An ABCA1 missense variant decreases cholesterol efflux and confers Alzheimer's disease risk in the Chinese population

Sze Kei Liu; Han Cao; Xin Yang; Xiaopu Zhou; Yu Chen; Wing-Yu Fu; San Yuen Chan; Fanny Cf Ip; Kin Y Mok; Vincent Ct Mok; Timothy Cy Kwok; John Hardy; Amy Ky Fu; Nancy Y Ip

doi:10.1177/13872877251350722

An ABCA1 missense variant decreases cholesterol efflux and confers Alzheimer's disease risk in the Chinese population

J Alzheimers Dis. 2025 Jul 1:13872877251350722. doi: 10.1177/13872877251350722. Online ahead of print.

Authors

Sze Kei Liu¹, Han Cao^{1

2}, Xin Yang¹, Xiaopu Zhou^{1

2}, Yu Chen^{1

3

4

5}, Wing-Yu Fu^{1

2}, San Yuen Chan¹, Fanny Cf Ip^{1

2

3}, Kin Y Mok^{1

2

6}, Vincent Ct Mok⁷, Timothy Cy Kwok⁸, John Hardy^{2

6

9}, Amy Ky Fu^{1

2

3

5}, Nancy Y Ip^{1

2

3

5}

Affiliations

¹ Division of Life Science, State Key Laboratory of Molecular Neuroscience and Molecular Neuroscience Center, The Hong Kong University of Science and Technology, HKSAR, China.
² InnoHK Hong Kong Center for Neurodegenerative Diseases, HKSAR, China.
³ Guangdong Provincial Key Laboratory of Brain Science, Disease and Drug Development, Shenzhen-Hong Kong Institute of Brain Science, HKUST Shenzhen Research Institute, Shenzhen, China.
⁴ The Brain Cognition and Brain Disease Institute, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
⁵ SIAT-HKUST Joint Laboratory for Brain Science, Shenzhen, China.
⁶ Department of Neurodegenerative Disease, Queen Square Institute of Neurology, University College London, London, UK.
⁷ Lau Tat-chuen Research Centre of Brain Degenerative Diseases in Chinese, Gerald Choa Neuroscience Institute, Lui Che Woo Institute of Innovative Medicine, Li Ka Shing Institute of Health Sciences, Division of Neurology, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, HKSAR, China.
⁸ Therese Pei Fong Chow Research Centre for Prevention of Dementia, Division of Geriatrics, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, HKSAR, China.
⁹ UK Dementia Research Institute, University College London, London, UK.

PMID: 40598857
DOI: 10.1177/13872877251350722

Abstract

BackgroundGenetic studies have revealed that single-nucleotide polymorphisms (SNPs) of ABCA1 are associated with Alzheimer's disease (AD) risk. However, their AD-related effects in non-European populations are not well studied. Moreover, the functional implications of these AD-associated SNPs remain unclear.ObjectiveWe examined the AD associations of ABCA1 SNPs in the Chinese population and investigated the underlying mechanisms whereby these SNPs modulate AD risk.MethodsWe conducted a genetic analysis in a Hong Kong Chinese AD cohort (n = 332 patients with AD, n = 316 normal controls). Specifically, we analyzed 6 independent ABCA1 SNPs reported to be associated with AD risk in populations of European descent. To investigate the effects of these SNPs on ABCA1 protein function and brain molecular phenotypes, we analyzed cholesterol efflux in human glioblastoma cells as well as the associations between the AD risk SNPs and brain transcriptomic profiles, respectively.ResultsThe ABCA1 coding SNP, rs2230806 (p.R219 K), was significantly associated with AD in the Chinese population, specifically in females (odds ratio [95% confidence interval] = 1.65 [1.16-2.33]). Notably, human glioblastoma cells expressing the ABCA1 R219 K showed a 17% cholesterol efflux reduction (p < 0.001). Moreover, ABCA1 rs2230806 was associated with changes in the expression of oligodendrocyte genes involved in myelination in the brain in females.ConclusionsWe identified a significant AD risk ABCA1 coding variant in the Chinese population and demonstrated its effects on cholesterol efflux and brain molecular phenotypes. These results shed light on the genetic basis whereby an ABCA1 genetic variant contributes to AD pathogenesis.

Keywords: ABCA1; Alzheimer's disease; genetics; oligodendrocytes; transcriptomic analysis.