1  Mice by group and batch

1.1 Switch mice distribution across batches

Batch 1 included only GFP control mice, while Batch 2 contained both GFP controls and Cre-AAV–treated animals. Although tissue and sex distribution was balanced within each batch (50 % brain and 50 % liver for both sexes), the absence of Cre-AAV samples in Batch 1 creates a clear batch–treatment confounding.

Male switch mice

	1	2
	GFP Control	Cre-AAV	GFP Control
	N=10	N=10	N=4
Tissue:
Brain	5 (50.0%)	5 (50.0%)	2 (50.0%)
Liver	5 (50.0%)	5 (50.0%)	2 (50.0%)

Female switch mice

	1	2
	GFP Control	Cre-AAV	GFP Control
	N=8	N=10	N=2
Tissue:
Brain	4 (50.0%)	5 (50.0%)	1 (50.0%)
Liver	4 (50.0%)	5 (50.0%)	1 (50.0%)

1.2 TR mice

All TR mice were male and processed in batch 2. The cohort included three animals per genotype (E2/E2, E3/E3, and E4/E4), with both liver and brain collected from the same individuals. Because all TR samples belong to a single batch, there is no internal batch variation, but comparisons with switch mice are affected by a strong batch effect since the TR cohort was entirely processed separately.

TR mice (all male, all in batch 2)

	E2/E2; F/+	E3/E3; F/+	E4/E4; F/+
	N=6	N=6	N=6
Tissue:
Brain	3 (50.0%)	3 (50.0%)	3 (50.0%)
Liver	3 (50.0%)	3 (50.0%)	3 (50.0%)