# Field-specific reporting

Please select the one below that is the best fit for your research. If you are not sure, read the appropriate sections before making your selection.

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Life sciences

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Behavioural & social sciences

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Ecological, evolutionary & environmental sciences

For a reference copy of the document with all sections, see [nature.com/documents/nr-reporting-summary-flat.pdf](https://nature.com/documents/nr-reporting-summary-flat.pdf)

# Life sciences study design

All studies must disclose on these points even when the disclosure is negative.

Sample size

Raw data used in this study was collected by the EADB consortia and summary statistics were recruited by external sources used for meta-analysis. Sample size was not pre-determined and was chosen based on all known available cohorts with relevant data collected to date, after quality control steps were performed in each cohort (described in detail in Supplementary Information) in particular to avoid any sample duplications. The sample size was calculated as the number of individuals summed across all studies in the meta-analysis, N=487,511.

Data exclusions

We excluded samples and variants based on standard quality control procedures for GWAS (Samples: Heterozygosity and missingness, Population outliers, Sex-check, Relatedness, Possibly problematic chips batch; Variants: Missingness and Hardy-Weinberg equilibrium, Frequency checks, Ambiguous variants, Duplicated variants). Complete details of our quality control procedures are provided in the methods and supplementary information section of the manuscript.

Replication

The meta-analysis strategy includes replication by default, as it weights the reported test statistics by the evidence of association across multiple samples. Further, SNP-based replication was carried out for the top GWAS association signals in an independent sample (N= 25,392 Alzheimer's disease cases and 276,086 controls; see Methods and supplementary information).

Randomization

Samples were randomized by case and control status on plates during genotyping at their independent study sites.

Blinding

genotyping was done blind without knowing the status of the individuals. The analysts were not blinded to the status of the individuals because QC procedures require knowing case and control status.

# Reporting for specific materials, systems and methods

We require information from authors about some types of materials, experimental systems and methods used in many studies. Here, indicate whether each material, system or method listed is relevant to your study. If you are not sure if a list item applies to your research, read the appropriate section before selecting a response.

## Materials & experimental systems

<table><thead><tr><th>n/a</th><th>Involved in the study</th></tr></thead><tbody><tr><td>☑</td><td>Antibodies</td></tr><tr><td>☑</td><td>Eukaryotic cell lines</td></tr><tr><td>☑</td><td>Palaeontology and archaeology</td></tr><tr><td>☑</td><td>Animals and other organisms</td></tr><tr><td>☐☑</td><td>Human research participants</td></tr><tr><td>☑</td><td>Clinical data</td></tr><tr><td>☑</td><td>Dual use research of concern</td></tr></tbody></table>

## Methods

<table><thead><tr><th>n/a</th><th>Involved in the study</th></tr></thead><tbody><tr><td>☑</td><td>ChIP-seq</td></tr><tr><td>☑</td><td>Flow cytometry</td></tr><tr><td>☑</td><td>MRI-based neuroimaging</td></tr></tbody></table>

# Human research participants

Policy information about [studies involving human research participants](#)

Population characteristics

We used multiple independent sets of participants in this study. We adjusted the analysis for principal components. Sample sizes, age and gender characteristics for our sample can be found per cohort and overall in Supplementary Tables 1 and Supplementary Information.

Recruitment

Participants from case-control studies were primarily recruited from clinics, nursing homes, disease registries, and hospitals, with controls being drawn from various ongoing studies and screened to exclude dementia/cognitive decline (see description of the samples in the supplementary information). Cases were recruited according to clinical diagnosis and defined as probable AD cases with a potential risk of misdiagnosis (estimated between 10 and 20% in the literature). Controls included in the study were free of cognitive decline but a large part of them did not have any follow-up with the possibility that they developed dementia years later.

The UK Biobank recruited adult volunteers from national health registration records. UK Biobank participants are healthier than the general population, but since the data used in this study referred to parental diagnoses, the impact of selection bias should be minor.
Note that full information on the approval of the study protocol must also be provided in the manuscript.