Mount Sinai reversed APOE4 vessel scarring in aged mice by blocking TGF-beta

Pericytes are the mural cells that wrap capillaries, keep the vessel wall intact and help regulate blood flow ^[8]. Researchers have generally treated the deterioration of those vessels in APOE4 carriers as passive collateral damage from Alzheimer's ^[12]. "We show that APOE4 converts blood-vessel support cells into scar-producing cells, causing amyloid or abnormal protein buildup to accumulate around the brain's vessels," said Braxton R. Schuldt, first author on the Cell paper and an MD/PhD candidate in the Blanchard laboratory ^[15][17].

The two studies carry different kinds of evidence. A single-cell transcriptomic atlas of the human brain vasculature ^[4] shows which cells differ between genotypes, and leaves open which of those differences does the damaging. The causal weight sits on the animal experiment ^[6], and specifically on the animals being old: the blockade went in after the fibrosis and the perivascular amyloid had built up, which is a harder test than preventing them in a young mouse.

"Damage to the brain's blood vessels is not simply a late consequence of Alzheimer's disease; it is a biologically active process caused by APOE4 that may be reversible," said Joel W. Blanchard, the corresponding author and an associate professor of neuroscience and of stem cell biology and regenerative medicine at the Icahn School of Medicine at Mount Sinai ^[13][16]. He said the findings "reveal new therapeutic targets for preserving vascular function and limiting amyloid accumulation" ^[14].

The second arm is a claim about disposal capacity. Cholesterol loading paralyses the lysosomal system in APOE4 astrocytes, and the aggregate that then accumulates and moves into neurons is alpha-synuclein ^[9]. Because the model tissue holds neurons, glia and working vessels together ^[10], the lipid arm and the vessel arm can in principle be run on the same piece of tissue.

Alzheimer's affects more than seven million older adults in the United States ^[11]. Both reversals reported here came out of model systems: aged APOE4 mice and stem-cell-derived human tissue ^[19]. I would weight the aged-mouse intervention above the atlas, and hold both below a replication in another lab's APOE4 tissue. The release does not include sample sizes, effect sizes, or results from behavioural testing ^[20].