Cerebrovascular Disease in Amyotrophic Lateral Sclerosis: Epidemiology, Mechanisms, and Clinical Implications

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disease primarily affecting upper and lower motor neurons. Although cerebrovascular disease (CVD) and ALS have traditionally been studied as distinct entities, a growing body of evidence indicates meaningful epidemiological, pathophysiological, and clinical overlap between the two conditions. This narrative review synthesizes current evidence on the coexistence of ALS and cerebrovascular disease, examines shared mechanistic pathways, addresses diagnostic challenges, including stroke mimicry, considers clinical management implications, and identifies priorities for future research. A search of PubMed, Scopus, Web of Science, and EMBASE was conducted through February 2026 using the terms “amyotrophic lateral sclerosis,” “motor neuron disease,” “cerebrovascular disease,” “stroke,” “ischemic stroke,” “blood-brain barrier,” “neuroinflammation,” and “neurovascular coupling,” alone and in combination. Peer-reviewed original research, systematic reviews, meta-analyses, population-based studies, registry analyses, and expert consensus statements were included. Studies were assessed for methodological quality and relevance to the review objectives. This review is reported as a narrative synthesis. Population-based data demonstrate a bidirectional relationship between ALS and cerebrovascular events. ALS patients face an approximately 2.6-fold elevated risk of ischemic stroke, and prior cerebrovascular injury modestly increases subsequent ALS risk. Shared pathophysiological mechanisms include neuroinflammation with microglial M1/M2 polarization imbalance, pro-inflammatory cytokine cascades mediated via NF-κB signaling, oxidative stress and SOD1 pathway dysregulation, glutamate excitotoxicity, blood–brain barrier (BBB) dysfunction, and impaired neurovascular coupling. Diagnostic confusion arises because upper motor neuron–predominant ALS can closely mimic acute ischemic stroke. Concurrent cerebrovascular disease appears to accelerate functional decline and reduce survival in ALS. Resource-limited settings face compounded challenges from diagnostic misclassification, restricted EMG access, and limited specialist availability. The ALS–cerebrovascular overlap is clinically relevant, biologically plausible, and systematically understudied. Integrated multidisciplinary management, prospective longitudinal cohort studies, and linked registry analyses are urgently needed to clarify causal relationships, characterize shared disease mechanisms, and improve patient outcomes.