Clinical Features of Alzheimer Disease With and Without Lewy Bodies

Chung, Eun Joo; Babulal, Ganesh M.; Monsell, Sarah E.; Cairns, Nigel J.; Roe, Catherine M.; Morris, John C.

doi:10.1001/jamaneurol.2015.0606

Cited by 89 publications

(95 citation statements)

References 56 publications

(84 reference statements)

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“…This finding has not been previously reported, but it is consistent with prior evidence that cortical LBD is associated with higher amyloid burden, but not higher Braak stage (Obi et al, 2008), and that demented individuals with mixed neuropathologies typically have lower levels of ADNC compared to individuals with ADNC only (Nagy et al, 1997; Postupna et al, 2015). Discrepancies in prior findings regarding LBD and neurofibrillary tangles, in which some studies found positive associations (Iseki et al., 2003; Jellinger and Attems, 2008; Sonnen et al, 2010) while others did not (Chung et al, 2015; Kotzbauer et al, 2012; Obi et al, 2008; Schneider et al., 2012) may be accounted for by the non-monotonic association we observed between cortical LBD and level of ADNC. Interactions between amyloid and α-synuclein may lead to an alternative pathologic and clinical presentation than ADNC only, in which neurofibrillary tangles are more predominant (Jellinger and Attems, 2008; Swirski et al, 2014; Wirths et al, 2000).…”

Section: Discussioncontrasting

confidence: 96%

“…In brains of many people with ADNC, Lewy bodies are limited to the amygdala with little involvement of other regions (Hamilton, 2000). But cortical LBD is also associated with amyloid burden in most studies (Obi et al, 2008; Jellinger and Attems, 2008; Sonnen et al, 2010; Kotzbauer et al, 2012; Swirski et al, 2014) and with neurofibrillary tangles in some studies (Jellinger and Attems, 2008; Sonnen et al, 2010)but not others (Chung et al, 2015; Kotzbauer et al, 2012; Obi et al., 2008). …”

Section: Introductionmentioning

confidence: 90%

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Alzheimer's disease neuropathologic change, Lewy body disease, and vascular brain injury in clinic- and community-based samples

Brenowitz

Keene

Hawes

et al. 2017

Neurobiology of Aging

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We examined the relationships between Alzheimer’s disease neuropathologic change (ADNC), Lewy body disease (LBD), and vascular brain injury (VBI) in two large autopsy samples. Because findings may differ between study populations, data came from U.S. Alzheimer’s Disease Centers contributing to the National Alzheimer’s Coordinating Center (NACC, n=2,742) and from the population-based Adult Changes in Thought study (ACT, n=499). Regardless of study population, over 50% of participants with ADNC had co-occurring LBD or VBI; the majority of whom had a clinical AD dementia diagnosis prior to death. Overlap of pathologies was similar between studies, especially after standardizing to the distribution of age and dementia status in the ACT population. LBD, but not VBI, was positively associated with ADNC in both studies. Interestingly, cortical LBD was more common in those with intermediate ADNC compared to low or high ADNC, especially in NACC (p<0.001). High prevalence of co-occurring neuropathologies among older adults with dementia has implications for accurate diagnosis of dementia etiologies and development of disease-modifying strategies.

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Section: Discussioncontrasting

confidence: 96%

Section: Introductionmentioning

confidence: 90%

Alzheimer's disease neuropathologic change, Lewy body disease, and vascular brain injury in clinic- and community-based samples

Brenowitz

Keene

Hawes

et al. 2017

Neurobiology of Aging

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“…Similarly, Sweet and colleagues also did not find an association between psychosis and AD pathology after controlling for Lewy bodies [54]. It has been previously demonstrated that the APOE ε4 allele may mediate psychosis through the development of Lewy bodies [19, 33, 55, 56]. Chung et al [33] found that having at least one APOE ε4 allele increased the likelihood of having Lewy body pathology in addition to AD pathology, and that the presence of Lewy bodies increased the risk of, as well as the severity of, delusions and hallucinations.…”

Section: Discussionmentioning

confidence: 99%

“…It has been previously demonstrated that the APOE ε4 allele may mediate psychosis through the development of Lewy bodies [19, 33, 55, 56]. Chung et al [33] found that having at least one APOE ε4 allele increased the likelihood of having Lewy body pathology in addition to AD pathology, and that the presence of Lewy bodies increased the risk of, as well as the severity of, delusions and hallucinations. The authors concluded that AD patients with and without accompanying Lewy body pathology have separate phenotypes.…”

Section: Discussionmentioning

confidence: 99%

“…However, the results have been conflicting, with some studies reporting a positive association [13–19] while the majority did not find any association [20–32]. Recently, the APOE ε4 allele has been linked to the development of Lewy bodies [19, 33]. Given that Lewy body pathology is a core feature of Lewy body dementia (DLB), a dementia type where psychosis is highly prevalent, and that Lewy bodies co-occur with Alzheimer pathology 50% of the time [34], it has been speculated that APOE ε4 promotes psychosis through the formation of Lewy bodies [19].…”

