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. 2025 Apr;104(3):933-942.
doi: 10.1177/13872877251320670. Epub 2025 Mar 14.

Associations between neuropsychiatric symptoms and pathology in clinicopathologically defined Alzheimer's disease, Alzheimer's disease with Lewy bodies, and dementia with Lewy bodies

Cecilia Tremblay  1 , Neha Shakir  2 , Nan Zhang  3 , Charles H Adler  4 , Holly A Shill  5 , Shyamal Mehta  4 , Erika Driver-Dunckley  4 , Christine M Belden  6 , Alireza Atri  6   7   8 , Thomas G Beach  1 , Geidy E Serrano  1 , Parichita Choudhury  6
Affiliations

Associations between neuropsychiatric symptoms and pathology in clinicopathologically defined Alzheimer's disease, Alzheimer's disease with Lewy bodies, and dementia with Lewy bodies

Cecilia Tremblay et al. J Alzheimers Dis. 2025 Apr.

Abstract

BackgroundNeuropsychiatric symptoms (NPS) are frequent in Alzheimer's disease (AD) dementia, but a higher NPS burden is found in dementia with Lewy bodies (DLB). Lewy body (LB) pathology frequently co-occurs with AD pathology and may not meet neuropathological criteria for DLB (ADLB). NPS trajectories over disease course in these subgroups is not well understood.ObjectiveWe investigated changes in NPS severity over time, at two time points, comparing clinicopathologically defined cohorts of AD (without LB), ADLB, DLB, and controls.MethodsCases with two available Neuropsychiatric Inventory-Questionnaire (NPIQ), at the time of enrollment and within 2.5 years of death, were selected from the Arizona Study of Aging and Neurodegenerative Disorders. Differences and rate of change in NPIQ scores were compared between AD (n = 75), ADLB (n = 48) DLB (n = 65), and controls (n = 32) with covariates for age, sex, and cognition.ResultsFirst NPIQ scores were highest in ADLB when compared to AD (p = 0.04) and controls (p = 0.01) but not different from DLB. A significant increase in NPS severity was observed in DLB and AD (p < 0.001) over a mean follow up time of 4.9 ± 3.0 years, and the rate of change was significantly greater in DLB when compared to other groups. Final NPIQ scores were highest in DLB when compared to AD (p = 0.03) but not ADLB, and in DLB, ADLB, and AD than controls (all p < 0.001).ConclusionsEarly NPS burden as well as NPS severity progression rate, independently of cognitive status, might be useful clinical metrics and may help predict underlying pathological diagnoses.

Keywords: Alzheimer's disease; Lewy body dementia; aging; alpha-synuclein; apathy; cognition; neuropsychiatric inventory-questionnaire.

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Conflict of interest statement

Declaration of conflicting interests

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: CT has been supported by fellowships from the Canadian Institutes of Health Research (CIHR) and Quebec’s Health Research Funds (FRQS). CHA received consulting fees from CND Life Sciences. HAS has received research support from Intra-cellular Therapeutics, Transposon, Parkinson Study Group/UCB, Parkinson’s Foundation, NINDS, Supernus/US World Meds, MJFF, Jazz Pharmaceuticals, Barrow Neurological Foundation, Saccadous Inc, and Cerevel Therapeutics. Dr Shill has additionally served as a consultant for the Parkinson Study Group/Nq, Biogen, AbbVie, Sage/Biogen, Praxis, KeifeRx, Fasikl and Jazz Pharmaceuticals. SM receive funding from PPMI. TGB has received consulting fees from Aprinoia Therapeutics, Biogen and Acadia Pharmaceuticals. He has received payment or honoraria from the National Institutes of Health, International Movement Disorders Association, World PD Coalition, Mayo Clinic Florida, Stanford University, and the IOS Press-Journal of Parkinson’s Disease and support for attending meetings from the Alzheimer’s Association, AD/PD/Kenes Group, Mayo Clinic Florida, and the Universitätsklinikum Hamburg-Eppendorf. He also has a leadership/fiduciary role and stock options with Vivid Genomics. AA has received honoraria or support for consulting; participating in independent data safety monitoring boards; providing educational lectures, programs, and materials; or serving on advisory boards for Acadia, Alzheimer’s Association, Alzheimer’s Disease International (ADI), AriBio, Biogen, Eisai, Life Molecular Imaging, Lundbeck, Merck, Novo Nordisk, ONO, Prothena, and Roche/Genentech. Dr Atri receives book royalties from Oxford University Press for a medical book on dementia. Dr Atri receives institutional research grant/contract funding from NIA/NIH 1P30AG072980, NIA/NIH U24AG057437, AZ DHS CTR040636, the Foundation for NIH, Washington University St Louis, and Gates Ventures. Dr Atri’s institution (Banner Health) receives/received funding for clinical trial grants, contracts and projects from government, consortia, foundations and companies for which he serves/served as contracted site-PI. PC has received research support from Lewy Body Dementia Association and Arizona Alzheimer’s Consortium.

The remaining authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1.
Figure 1.
Rate of change over time between first and last NPIQ in comparison between AD, DLB, ADLB, and controls. DLB shows a significantly greater rate of change in comparison to other groups.
Figure 2.
Figure 2.
Scatterplots representing the differences between first and last NPIQ tests for each group. A significant increase in NPS severity between the first and last NPIQ tests was observed in the AD and DLB groups. Results are presented as mean and standard error of the mean.
Figure 3.
Figure 3.
Severity of NPS for each subdomain in comparison between each group for the first NPIQ (A) and the last NPIQ (B). Each line represents a different group, the middle of the spider diagram represents gradings of 0 while the extremities represent a higher severity of NPS.
Figure 4.
Figure 4.
Percentage of cases presenting with NPS for each subdomain of the NPIQ. Only differences between pathologic groups (AD, ADLB, DLB) and not with controls are represented. Chi-square tests *p < 0.005. See Supplemental Table 2 for statistical tests results.
See this image and copyright information in PMC

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