*2.2. Participants*

Informed consent/assent was obtained from all participants involved in the study. The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the ethics committees from each of the participating universities. Medical histories of enrollees were reviewed at each clinical performance site to identify those with a history of acute regression. A total of five individuals were identified and medical histories were reviewed from the period of time during which regression purportedly occurred. A diagnosis was confirmed if there was evidence of a significant loss of communication skills and adaptive functioning. As described in Table 1, diagnoses at the time included depression (*N* = 1) and dementia (*N* = 3). Age at the time of reported regression ranged from the early to late 20s. None of the individuals returned to prior levels of functioning. Current estimated mental ages ranged from <2 years 0 months to 6 years 5 months, based upon the PPVT4 [25], a measure of receptive vocabulary. Those initially diagnosed with dementia have since had their diagnoses removed.

The five individuals with histories of regression were matched with 15 other ABC-DS participants (without reported histories of acute regression) based on biological sex, age, site and ApoE status. None of the individuals with regression, or the matched participants, had current diagnoses of AD based upon a consensus conference (comprised of study staff, a physician and a psychologist who had participated in the study visit) that included a review of neuropsychological assessment battery results, caregiver-completed questionnaires on adaptive functioning, behavioral concerns and possible symptoms of AD. In addition, the consensus conference members had access to each participant's medical history and the results of a physical/neurological examination conducted as part of their study visit.

Consensus conference members were blinded as to neuroimaging, omics and genetics results. Some individuals were given diagnoses of "unable to determine" due to the likely possibility that other factors (e.g., a recent illness, change in living situation or job) might have accounted for any reported changes in overall functioning. ApoE carrier status was obtained and karyotyping was conducted to confirm the trisomy 21 diagnosis. Table 2 provides demographic information for the "regression group" and the 15 "matched controls". The only meaningful difference between the two groups was estimated mental age, with the regression group having a mean MA considerably lower than the comparison group.
