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  • Review Article
  • Published:

Multifaceted roles of APOE in Alzheimer disease

Abstract

For the past three decades, apolipoprotein E (APOE) has been known as the single greatest genetic modulator of sporadic Alzheimer disease (AD) risk, influencing both the average age of onset and the lifetime risk of developing AD. The APOEε4 allele significantly increases AD risk, whereas the ε2 allele is protective relative to the most common ε3 allele. However, large differences in effect size exist across ethnoracial groups that are likely to depend on both global genetic ancestry and local genetic ancestry, as well as gene–environment interactions. Although early studies linked APOE to amyloid-β — one of the two culprit aggregation-prone proteins that define AD — in the past decade, mounting work has associated APOE with other neurodegenerative proteinopathies and broader ageing-related brain changes, such as neuroinflammation, energy metabolism failure, loss of myelin integrity and increased blood–brain barrier permeability, with potential implications for longevity and resilience to pathological protein aggregates. Novel mouse models and other technological advances have also enabled a number of therapeutic approaches aimed at either attenuating the APOEε4-linked increased AD risk or enhancing the APOEε2-linked AD protection. This Review summarizes this progress and highlights areas for future research towards the development of APOE-directed therapeutics.

Key points

  • The risk of Alzheimer disease associated with the APOE genotype is modulated by global and local genetic ancestries, other genetic risk loci and the lifetime exposome of an individual.

  • APOE missense mutations are providing key insights into the pathophysiology of the classic three APOE isoforms.

  • The APOE genotype might modulate the risk of other neurodegenerative diseases by influencing the pathobiology of their culprit aggregation-prone proteins.

  • The APOE isoforms affect a wide range of molecular and cellular functions in multiple brain cell types via cell-autonomous and non-autonomous mechanisms.

  • Several strategies to target APOE therapeutically have shown efficacy in preclinical studies and hold promise for translation into clinical trials.

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Fig. 1: Schematic illustration of structural and functional regions of APOE.
Fig. 2: Multifaceted roles of APOE in Alzheimer disease pathophysiology.
Fig. 3: Therapeutic approaches targeting APOE.

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Acknowledgements

NIH/NIA (2RF1AG047644 to R.J.J. and B.T.H., 1RF1AG073236 to R.J.J., R56AG080525 to R.J.J. and B.T.H., 5U01NS111671 to B.T.H., 5K08AG064039 to A.S.-P. and P30AG062421 to A.S.-P. and B.T.H.), The Karen Toffler Charitable Trust (to A.S.-P. and B.T.H.), The Harrison Gardner Jr Innovation Award (to A.S.-P.) and The JPB Foundation (to B.T.H.).

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R.J.J. and A.S.-P. reviewed the literature and wrote the manuscript draft. B.T.H. reviewed and edited the draft.

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Correspondence to Bradley T. Hyman or Alberto Serrano-Pozo.

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Competing interests

R.J.J. declares no competing interest. B.T.H. serves on the SAB of Latus and of Dewpoint and has a family member who is employed by Novartis. A.S.-P. has signed a material transfer agreement with Ionis Pharmaceuticals, Inc.

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Glossary

Adeno-associated viral vectors

Small non-pathogenic viruses that can infect cells and deliver a small single-stranded DNA cargo of <5 kb. This DNA is then transcribed and translated by the target cell generating the protein of interest.

Antisense oligonucleotides

(ASOs). ASOs are short RNA transcripts that are synthesized to be complementary to the sequence of a specific RNA target with the goals of preventing its translation into the protein and promoting its degradation. ASOs are often chemically modified to increase stability (resistance to degradation by RNAse enzymes) and enhance cellular uptake.

ATP-binding cassette (ABC) transporters such as ABCA1 and ABCG

Transmembrane proteins that transport cholesterol and phospholipids out of the cell to lipid-poor apolipoproteins such as APOE.

Cell-autonomous and non-autonomous

Cell-autonomous effects are those that a perturbed cell exerts on itself or other cells of the same type. Cell-non-autonomous effects are those that a perturbed cell type (for example, astrocytes) exerts on other cell types (for example, microglia), either directly or via its secretome.

Exposome

Set of non-genetic risk factors that can impact the risk of developing certain disease (for example, cancer or Alzheimer disease) of an individual, including cumulative lifetime environmental exposures and lifestyle habits.

Global genetic ancestry

Genetic variability across the genome that determines the race and ethnicity of an individual based on the relative proportions of various population ancestries (for example, European, African, Amerindian or East Asian), not always coincident with self-reported categories.

Human-inducible pluripotent stem cells

(hiPSCs). Cells derived from skin or blood cells after reprogramming them back to a pluripotent embryonic-like state, which can be then differentiated to recapitulate any main brain cell type, although often embryonic or fetal in nature. Isogenic versions that are genetically identical except for the gene of interest (for example, APOE) can be generated with CRISPR–Cas9 technology.

Local genetic ancestry

Genetic variability surrounding a specific locus in the genome of an individual, which can include zero, one or two copies of an allele from each ancestral population, thereby affecting the expression of a gene of interest (for example, APOE).

Polygenic risk score

(PRS). An estimate of the genetic relative risk of an individual to develop a certain disease, calculated by applying the summary statistics from meta-analysis of genome-wide association studies involving thousands of cases and controls to the genetic variants of that particular individual.

Triggering receptor expressed on myeloid cells 2

(TREM2). A receptor expressed on the cell surface of immune cells, including microglia, that activates phagocytosis in response to extracellular stress signals (for example, Aβ) through the TYROBP–DAP12 signalling pathway.

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Jackson, R.J., Hyman, B.T. & Serrano-Pozo, A. Multifaceted roles of APOE in Alzheimer disease. Nat Rev Neurol (2024). https://doi.org/10.1038/s41582-024-00988-2

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