Thus, cortical atrophy and cognitive decline may be indirectly caused by degeneration of subcortical projection systems before alpha-synuclein pathology itself accumulates in the cortex, suggesting phenomena that cannot be explained by the simple equation of “cortical degeneration = presence of alpha-synuclein pathology in that region.” Additionally, pathological mechanisms related to Alzheimer’s disease (AD) may be involved. The gene discussed is SNCA; the disease is early-onset autosomal dominant Alzheimer disease.