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. 2023 Apr 28;18(4):e0281440.
doi: 10.1371/journal.pone.0281440. eCollection 2023.

What does heritability of Alzheimer's disease represent?

Emily Baker  1   2 , Ganna Leonenko  1   2 , Karl Michael Schmidt  3 , Matthew Hill  2 , Amanda J Myers  4 , Maryam Shoai  5 , Itziar de Rojas  6   7 , Niccoló Tesi  8   9   10 , Henne Holstege  8   9   10   11 , Wiesje M van der Flier  9   11 , Yolande A L Pijnenburg  9   11 , Agustin Ruiz  6   7 , John Hardy  5 , Sven van der Lee  8   9   11 , Valentina Escott-Price  1
Affiliations

What does heritability of Alzheimer's disease represent?

Emily Baker et al. PLoS One. .

Erratum in

  • Correction: What does heritability of Alzheimer's disease represent?
    Baker E, Leonenko G, Schmidt KM, Hill M, Myers AJ, Shoai M, de Rojas I, Tesi N, Holstege H, van der Flier WM, Pijnenburg YAL, Ruiz A, Hardy J, van der Lee S, Escott-Price V. Baker E, et al. PLoS One. 2025 May 12;20(5):e0323769. doi: 10.1371/journal.pone.0323769. eCollection 2025. PLoS One. 2025. PMID: 40354321 Free PMC article.

Abstract

Introduction: Both late-onset Alzheimer's disease (AD) and ageing have a strong genetic component. In each case, many associated variants have been discovered, but how much missing heritability remains to be discovered is debated. Variability in the estimation of SNP-based heritability could explain the differences in reported heritability.

Methods: We compute heritability in five large independent cohorts (N = 7,396, 1,566, 803, 12,528 and 3,963) to determine whether a consensus for the AD heritability estimate can be reached. These cohorts vary by sample size, age of cases and controls and phenotype definition. We compute heritability a) for all SNPs, b) excluding APOE region, c) excluding both APOE and genome-wide association study hit regions, and d) SNPs overlapping a microglia gene-set.

Results: SNP-based heritability of late onset Alzheimer's disease is between 38 and 66% when age and genetic disease architecture are correctly accounted for. The heritability estimates decrease by 12% [SD = 8%] on average when the APOE region is excluded and an additional 1% [SD = 3%] when genome-wide significant regions were removed. A microglia gene-set explains 69-84% of our estimates of SNP-based heritability using only 3% of total SNPs in all cohorts.

Conclusion: The heritability of neurodegenerative disorders cannot be represented as a single number, because it is dependent on the ages of cases and controls. Genome-wide association studies pick up a large proportion of total AD heritability when age and genetic architecture are correctly accounted for. Around 13% of SNP-based heritability can be explained by known genetic loci and the remaining heritability likely resides around microglial related genes.

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Conflict of interest statement

The authors have read the journal’s policy and have the following competing interests: MH hold shares in Vertex Pharmaceuticals. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents or patents, products in development or marketed products associated with this research to declare.

Figures

Fig 1
Fig 1
Heritability Estimates for AD prevalence of 2%, 5%, 15% in A) ADC with amyloid confirmed AD cases, B) GR@ACE, C) KRONOS/Tgen, D) ADC with clinical AD cases, E) ROSMAP/MSBB/MAYO, F) UKBB AD cases with controls aged 70+. Two models are considered: estimates adjusted for PCs and sex and PCs, sex and age.
See this image and copyright information in PMC

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