Key papers

The studies that define what we know

Grouped by topic. Each link opens the paper.

Genetics and risk

Corder EH, Saunders AM, Strittmatter WJ, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 1993. Read
First showed that risk rises and age at onset falls with each ε4 copy.
Strittmatter WJ, Saunders AM, Schmechel D, et al. Apolipoprotein E: high-avidity binding to β-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. PNAS 1993. Read
Linked APOE to Alzheimer’s and to amyloid binding.
Farrer LA, Cupples LA, Haines JL, et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease: a meta-analysis. JAMA 1997. Read
Classic estimates of risk by genotype, age, sex and ancestry.
Genin E, Hannequin D, Wallon D, et al. APOE and Alzheimer disease: a major gene with semi-dominant inheritance. Molecular Psychiatry 2011. Read
Lifetime risk estimates for ε4/ε4.
Belloy ME, Andrews SJ, Le Guen Y, et al. APOE genotype and Alzheimer disease risk across age, sex, and population ancestry. JAMA Neurology 2023. Read
Large modern estimates across ancestries.
Fortea J, Pegueroles J, Alcolea D, et al. APOE4 homozygosity represents a distinct genetic form of Alzheimer’s disease. Nature Medicine 2024. Read
Near-full penetrance of pathology and predictable onset in ε4/ε4.

Greenberg SM, Rebeck GW, Vonsattel JP, Gomez-Isla T, Hyman BT. Apolipoprotein E ε4 and cerebral hemorrhage associated with amyloid angiopathy. Annals of Neurology 1995. Read
About 13-fold higher odds of moderate to severe amyloid angiopathy with two ε4 copies.
Jansen WJ, Ossenkoppele R, Knol DL, et al. Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis. JAMA 2015. Read
Amyloid positivity by age and APOE genotype in people without dementia.
Montagne A, Nation DA, Sagare AP, et al. APOE4 leads to blood–brain barrier dysfunction predicting cognitive decline. Nature 2020. Read
A vascular route for APOE4 effects, independent of amyloid and tau.
Independent effects of white matter lesion volume and APOE ε4 on ARIA-H in the A4 Study. Alzheimer’s & Dementia 2025. Read
ε4/ε4 predicts accumulating small bleeds in people without symptoms.

APOE ε4 carriership determines a faster plasma p-tau217 progression in Aβ-positive individuals. Alzheimer’s & Dementia 2025. Read
In amyloid-positive people, p-tau217 rises faster in ε4 carriers (TRIAD and ADNI).
APOE4 impact on soluble and insoluble tau pathology is mostly influenced by amyloid-β. 2025. Read
A contrasting view: in BioFINDER and WRAP, APOE4 effects on p-tau217 largely run through amyloid.

Shi Y, Yamada K, Liddelow SA, et al. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature 2017. Read
APOE4 worsens tau damage, partly through microglia.
Lin YT, Seo J, Gao F, et al. APOE4 causes widespread molecular and cellular alterations associated with Alzheimer’s disease phenotypes in human iPSC-derived brain cell types. Neuron 2018. Read
Matched human cell models of APOE3 versus APOE4.
Blanchard JW, Akay LA, Davila-Velderrain J, et al. APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes. Nature 2022. Read
Cholesterol handling and myelin loss in human ε4 brains and cells.
Haney MS, Pálovics R, Munson CN, et al. APOE4/4 is linked to damaging lipid droplets in Alzheimer’s disease microglia. Nature 2024. Read
Lipid-laden microglia in ε4/ε4 brains.

Arboleda-Velasquez JF, Lopera F, O’Hare M, et al. Resistance to autosomal dominant Alzheimer’s disease in an APOE3 Christchurch homozygote: a case report. Nature Medicine 2019. Read
A rare APOE variant that appears to protect against early-onset disease, pointing to APOE as a drug target.
Le Guen Y, et al. Association of rare APOE missense variants V236E and R251G with risk of Alzheimer disease. JAMA Neurology 2022. Read
R251G, inherited together with ε4, roughly halves its risk effect, showing that ε4 risk can be offset.
Nelson MR, et al. The APOE-R136S mutation protects against APOE4-driven Tau pathology, neurodegeneration and neuroinflammation. Nature Neuroscience 2023. Read
The Christchurch change blocks APOE4-driven tau damage in mice, supporting APOE-directed therapies.

Belloy ME, Napolioni V, Greicius MD. A quarter century of APOE and Alzheimer’s disease: progress to date and the path forward. Neuron 2019. Read
Broad review of APOE genetics and biology.
Yamazaki Y, Zhao N, Caulfield TR, Liu CC, Bu G. Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. Nature Reviews Neurology 2019. Read
Mechanisms and therapeutic approaches.
Hampel H, Elhage A, Cho M, Apostolova LG, Nicoll JAR, Atri A. Amyloid-related imaging abnormalities (ARIA): radiological, biological and clinical characteristics. Brain 2023. Read
What ARIA is, how it is detected, and why ε4/ε4 raises risk.

UsAgainstAlzheimer’s. FDA Patient Listening Session: Alzheimer’s disease and APOE ε4 homozygotes. Summary, July 2025. Read
APOE ε4 homozygotes describe their needs and the lack of treatment options to FDA staff.

van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in early Alzheimer’s disease. New England Journal of Medicine 2023. Read
Clarity AD; ARIA rates reported by APOE genotype.
Sims JR, Zimmer JA, Evans CD, et al. Donanemab in early symptomatic Alzheimer disease: the TRAILBLAZER-ALZ 2 randomized clinical trial. JAMA 2023. Read
ARIA rates reported by APOE genotype.
Efficacy and safety of oral valiltramiprosate in APOE4/4 homozygotes with early AD: topline results from the APOLLOE4 Phase 3 trial. 2025. Read
The first completed Phase 3 trial run only in ε4/ε4.