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. 2024;100(3):1055-1073.
doi: 10.3233/JAD-240125.

Cognition Mediates the Association Between Cerebrospinal Fluid Biomarkers of Amyloid and P-Tau and Neuropsychiatric Symptoms

Brandon Frank  1   2   3 , Michael Walsh  2 , Landon Hurley  1 , Jenna Groh  2 , Kaj Blennow  4   5 , Henrik Zetterberg  4   5   6   7   8   9 , Yorghos Tripodis  2   10 , Andrew E Budson  1   2   3 , Maureen K O'Connor  2   3   11 , Brett Martin  2   12 , Jason Weller  2   3 , Ann McKee  2   3   12   13 , Wendy Qiu  2   14   15 , Thor D Stein  2   3   12   13 , Robert A Stern  2   3   16   17 , Jesse Mez  2   3   18 , Rachel Henson  19 , Justin Long  19 , Andrew J Aschenbrenner  19 , Ganesh M Babulal  19 , John C Morris  19 , Suzanne Schindler  19 , Michael L Alosco  2   3
Affiliations

Cognition Mediates the Association Between Cerebrospinal Fluid Biomarkers of Amyloid and P-Tau and Neuropsychiatric Symptoms

Brandon Frank et al. J Alzheimers Dis. 2024.

Abstract

Background: Neuropsychiatric symptoms (NPS) can be an early manifestation of Alzheimer's disease (AD). However, the associations among NPS, cognition, and AD biomarkers across the disease spectrum are unclear.

Objective: We analyzed cross-sectional mediation pathways between cerebrospinal fluid (CSF) biomarkers of AD (Aβ1-42, p-tau181), cognitive function, and NPS.

Methods: Primary models included 781 participants from the National Alzheimer's Coordinating Center (NACC) data set who had CSF analyzed for AD biomarkers using Lumipulse. NPS were assessed with the Neuropsychiatric Inventory Questionnaire (NPI-Q). We assessed cognition with the harmonized MMSE/MoCA, as well as neuropsychological tests sensitive to AD pathology: story recall, naming, animal fluency, and Trails B. The Clinical Dementia Rating (CDR®) scale assessed dementia severity. Mediation models were estimated with Kemeny metric covariance in a structural equation model framework, controlling for age, education, sex, and APOEɛ4.

Results: The sample was older adults (M = 73.85, SD = 6.68; 49.9% male, 390; 27.9% dementia, 218) who were predominantly white (n = 688, 88.1%). Higher p-tau181/Aβ1-42 ratio predicted higher NPI-Q, which was partially mediated by the MMSE/MoCA and, in a second model, story recall. No other pathway was statistically significant. Both the MMSE/MoCA and NPI-Q independently mediated the association between p-tau181/Aβ1-42 ratio and CDR global impairment. With dementia excluded, p-tau181/Aβ1-42 ratio was no longer associated with the NPI-Q.

Conclusions: NPS may be secondary to cognitive impairment and AD pathology through direct and indirect pathways. NPS independently predict dementia severity in AD. However, AD pathology likely plays less of a role in NPS in samples without dementia.

Keywords: Alzheimer’s disease; amyloid; biomarkers; cerebrospinal fluid; cognition; neuropsychiatric symptoms; p-tau.

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Conflict of interest statement

Conflict of Interest: Drs. Henrik Zetterberg and Ganesh Babulal are Editorial Board Members of this journal but were not involved in the peer-review process of this article nor had access to any information regarding its peer-review. MLA receives research support from Life Molecular Imaging Inc and Rainwater Charitable Foundation Inc. He has also received a single time honorarium from the Michael J Fox Foundation for services unrelated to this study. He received royalties from Oxford University Press Inc. SES served on advisory boards for Eisai. AEB receives research support from Bristol-Myers Squibb and Vox Neuro. He receives consulting monies from Eli Lilly and AbbVie. He receives royalties from Elsevier and Oxford University Press. HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Alzecure, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). None of this research, consulting, or royalties are related to this study.

