Background The expression of autism traits sufficient to meet criteria for a diagnosis can occur early (by 3 years) or later (from mid-childhood onwards). It remains unknown whether variation in age of onset is due to clinical recognition or whether it reflects distinct biological pathways. One way of addressing this question is by investigating biological differences very early in development associated with age of onset. We use a prospective design to look at event related potentials to faces, one of the most robust biomarkers in autism.

Methods A sample of 102 infants (aged 6-10 months, 54% female) with an older autistic sibling had EEG recorded whilst viewing faces (faces versus noise; gaze towards versus away). Autism diagnostic assessments were conducted at three years and again in mid-childhood (aged 6-12 years), resulting in early diagnosed (at age 3; N=22), later diagnosed (at mid-childhood; N=21) and no autism (N=59) groups.

Results While a short latency response (P1) does not associate with autism outcome, a mid-latency component (N290) associates with early onset autism only, and a later latency component (P400) associates with both early and later onset autism.

Conclusion Temporal stages of face processing in infancy differentially associate with age of autism onset such that an earlier age of diagnosis is associated with earlier stage deviation within the event-related waveform. Early and later onset autism may represent different biological subtypes, with different early brain development, challenging the view of one etiological pathway and that variation in diagnostic age is solely due to clinical ascertainment.

TC has served as a paid consultant to F. Hoffmann-La Roche Ltd. and receives royalties from Sage Publications and Guilford Publications. MHJ receives royalties from Wiley-Blackwell, OUP and MIT Press. The remaining authors have declared that they have no competing or potential conflicts of interest.

This research was supported by awards from the Medical Research Council (MR/R011427/1, G0701484, MR/K021389/1, MR/T003057/1), BASIS funding consortium led by Autistica, Autism Speaks. The results leading to this publication have received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 777394 for the project AIMS-2-TRIALS. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA and AUTISM SPEAKS, Autistica, SFARI. Any views expressed are those of the authors and not necessarily those of the funders (IHI-JU2). European Union Horizon Europe grant no. 101057385 (R2D2-MH) and UK Research and Innovation (UKRI) under the UK governments Horizon Europe funding guarantee [grant no.10039383] and by the Swiss State Secretariat for Education, Research and Innovation (SERI) under contract number 22.00277. TB is supported by a grant from the UK Medical Research Council (MR/X010716/1). Views and opinions expressed are however those of the authors only and do not necessarily reflect those of the European Union. Neither the European Union nor the granting authority can be held responsible for them. Capital equipment funding from the Maudsley Charity (980) and Guys and St Thomas Charity (STR130505). The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

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Ethics Committee of the National Health Service (NHS, National Research Ethics Service) gave ethical approval for this work (NHS RES London REC 06/MRE02/73, 08/H0718/76 and 14/LO/0170)

IRB of Kings College London (Psychiatry, Nursing, and Midwifery Research Ethics Subcommittee) gave ethical approval for this work (RESCM-18/19-10556).

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