Disentangling the Genetic Underpinnings of Neuropsychiatric Symptoms in Alzheimer's Disease in the Alzheimer's Disease Sequencing Project: Study Design and Methodology

Overview

Journal Alzheimers Dement (Amst)

Date 2024 Aug 26

PMID 39183746

Authors

Nicholas R Ray

Ajneesh Kumar

Andrew Zaman

Pamela Del Rosario

Pedro R Mena

Masood Manoochehri

Colin Stein

Alyssa N De Vito

Robert A Sweet

Timothy J Hohman

Michael L Cuccaro

Gary W Beecham

Edward D Huey

Christiane Reitz

Affiliations

Soon will be listed here.

Abstract

Introduction: Neuropsychiatric symptoms (NPS) are highly prevalent in Alzheimer's disease (AD). There are no effective treatments targeting these symptoms.

Methods: To facilitate identification of causative mechanistic pathways, we initiated an effort (NIH: U01AG079850) to collate, harmonize, and analyze all available NPS data (≈ 100,000 samples) of diverse ancestries with whole-genome sequencing data from the Alzheimer's Disease Sequencing Project (ADSP).

Results: This study will generate a genomic resource for Alzheimer's disease with both harmonized whole-genome sequencing and NPS phenotype data that will be publicly available through NIAGADS. Primary analyses will (1) identify novel genetic risk factors associated with NPS in AD, (2) characterize the shared genetic architecture of NPS in AD and primary psychiatric disorders, and (3) assess the role of ancestry effects in the etiology of NPS in AD.

Discussion: Expansion of the ADSP to harmonize and refine NPS phenotypes coupled with the proposed core analyses will lay the foundation to disentangle the molecular mechanisms underlying these detrimental symptoms in AD in diverse populations.

Highlights: Neuropsychiatric symptoms (NPS) are highly prevalent in Alzheimer's disease (AD).There are no effective treatments targeting NPS in AD.The current effort aims to collate, harmonize, and analyze all NPS data from the Alzheimer's Disease Sequencing Project.Core analyses will identify underlying genetic factors and mechanistic pathways.The harmonized genomic and phenotypic data from this initiative will be available through National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site.

Citing Articles

Identification of therapeutic targets for Alzheimer's Disease Treatment using bioinformatics and machine learning.

Xie Z, Situ Y, Deng L, Liang M, Ding H, Guo Z Sci Rep. 2025; 15(1):3888.

PMID: 39890844 PMC: 11785788. DOI: 10.1038/s41598-025-88134-w.

References

Devanand D, Lee J, Luchsinger J, Manly J, Marder K, Mayeux R . Lessons from epidemiologic research about risk factors, modifiers, and progression of late onset Alzheimer's Disease in New York City at Columbia University Medical Center. J Alzheimers Dis. 2012; 33 Suppl 1:S447-55. PMC: 4149254. DOI: 10.3233/JAD-2012-129041. View

Chen J, Borson S, Scanlan J . Stage-specific prevalence of behavioral symptoms in Alzheimer's disease in a multi-ethnic community sample. Am J Geriatr Psychiatry. 2000; 8(2):123-33. View

Huang M, Lee W, Yeh Y, Liao Y, Wang S, Yang Y . Genetics of neuropsychiatric symptoms in patients with Alzheimer's disease: A 1-year follow-up study. Psychiatry Clin Neurosci. 2020; 74(12):645-651. DOI: 10.1111/pcn.13150. View

Huey E, Lee S, Brickman A, Manoochehri M, Griffith E, Devanand D . Neuropsychiatric effects of neurodegeneration of the medial versus lateral ventral prefrontal cortex in humans. Cortex. 2015; 73:1-9. PMC: 4689656. DOI: 10.1016/j.cortex.2015.08.002. View

Bacanu S, Devlin B, Chowdari K, DeKosky S, Nimgaonkar V, Sweet R . Heritability of psychosis in Alzheimer disease. Am J Geriatr Psychiatry. 2005; 13(7):624-7. DOI: 10.1176/appi.ajgp.13.7.624. View

Lanctot K, Amatniek J, Ancoli-Israel S, Arnold S, Ballard C, Cohen-Mansfield J . Neuropsychiatric signs and symptoms of Alzheimer's disease: New treatment paradigms. Alzheimers Dement (N Y). 2017; 3(3):440-449. PMC: 5651439. DOI: 10.1016/j.trci.2017.07.001. View