Figures

Figure 1.
Figure 1.
Schema for Mediation Analyses. An initial structural equation model estimated the c path, which is the total direct effect of the predictors on the outcome. Next, the same direct path was estimated (c’) while simultaneously estimating mediation effects (indirect pathway a × b). The total effect is the sum of direct and indirect pathways for a predictor. Mediators included 1) harmonized MMSE/MoCA scores, or 2) harmonized neuropsychological tests: Story Recall, Naming, Animal Fluency, and Trail Making Test Part B. Note: 42-Residue-Long Amyloid β Isoform (Aβ1–42); Neuropsychiatric Inventory Questionnaire (NPI-Q); Tau Phosphorylated at Threonine-181 (p-tau181).
Figure 2a.
Figure 2a.
Mediation Model for Cerebrospinal Fluid Biomarkers, MMSE/MoCA scores, and Neuropsychiatric Symptoms. Note: Dashed lines represent indirect (mediation) pathways. Sample included NACC participants with Lumipulse-generated biomarker results and complete data on the MMSE/MoCA (n=760). Amyloid-β protein (Aβ); Mini-Mental State Examination or Montreal Cognitive Assessment (MMSE/MoCA); Neuropsychiatric Inventory Questionnaire (NPI-Q); Phosphorylated-tau (p-tau).
Fig 3 Figure 2b.
Fig 3 Figure 2b.
Mediation Model for Cerebrospinal Fluid Biomarkers, Neuropsychological Tests, and Neuropsychiatric Symptoms. Note: Dashed lines represent indirect (mediation) pathways. For simplicity, indirect pathways that are not statistically significant are omitted. Sample included NACC participants with Lumipulse-generated biomarker results and complete data on neuropsychological tests (n=713). Amyloid-β protein (Aβ); Boston Naming Test or Multilingual Naming Test (Naming); Logical Memory Delayed Recall or Craft Story Recall (Story Recall); Neuropsychiatric Inventory Questionnaire (NPI-Q); Phosphorylated-tau (p-tau); Trail Making Test Part B (TMT-B).
Fig 4 Figure 2c.
Fig 4 Figure 2c.
Mediation Model for Cerebrospinal Fluid Biomarkers, MMSE/MoCA scores, Neuropsychiatric Symptoms, and Dementia Severity. Note: Dashed lines represent indirect (mediation) pathways. Sample included NACC participants with Lumipulse-generated biomarker results and complete data on the MMSE/MoCA (n=760). Amyloid-β protein (Aβ); Clinical Dementia Rating (CDR®) Global Impairment Scores; Mini-Mental State Examination or Montreal Cognitive Assessment (MMSE/MoCA); Neuropsychiatric Inventory Questionnaire (NPI-Q); Phosphorylated-tau (p-tau).
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References

    1. Lyketsos CG, Carrillo MC, Ryan JM, Khachaturian AS, Trzepacz P, Amatniek J, Cedarbaum J, Brashear R, Miller DS (2011) Neuropsychiatric symptoms in Alzheimer’s disease. Alzheimers Dement J Alzheimers Assoc 7, 532–539. - PMC - PubMed
    1. Masters MC, Morris JC, Roe CM (2015) “Noncognitive” symptoms of early Alzheimer disease. Neurology 84, 617–622. - PMC - PubMed
    1. Šimić G, Babić Leko M, Wray S, Harrington CR, Delalle I, Jovanov-Milošević N, Bažadona D, Buée L, de Silva R, Di Giovanni G, Wischik CM, Hof PR (2017) Monoaminergic neuropathology in Alzheimer’s disease. Prog Neurobiol 151, 101–138. - PMC - PubMed
    1. Simic G, Stanic G, Mladinov M, Jovanov-Milosevic N, Kostovic I, Hof PR (2009) Does Alzheimer’s disease begin in the brainstem? Neuropathol Appl Neurobiol 35, 532–554. - PMC - PubMed
    1. Ismail Z, Smith EE, Geda Y, Sultzer D, Brodaty H, Smith G, Agüera-Ortiz L, Sweet R, Miller D, Lyketsos CG, ISTAART Neuropsychiatric Symptoms Professional Interest Area (2016) Neuropsychiatric symptoms as early manifestations of emergent dementia: Provisional diagnostic criteria for mild behavioral impairment. Alzheimers Dement J Alzheimers Assoc 12, 195–202. - PMC - PubMed

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