition is positive (Fig. 1B, C). Moreover, Whole Genome Sequencing is used for gene detection, but no potential genetic mutation related to the disease was found, which escalated the difficulty of diagnosis to a certain extent. Combining the history of the patient illness with the result of amyloid PET, FDG, and Aβ_1–42 in CSF, the patient met the NIA-AA criteria for probable AD dementia with evidence of the AD pathophysiological process.

Fig. 1

A) ¹⁸F-FDG PET showed low metabolism in frontal and temporal lobes. (The normal radioactive ingestion area was colored red and the reduced was colored yellow.) B, C) ¹¹C-PIB-PET showed radioactive concentration in the cerebral cortex, predominantly in the occipital lobe, thalamus, and midbrain, and is considered positive for amyloid deposition. (The high ¹1C-PiB retention area was red).

DISCUSSION

CS was characterized by the delusion that another person, usually a close relative, has been replaced by a double, whose manifestation in functional disorders and organic disorders was a little bit different [6]. A malevolent intent accompanied by paranoid delusions, auditory hallucinations, homicide, and aggression was significantly more associated with functional than organic disorders [2]. The occurrence of CS among the reported late-onset Alzheimer’s disease (LOAD) patients ranges from 10.1% to 14.8%, more common in the late stage, and the mean age of onset ranged from 72 to 82 [7, 8]. In the previous cases, only 3 cases described CS in patients with early-onset AD, and the youngest age is 50 years old [9, 10]. We described a case of a 43-year-old male with gradual onset of auditory hallucinations, persecuted delusion, cognitive impairment, and CS within 18 months who more likely indicated late-onset schizophrenia based on the clinical manifestation and brain MRI. However, the diagnosis of schizophrenia cannot fully explain subsequent symptoms. Biomarkers became the crucial clue for diagnosis. Combining the history of the patient illness with the result of amyloid PET, FDG, and Aβ_1–42 in CSF, the patient met the NIA-AA criteria for probable AD dementia with evidence of the AD pathophysiological process.

Antipsychotic medications added based on the appropriate treatment to target the underlying disorder may be an effective management strategy for CS [11, 12]. CS was thought of as a phenotype of Behavioral and Psychological Symptoms of Dementia (BPSD) in patients with EOAD, thus we gave the patient memantine and olanzapine. Except for drug treatment, patient counseling or education and interprofessional team care are also some benefits [9]. After the comprehensive treatment, his condition, especially the psychiatric symptoms improved as a result. In addition, the patient was not observed any symptoms or signs of vertebral system or extra-vertebral system during an out-patient follow-up visit. Notably, the differences in the therapeutic effects of olanzapine and other atypical antipsychotics, such as risperidone, quetiapine, may need to be further studied.

This case indicated EOAD may manifest as prominent psychiatric symptoms in young people, leading to a misdiagnosis of psychosis. We reviewed all previously similar reported cases. A search of the PubMed databases using the terms: (“Alzheimer Disease” AND “early onset”) AND (“psychosis” OR “psychiatric”) covering the period from 1993 to 2021, retrieved 28 published reports, 18 of which were considered EOAD cases describing clear psychiatric symptoms. Studies not available in English were excluded. Of these reports, 12(66.7%) cases were familial cases. The sporadic cases of 7 EOAD patients with neuropsychiatric disorder including our patient are summarized in Table 1 [10 , 16–18].

Table 1

Demographics data, and clinical and therapeutic summary of sporadic EOAD cases associated with neuropsychiatric symptoms

Authors	Age of onset/Gender	Neuropsychiatric symptoms	Mistaken diagnosis	Treatment	Result	Delayed years	Gene mutation	Crucial evident of diagnosis	Treatment
Bartesaghi et al. [13]	28 years/Female	Depressive severe anxiety with frequent bursts of tears, and interpretative thinking toward her family members	postpartum depression with psychotic symptoms dissociative picture with depressive elements	Antipsychotic drug and antidepressants Aripiprazole, escitalopram, duloxetine, and olanzapine	Never completely recovered extrapyramidal symptoms onset and had no beneficial effect on her cognition	8 years	PSEN1 L226F	Complete neuropsychological examinations, CSF analysis, MRI, FDG-PET, and Florbetaben-PET	Quetiapine and pregabalin (behavior) Rivastigmine (cognitive)
Li et al. [14]	61 years/Female	Persecuted delusions Auditory hallucination diminished emotional expression and avolition	Schizophrenia	Olanzapine 5mg	Delusions and hallucinations disappeared after 1 month treatment, but began to experience rigidity, bradykinesia, and impaired cognitive function.	3 years	heterozygous variant in SORL1 (c.296A > G)	Neuropsychological Assessment,MRI, FDG-PET, and gene mutation analysis	memantine (10 mg/d) donepezil (10 mg/d)
Ng et al. [10]	48 years/Male	Persecuted delusions Auditory hallucination Capgras syndrome Apathy, suicidal thought	Not reported	Not reported	Not reported	1.5 years	APOE ɛ4/ɛ4	MRI, FDG-PET, and amyloid PET	Not reported
Marini et al. [15]	58 years/Female	mood depression, unmotivated jealousy, and excessive concern for familial finances	Not reported	Not reported	Not reported	1 years	PSEN1 Thr354Ile	CSF analysis, and FDG-PET	Not reported
Matsuoka et al. [16]	< 63 years/Female	Delusions, and auditory hallucination	Schizophrenia	Risperidone	Not improved	2 years	Not reported	MMSE,MRI, and SPECT	Donepezil
Pedrosa et al. [17]	< 51 years/Female	Depressive	Depression	long-term antidepressant therapy (escitalopram, 20 mg daily)	Depressive symptoms improved, but there was progressive cognitive deterioration.	Not reported	Not reported	MRI, and SPECT	Not reported
	41 years/Male	Apathy, persecuted delusions, auditory hallucination, Capgras syndrome	Schizophrenia	risperidonequetiapine Electroconvulsive treatment	Not improved but to worsen	1.5 years	Not found	Neuropsychological Assessment,CSF analysis,MRI,FDG-PET, and Amyloid PET	memantine olanzapine

