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Genomics of Alzheimer’s disease implicates the innate and adaptive immune systems

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Abstract

Alzheimer’s disease (AD) is a chronic neurodegenerative disease characterised by cognitive impairment, behavioural alteration, and functional decline. Over 130 AD-associated susceptibility loci have been identified by genome-wide association studies (GWAS), while whole genome sequencing (WGS) and whole exome sequencing (WES) studies have identified AD-associated rare variants. These variants are enriched in APOE, TREM2, CR1, CD33, CLU, BIN1, CD2AP, PILRA, SCIMP, PICALM, SORL1, SPI1, RIN3, and more genes. Given that aging is the single largest risk factor for late-onset AD (LOAD), the accumulation of somatic mutations in the brain and blood of AD patients have also been explored. Collectively, these genetic findings implicate the role of innate and adaptive immunity in LOAD pathogenesis and suggest that a systemic failure of cell-mediated amyloid-β (Aβ) clearance contributes to AD onset and progression. AD-associated variants are particularly enriched in myeloid-specific regulatory regions, implying that AD risk variants are likely to perturbate the expression of myeloid-specific AD-associated genes to interfere Aβ clearance. Defective phagocytosis, endocytosis, and autophagy may drive Aβ accumulation, which may be related to naturally-occurring antibodies to Aβ (Nabs-Aβ) produced by adaptive responses. Passive immunisation is providing efficiency in clearing Aβ and slowing cognitive decline, such as aducanumab, donanemab, and lecanemab (ban2401). Causation of AD by impairment of the innate immunity and treatment using the tools of adaptive immunity is emerging as a new paradigm for AD, but immunotherapy that boosts the innate immune functions of myeloid cells is highly expected to modulate disease progression at asymptomatic stage.

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All data analysed and summarised during this study were included in this article and its supplementary information files.

Notes

  1. www.Alzforum.org.

  2. www.genecards.org.

  3. https://www.alz.org/alzheimers-dementia/treatments/aducanumab.

  4. https://www.alzforum.org/therapeutics/donanemab.

  5. https://investor.lilly.com/news-releases/news-release-details/lillys-donanemab-receives-us-fdas-breakthrough-therapy.

  6. https://investors.biogen.com/news-releases/news-release-details/eisai-and-biogen-inc-announce-us-fda-grants-breakthrough-therapy.

Abbreviations

AD:

Alzheimer's disease

ADNI:

Alzheimer’s Disease Neuroimaging Initiative

ADSP:

Alzheimer’s Disease Sequencing Project

APC:

Antigen-presenting cells

APOE:

Apolipoprotein E

APP:

Amyloid precursor protein

ATAC-seq:

Transposase-accessible chromatin using sequencing

AUC:

Area under curve

Aβ:

β-Amyloid

Aβ1-40 :

Aβ ending in residue 40

Aβ1-42 :

Aβ ending in residue 42

BBB:

Blood–brain barrier

cDNA:

Complementary DNA

ChIP-seq:

Chromatin immunoprecipitation sequencing

CN:

Cognitively normal

CNS:

Central nervous system

CNV:

Copy number variants

CSF:

Cerebrospinal fluid

DAM:

Disease-associated microglia

DMT:

Disease-modifying treatments

DSB:

Double-strand breaks

EOAD:

Early-onset Alzheimer's disease

eQTL:

Expression quantitative trait loci

FDA:

Food and Drug Administration

GWAS:

Genome-wide association studies

GWAX:

Genome-wide association studies by proxy

HSV-1:

Herpes simplex virus type 1

INDEL:

Insertions and deletions

iPSC:

Induced pluripotent stem cells

IRM:

Interferon-responsive microglia

ISF:

Interstitial fluid

ITAM:

Immunoreceptor tyrosine‐based activation motif

ITIM:

Immunoreceptor tyrosine-based inhibitory motif

LD:

Linkage disequilibrium

LOAD:

Late-onset Alzheimer's disease

LOF:

Loss-of-function

MAF:

Minor allele frequency

MAPK:

Mitogen-activated protein kinase

MCI:

Mild cognitive impairment

MHC:

Major histocompatibility complex

NAbs-Aβ:

Naturally-occurring antibodies to β-amyloid

NFT:

Neurofibrillary tangles

NF-κB:

Nuclear factor kappa light chain enhancer of activated B cells

OR:

Odds ratio

PET:

Positron emission tomography

PFC:

Prefrontal cortex

PI3K/Akt:

Phosphoinositide-3-kinase/Protein kinase B

PLAC-seq:

Proximity ligation-assisted ChIP-seq

PRR:

Pattern recognition receptors

PRS:

Polygenic risk score

PSEN1:

Presenilin 1

PSEN2:

Presenilin 2

p-tau:

Hyperphosphorylated tau

ROS:

Reactive oxygen species

sCR1:

Soluble CR1

scRNA-seq:

Single-cell RNA sequencing

SH2:

Src homology 2

Siglec:

Sialic acid-binding immunoglobulin-like lectin

SNP:

Single nucleotide polymorphisms

snRNA-seq:

Single-nucleus RNA sequencing

SNV:

Single nucleotide variants

SSB:

Single-strand breaks

sTREM2:

Soluble TREM2

TF:

Transcription factor

TGN:

Trans-Golgi network

TIR:

Toll/interleukin-1 receptor

TLR:

Toll-like receptors

UKB:

United Kingdom Biobank

VAF:

Variant allelic frequency

WES:

Whole-exome sequencing

WGS:

Whole-genome sequencing

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Acknowledgements

The authors were grateful to the University of Melbourne for providing open access to PubMed for literature reading.

Funding

This work was supported by the Melbourne Research Scholarship provided by the Florey Institute of Neuroscience and Mental Health, the University of Melbourne, and Qiankang Life Science Melbourne R&D Centre.

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  1. The Florey Institute, The University of Melbourne, 30 Royal Parade, Parkville, VIC, 3052, Australia

    Yihan Li, Luke A. Miles, James S. Wiley, Xin Huang, Colin L. Masters & Ben J. Gu

  2. Centre for Precision Health, Edith Cowan University, 270 Joondalup Dr, Joondalup, WA, 6027, Australia

    Simon M. Laws

  3. Collaborative Genomics and Translation Group, School of Medical and Health Sciences, Edith Cowan University, 270 Joondalup Dr, Joondalup, WA, 6027, Australia

    Simon M. Laws

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Li, Y., Laws, S.M., Miles, L.A. et al. Genomics of Alzheimer’s disease implicates the innate and adaptive immune systems. Cell. Mol. Life Sci. 78, 7397–7426 (2021). https://doi.org/10.1007/s00018-021-03986-5

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