Alzheimer's disease (AD) pathogenesis involves complex interactions between multiple neuropathological processes, yet traditional approaches focus on individual markers. The cumulative effects of multiple pathologies and their interactions with cerebrovascular compromise and age remain poorly understood. This study aimed to develop a comprehensive Pathological Burden Score (PBS) and examine its relationship with AD risk, including interactions with stroke history and age.

We analyzed 11,308 participants from the National Alzheimer's Coordinating Center database. A PBS was constructed integrating six neuropathological domains: Braak neurofibrillary tangle staging, CERAD neuritic plaque density, Thal amyloid-β phasing, stroke history, white matter rarefaction severity, and cerebral atrophy severity (range 0-16 points). PBS was categorized into four burden levels: low (0-4), moderate (5-8), high (9-12), and very high (13-16). Multivariable logistic regression examined associations between PBS categories and AD risk, with formal interaction testing for stroke × PBS effects. Age-stratified analyses were conducted using a 75-year cutpoint.

A clear dose-response relationship was observed between PBS and AD risk, with very high burden conferring over 5-fold increased odds compared to low burden. Significant stroke × PBS interaction was detected (interaction OR 1.23, p<0.001), with stroke amplifying pathological burden effects. Among participants with very high burden, AD risk was 92.5% in stroke patients versus 24.1% in non-stroke patients. Age-dependent effects were profound: younger participants (<75 years) with high burden plus stroke showed 18.67-fold increased odds, while older participants (≥75 years) with equivalent burden showed 7.89-fold increased odds.

Cumulative pathological burden demonstrates a strong dose-response relationship with AD risk, significantly amplified by stroke history. The pronounced age-dependent effects highlight the need for age-specific prevention strategies, with particular emphasis on aggressive vascular risk management in younger populations. These findings support comprehensive pathological burden assessment for enhanced risk stratification and personalized dementia care approaches.