MAPT and early-onset autosomal dominant Alzheimer disease: GS dysfunction operates both upstream in neurodegeneration—including Alzheimer’s disease—via reduced clearance of β-amyloid and tau [2], and downstream of cerebrovascular pathology and white-matter injury [3, 4] a bidirectional architecture consistent with a feed-forward loop in which vascular and white-matter alterations blunt clearance and impaired clearance accelerates protein aggregation and tissue stress [5].