Cell-type-specific Alzheimer's disease polygenic risk scores are associated with distinct disease processes in Alzheimer's disease

Hyun-Sik Yang; Ling Teng; Daniel Kang; Vilas Menon; Tian Ge; Hilary K Finucane; Aaron P Schultz; Michael Properzi; Hans-Ulrich Klein; Lori B Chibnik; Julie A Schneider; David A Bennett; Timothy J Hohman; Richard P Mayeux; Keith A Johnson; Philip L De Jager; Reisa A Sperling

doi:10.1038/s41467-023-43132-2

Cell-type-specific Alzheimer's disease polygenic risk scores are associated with distinct disease processes in Alzheimer's disease

Nat Commun. 2023 Nov 30;14(1):7659. doi: 10.1038/s41467-023-43132-2.

Authors

Hyun-Sik Yang^{1

2

3

4}, Ling Teng^{5

6}, Daniel Kang⁷, Vilas Menon^{8

9}, Tian Ge^{10

6

11

12}, Hilary K Finucane^{10

6

13}, Aaron P Schultz^{7

10}, Michael Properzi⁷, Hans-Ulrich Klein^{8

9}, Lori B Chibnik^{7

6

14}, Julie A Schneider¹⁵, David A Bennett¹⁵, Timothy J Hohman¹⁶, Richard P Mayeux⁹, Keith A Johnson^{5

7

10

17}, Philip L De Jager^{8

9}, Reisa A Sperling^{5

7

10}

Affiliations

¹ Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA. [email protected].
² Department of Neurology, Massachusetts General Hospital, Boston, MA, USA. [email protected].
³ Harvard Medical School, Boston, MA, USA. [email protected].
⁴ Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected].
⁵ Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.
⁶ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁷ Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
⁸ Center for Translational & Computational Neuroimmunology, Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA.
⁹ Department of Neurology and the Taub Institute for the Study of Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY, USA.
¹⁰ Harvard Medical School, Boston, MA, USA.
¹¹ Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
¹² Center for Precision Psychiatry, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
¹³ Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
¹⁴ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹⁵ Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
¹⁶ Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁷ Department of Radiology, Massachusetts General Hospital, Boston, MA, USA.

Abstract

Many of the Alzheimer's disease (AD) risk genes are specifically expressed in microglia and astrocytes, but how and when the genetic risk localizing to these cell types contributes to AD pathophysiology remains unclear. Here, we derive cell-type-specific AD polygenic risk scores (ADPRS) from two extensively characterized datasets and uncover the impact of cell-type-specific genetic risk on AD endophenotypes. In an autopsy dataset spanning all stages of AD (n = 1457), the astrocytic ADPRS affected diffuse and neuritic plaques (amyloid-β), while microglial ADPRS affected neuritic plaques, microglial activation, neurofibrillary tangles (tau), and cognitive decline. In an independent neuroimaging dataset of cognitively unimpaired elderly (n = 2921), astrocytic ADPRS was associated with amyloid-β, and microglial ADPRS was associated with amyloid-β and tau, connecting cell-type-specific genetic risk with AD pathology even before symptom onset. Together, our study provides human genetic evidence implicating multiple glial cell types in AD pathophysiology, starting from the preclinical stage.

MeSH terms

Aged
Alzheimer Disease* / metabolism
Amyloid beta-Peptides / metabolism
Humans
Neurofibrillary Tangles / genetics
Neurofibrillary Tangles / metabolism
Plaque, Amyloid / metabolism
Risk Factors
tau Proteins / genetics
tau Proteins / metabolism

Substances

tau Proteins
Amyloid beta-Peptides

Abstract

MeSH terms

Substances

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