Brain aging and cognitive decline accelerate beyond a threshold of periventricular white matter hyperintensity

A substantial subset of cognitively normal (CN) older adults accumulates high burdens of Periventricular (PVWMH) and Deep White Matter Hyperintensities (DWMH), surrogate neuroimaging-markers of cerebral small-vessel disease, while others have minimal or no white matter hyperintensity (WMH). Using multi-modal Magnetic Resonance Imaging (MRI) from National Alzheimer's Coordinating Centre (NACC) (n = 986) and Alzheimer's Disease Neuroimaging Initiative (ADNI) (n = 382) cohorts spanning CN, cognitively impaired (CI), and CI with Alzheimer's etiology (CI-AD) aged 50-94 years, we investigated whether total WMH burden or specifically PVWMH and DWMH, surpassing a threshold disrupts neuroanatomy and cognition. PVWMH and DWMH volume increased exponentially with age, but PVWMH rose twice as fast, with inflection at 61 years. PVWMH > 2.3 mL, independent of age, was associated with structural atrophy (rostralmiddlefrontal, pre/postcentral gyri, lingual-gyrus, nucleus-accumbens), global fiber disintegration, and impairments in executive, attentional, semantic domains. DWMH effects were negligible. Longitudinal mixed-models in NACC and ADNI confirmed that PVWMH progression, not DWMH, predicted accelerated atrophy. PVWMH-related neuroanatomic loss mediates cognitive decline. The 2.3 mL threshold was validated in ADNI3. While both are visible on routine MRI, only PVWMH demonstrated threshold-dependent effects. Progression to ≥2.3 mL marks a threshold, demanding clinical surveillance, vascular-risk management, and recognition of accelerated brain-aging. Neuroimaging-based quantification of PVWMH, combined with domain-specific cognitive testing provides robust measures of clinical surveillance, definitive of brain health.