Mintzer J, Lanctot K, Scherer R, Rosenberg P, Herrmann N, van Dyck C . Effect of Methylphenidate on Apathy in Patients With Alzheimer Disease: The ADMET 2 Randomized Clinical Trial. JAMA Neurol. 2021; 78(11):1324-1332. PMC: 8477302. DOI: 10.1001/jamaneurol.2021.3356. View

van Dyck C, Swanson C, Aisen P, Bateman R, Chen C, Gee M . Lecanemab in Early Alzheimer's Disease. N Engl J Med. 2022; 388(1):9-21. DOI: 10.1056/NEJMoa2212948. View

Lyketsos C, Carrillo M, Ryan J, Khachaturian A, Trzepacz P, Amatniek J . Neuropsychiatric symptoms in Alzheimer's disease. Alzheimers Dement. 2011; 7(5):532-9. PMC: 3299979. DOI: 10.1016/j.jalz.2011.05.2410. View

10.

Murray P, Kumar S, Demichele-Sweet M, Sweet R . Psychosis in Alzheimer's disease. Biol Psychiatry. 2013; 75(7):542-52. PMC: 4036443. DOI: 10.1016/j.biopsych.2013.08.020. View

11.

Shah C, Demichele-Sweet M, Sweet R . Genetics of psychosis of Alzheimer disease. Am J Med Genet B Neuropsychiatr Genet. 2016; 174(1):27-35. PMC: 5154859. DOI: 10.1002/ajmg.b.32413. View

12.

Peters M, Schwartz S, Han D, Rabins P, Steinberg M, Tschanz J . Neuropsychiatric symptoms as predictors of progression to severe Alzheimer's dementia and death: the Cache County Dementia Progression Study. Am J Psychiatry. 2015; 172(5):460-5. PMC: 4416978. DOI: 10.1176/appi.ajp.2014.14040480. View

13.

Salazar R, Dwivedi A, Royall D . Cross-Ethnic Differences in the Severity of Neuropsychiatric Symptoms in Persons With Mild Cognitive Impairment and Alzheimer's Disease. J Neuropsychiatry Clin Neurosci. 2016; 29(1):13-21. DOI: 10.1176/appi.neuropsych.15120423. View

14.

Sink K, Holden K, Yaffe K . Pharmacological treatment of neuropsychiatric symptoms of dementia: a review of the evidence. JAMA. 2005; 293(5):596-608. DOI: 10.1001/jama.293.5.596. View

15.

Demichele-Sweet M, Klei L, Creese B, Harwood J, Weamer E, McClain L . Genome-wide association identifies the first risk loci for psychosis in Alzheimer disease. Mol Psychiatry. 2021; 26(10):5797-5811. PMC: 8660923. DOI: 10.1038/s41380-021-01152-8. View

16.

Lewinsohn P, Seeley J, Roberts R, Allen N . Center for Epidemiologic Studies Depression Scale (CES-D) as a screening instrument for depression among community-residing older adults. Psychol Aging. 1997; 12(2):277-87. DOI: 10.1037//0882-7974.12.2.277. View

17.

Borroni B, Grassi M, Agosti C, Costanzi C, Archetti S, Franzoni S . Genetic correlates of behavioral endophenotypes in Alzheimer disease: role of COMT, 5-HTTLPR and APOE polymorphisms. Neurobiol Aging. 2005; 27(11):1595-603. DOI: 10.1016/j.neurobiolaging.2005.09.029. View

18.

Devanand D, Jacobs D, Tang M, Sano M, Marder K, Bell K . The course of psychopathologic features in mild to moderate Alzheimer disease. Arch Gen Psychiatry. 1997; 54(3):257-63. DOI: 10.1001/archpsyc.1997.01830150083012. View

19.

Stern Y, Stallard E, Kinosian B, Zhu C, Cosentino S, Jin Z . Validation and demonstration of a new comprehensive model of Alzheimer's disease progression. Alzheimers Dement. 2021; 17(10):1698-1708. PMC: 8818260. DOI: 10.1002/alz.12336. View

20.

Antonsdottir I, Creese B, Klei L, Demichele-Sweet M, Weamer E, Garcia-Gonzalez P . Genetic associations with psychosis and affective disturbance in Alzheimer's disease. Alzheimers Dement (N Y). 2024; 10(2):e12472. PMC: 11114588. DOI: 10.1002/trc2.12472. View