Section: Introductionmentioning

confidence: 99%

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Association Between Psychosis Phenotype and APOE Genotype on the Clinical Profiles of Alzheimer's Disease

Qian

Fischer

Schweizer

et al. 2018

CAR

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Background: Psychosis is a common phenomenon in Alzheimer’s disease (AD). The APOE ε4 allele is the strongest genetic risk factor for the development of AD, but it’s association with psychosis remains unclear. Objective: We investigated the associations between psychosis, subdivided into delusions and hallucinations, as well as APOE ε4 allele on cognitive and functional outcomes. Secondarily, we investigated the associations between APOE ε4, Lewy bodies, and psychosis. Methods: Data from the National Alzheimer’s Coordinating Center (NACC) were used. Nine hundred patients with a confirmed diagnosis of AD based on the NIA-AA Reagan were included in the analysis. Global cognition was assessed using the Mini-Mental State Exam (MMSE) and functional status was assessed using the Functional Activities Questionnaire (FAQ). Psychosis status was determined using the Neuropsychiatric Inventory Questionnaire (NPI-Q). Factorial design was used to assess the effects of psychosis and APOE ε4, as well as their interaction. Results: Psychosis and the presence of APOE ε4 were both associated with lower MMSE scores, while only psychosis was associated with higher FAQ scores. Furthermore, patients with hallucinations had lower MMSE and higher FAQ scores than patients with only delusions. There was a significant interaction effect between psychosis and APOE ε4 on MMSE scores, with APOE ε4 negatively affecting patients with hallucinations-only psychosis. APOE ε4 was positively associated with the presence of Lewy body pathology, and both were found to be more prevalent in psychotic patients, with a stronger association with hallucinations. Conclusion: Psychosis in AD was associated with greater cognitive and functional impairments. Patients with hallucinations—with or without delusions—conferred even greater deficits compared to patients with only delusions. The APOE ε4 allele was associated with worse cognition, especially for patients with hallucination-only psychosis. APOE ε4 may mediate cognitive impairment in the hallucinations phenotype through the development of Lewy bodies. Our findings support that subtypes of psychosis should be evaluated separately.

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Tau maturation in the clinicopathological spectrum of Lewy body and Alzheimer's disease

Arezoumandan,

Cousins,

Ohm

et al. 2024

Ann Clin Transl Neurol

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ObjectiveAlzheimer's disease neuropathologic change and alpha‐synucleinopathy commonly co‐exist and contribute to the clinical heterogeneity of dementia. Here, we examined tau epitopes marking various stages of tangle maturation to test the hypotheses that tau maturation is more strongly associated with beta‐amyloid compared to alpha‐synuclein, and within the context of mixed pathology, mature tau is linked to Alzheimer's disease clinical phenotype and negatively associated with Lewy body dementia.MethodsWe used digital histology to measure percent area‐occupied by pathology in cortical regions among individuals with pure Alzheimer's disease neuropathologic change, pure alpha‐synucleinopathy, and a co‐pathology group with both Alzheimer's and alpha‐synuclein pathologic diagnoses. Multiple tau monoclonal antibodies were used to detect early (AT8, MC1) and mature (TauC3) epitopes of tangle progression. We used linear/logistic regression to compare groups and test the association between pathologies and clinical features.ResultsThere were lower levels of tau pathology (β = 1.86–2.96, p < 0.001) across all tau antibodies in the co‐pathology group compared to the pure Alzheimer's pathology group. Among individuals with alpha‐synucleinopathy, higher alpha‐synuclein was associated with greater early tau (AT8 β = 1.37, p < 0.001; MC1 β = 1.2, p < 0.001) but not mature tau (TauC3 p = 0.18), whereas mature tau was associated with beta‐amyloid (β = 0.21, p = 0.01). Finally, lower tau, particularly TauC3 pathology, was associated with lower frequency of both core clinical features and categorical clinical diagnosis of dementia with Lewy bodies.InterpretationMature tau may be more closely related to beta‐amyloidosis than alpha‐synucleinopathy, and pathophysiological processes of tangle maturation may influence the clinical features of dementia in mixed Lewy‐Alzheimer's pathology.

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Clinical Features of Alzheimer Disease With and Without Lewy Bodies

Cited by 89 publications

References 56 publications

Alzheimer's disease neuropathologic change, Lewy body disease, and vascular brain injury in clinic- and community-based samples

Alzheimer's disease neuropathologic change, Lewy body disease, and vascular brain injury in clinic- and community-based samples

Association Between Psychosis Phenotype and APOE Genotype on the Clinical Profiles of Alzheimer's Disease

Tau maturation in the clinicopathological spectrum of Lewy body and Alzheimer's disease

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