miR155, triplicated in Down syndrome, regulates the development of neural stem cells and GABAergic interneurons in Alzheimer's disease mouse and human iPSC models.

An extra copy of the amyloid precursor protein gene on chromosome 21 leads to overproduction of abnormal amyloid beta (Aβ), causing early‐onset Alzheimer's disease (AD) and/or cerebral amyloid angiopathy (CAA). The most common cause is de novo trisomy 21, responsible for Down syndrome (DS), a condition that includes intellectual disability and cardiac malformations., , In rare cases, a small segment of chromosome 21 is duplicated without the DS critical region (small distal region on 21q22.13), leading to autosomal dominant AD (ADAD). Carriers typically present with cognitive decline, hemorrhages, or seizures., In DS, early recognition of AD and/or CAA is complicated by intellectual disability and other co‐morbidities. In both ADAD duplications (dup) and DS‐AD, the age at onset (AAO) varies widely (40–65 years), making it difficult to predict AAO., , , , , , This heterogeneity in AAO likely reflects a combination of environmental and genetic factors. Identifying modifiers of AAO in dup and DS is crucial for care planning and optimizing the timing of treatment initiation for emerging disease‐modifying therapies. Among established genetic risk factors for AD, the apolipoprotein E () genotype is most prominent. Studies investigating across different causes of ADAD reported that the ε4 allele accelerated onset and the ε2 allele delayed onset, with inconsistent significance., , , , In dup carriers, no significant effect of was found, nor an association of duplication length or nearby duplicated genes with AAO or specific symptoms, possibly due to small sample size. In DS, ε4 has been linked to earlier AD onset and corresponding cerebrospinal fluid (CSF) changes, although associations with clinical onset measures have not been consistent., , These findings suggest that the genotype may influence the disease trajectory in individuals carrying an additional copy of . Genome‐wide association studies (GWASs) have identified > 80 other AD risk variants beyond . Aggregating the effects of these variants into an AD genetic risk score (AD‐GRS) provides a measure of cumulative genetic susceptibility to AD, which has been consistently associated with AAO. In ADAD and DS studies, the AD‐GRS has been associated with CSF biomarkers and cognitive decline,, , implying potential influence on AAO. These genetic variants are implicated in different biological pathways. Constructing pathway‐specific GRSs (pGRSs) allows us to determine which biological mechanisms most strongly modify AAO, thereby highlighting the pathways most relevant in individuals with an extra copy.