Five patients were female and two were male (mean age of onset is younger than 50 years old). Psychiatric symptoms are mostly included disturbance of mood, perception, and thought, and subsequent abnormal behavior. Of the 7 patients, 5 (71.4%) were experienced being wrongly diagnosed as a primary psychosis, and their symptoms never been completely relieved until EOAD is diagnosis. The crucial evidence of diagnosis was all including biomarkers testing of AD, 4 (57.1%) combined the result of partial or complete neuropsychological assessment. The known gene mutation involved PSN1, APOE, and SOLR1 (gene mutation has been not reported in 2 cases). A case reported a 50-year-old EOAD patient with CS and detected APOE 4/4 mutation; however, it did not mention the treatment [10].

The initial clinical manifestation of patients with EOAD was more heterogeneous, including apraxia, aphasia, visuospatial dysfunction, and neuropsychiatric disorders [18 –21], which increase the likelihood of those patients being diagnosed with mental illness at the initial evaluation, thus delaying the correct diagnosis. Because of an incorrect diagnosis, those patients would be advised to take sufficient antipsychotic drugs to control psychiatric symptoms. Then, just like our patients, their condition did not completely improve instead worsen. Treatment with only antipsychotic drugs has minimal efficacy on psychotic symptoms in EOAD, but causes substantial adverse effects, increasing the risk of death [22, 23]. Hence, differential diagnosis of psychosis as opposed to EOAD with psychiatric symptoms may consider especially difficult and important as prognosis and treatment are distinct.

Although the initial manifestations of EOAD overlap with the symptoms of psychosis, the neuropsychological underpinnings of the two are different [24]. For example, with delusions in AD, a false belief can explain reality, replacing an inability to recall accurate information, which indicated the core origin is not a psychotic episode, but memory loss. A detailed history, a systematic neuropsychological examination, and biomarkers are useful in identification, particularly biomarkers, as objective indexes, make it possible to enable the identification of AD pathophysiological in patients [25]. The advancing plasma and neuroimage biomarkers in recent years potentially allow the diagnosis to be more convenient and efficient. Clinicians may consider asking a neurologist for a consultation to exclude neurodegenerative disease in patients who present with new-onset mood, perception, behavior, or cognitive changes after age 40. Besides, regular follow-up to assess changes in the condition of patients without anatomical disorder detected and attention to evidence of insidious onset and progression or focal cognitive impairments could improve the accuracy of diagnosis.

Including EOAD as a differential diagnosis of mental disorders in young people would be beneficial to patients to receive a correct diagnosis in the early stages. Most importantly, an accurate diagnosis will prevent patients from receiving unsuitable therapies and instead will be started on appropriate treatment, as well as relieve the psychological pressure of caregivers.

Footnotes

ACKNOWLEDGMENTS

This work was supported by Capital’s Funds for Health Improvement and Research (CFH 2020-4-1033), Beijing Natural Science Foundation (JQ19024), and Beijing Municipal Science & Technology Commission (Z191100006619046).

Authors’ disclosures available online ().

References

Scheltens

, Blennow

, Breteler

, de Strooper

, Frisoni

, Salloway

, Van der Flier

(2016) Alzheimer’s disease. Lancet 388, 505–517.

Pandis

, Agrawal

, Poole

(2019) Capgras’ delusion: A systematic review of 255 published cases. Psychopathology 52, 161–173.

Coltheart

, Langdon

, McKay

(2007) Schizophrenia and monothematic delusions. Schizophr Bull 33, 642–647.

Suribhatla

, Baillon

, Dennis

, Marudkar

, Muhammad

, Munro

, Spreadbury

, Lindesay

(2004) Neuropsychological performance in early and late onset Alzheimer’s disease: Comparisons in a memory clinic population. Int J Geriatr Psychiatry 19, 1140–1147.

Canu

, Agosta

, Mandic-Stojmenovic

, Stojkovic

, Stefanova

, Inuggi

, Imperiale

, Copetti

, Kostic

, Filippi

(2017) Multiparametric MRI to distinguish early onset Alzheimer’s disease and behavioural variant of frontotemporal dementia. Neuroimage Clin 15, 428–438.

Fleminger

, Burns

(1993) The delusional misidentification syndromes in patients with and without evidence of organic cerebral disorder: A structured review of case reports. Biol Psychiatry 33, 22–32.

Josephs

(2007) Capgras syndrome and its relationship to neurodegenerative disease. Arch Neurol 64, 1762–1766.

Harwood

, Barker

, Ownby

, Duara

(1999) Prevalence and correlates of Capgras syndrome in Alzheimer’s disease. Int J Geriatr Psychiatry 14, 415–420.

Molchan

, Martinez

, Lawlor

, Grafman

, Sunderland

(1990) Reflections of the self: Atypical misidentification and delusional syndromes in two patients with Alzheimer’s disease. Br J Psychiatry 157, 605–608.

10.

, Wong

, Xie

, Kandiah

(2020) Capgras syndrome in the young: Schizophrenia or Alzheimer disease. Alzheimer Dis Assoc Disord 34, 94–96.

11.

Chadda

, Jain

(1990) An unusual case of Capgras’ syndrome. Am J Psychiatry 147, 369–370.

12.

Khouzam

(2002) Capgras syndrome responding to the antidepressant mirtazapine. Compr Ther 28, 238–240.

13.

Bartesaghi

, Rosci

, Rassiga

, Barbieri

, Gambini

, Floro

, D’Arrigo

, Del Sole

, Scarpini

, Galimberti

, Priori

(2020) Psychiatric disorders in Alzheimer disease with the presenilin-1 L226F mutation. Cogn Behav Neurol 33, 278–282.

14.

, Xiong

, Liu

, Yuan

, Deng

, Xiang

, Li

(2020) Case report of first-episode psychotic symptoms in a patient with early-onset Alzheimer’s disease. BMC Psychiatry 20, 9.

15.

Marini

, Lucidi

, Tedde

, Bessi

, Nacmias

(2013) A case of atypical early-onset Alzheimer’s disease carrying the missense mutation Thr354Ile in exon 10 of the PSEN1 gene. Neurol Sci 34, 1691–1692.

16.

Matsuoka

, Kitabayashi

, Shibata

, Okamura

, Narumoto

, Fukui

(2010) Schizophrenia-like psychosis and dysfunction of the right-dominant temporoparietal lobe in early-onset Alzheimer’s disease. J Neuropsychiatry Clin Neurosci 22, E8–E9.

17.

Pedrosa

, Teixeira-Sousa

, Fonseca

, Bastos-Leite

(2010) Early-onset Alzheimer disease: The contribution of neuroimaging for the diagnosis. Psychiatry Res Neuroimaging 182, 287–288.

18.

Mendez

, Lee

, Joshi

, Shapira

(2012) Nonamnestic presentations of early-onset Alzheimer’s disease. Am J Alzheimers Dis Other Demen 27, 413–420.

19.

Koedam

, Lauffer

, van der Vlies

, van der Flier

, Scheltens

, Pijnenburg

YAL

(2010) Early-versus late-onset Alzheimer’s disease: More than age alone. J Alzheimers Dis 19, 1401–1408.

20.

Zhu

, Sun

, Xiao

(2021) Case of early-onset Alzheimer’s disease with atypical manifestation. Gen Psychiatry 34, e100283.

21.

Baillon

, Gasper

, Wilson-Morkeh

, Pritchard

, Jesu

, Velayudhan

(2019) Prevalence and severity of neuropsychiatric symptoms in early- versus late-onset Alzheimer’s disease. Am J Alzheimers Dis Other Demen 34, 433–438.

22.

Davies

SJC

, Burhan

, Kim

, Gerretsen

, Graff-Guerrero

, Woo

, Kumar

, Colman

, Pollock

, Mulsant

, Rajji

(2018) Sequential drug treatment algorithm for agitation and aggression in Alzheimer’s and mixed dementia. J Psychopharmacol 32, 509–523.

23.

Maust

, Kim

, Seyfried

, Chiang

, Kavanagh

, Schneider

, Kales

(2015) Antipsychotics, other psychotropics, and the risk of death in patients with dementia number needed to harm. JAMA Psychiatry 72, 438–445.

24.

Van Assche

, Van Aubel

, Van de Ven

, Bouckaert

, Luyten

, Vandenbulcke

(2019) The neuropsychological profile and phenomenology of late onset psychosis: A cross-sectional study on the differential diagnosis of very-late-onset schizophrenia-like psychosis, dementia with Lewy bodies and Alzheimer’s type dementia with psychosis. Arch Clin Neuropsychol 34, 183–199.

25.

McKhann

, Knopman

, Chertkow

, Hyman

, Jack

, Kawas

, Klunk

, Koroshetz

, Manly

, Mayeux

, Mohs

, Morris

, Rossor

, Scheltens

, Carrillo

, Thies

, Weintraub

, Phelps

(2011) The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7, 263–269.