Sporadic inclusion-body myositis (s-IBM) is the most common progressive muscle disease of older persons. The muscle biopsy demonstrates mononuclear cell inflammation and vacuolated muscle fibers containing paired helical filaments and 6- to 10-nm fibrils, both resembling those of Alzheimer disease brain and Congo red positivity. The term hereditary inclusion-body myopathies (h-IBMs) designates autosomal-recessive or autosomal-dominant disorders with muscle biopsies cytopathologically similar to s-IBM but without inflammation. Vacuolated muscle fibers of both s-IBM and the h-IBMs contain accumulations of several "Alzheimer-characteristic proteins" including beta-amyloid protein and beta-amyloid precursor protein, and their paired helical filaments are composed of phosphorylated tau. We used six well characterized antibodies against several residues of presenilin 1 (PS1) to immunostain muscle biopsies of 12 patients with s-IBM, 5 patients with autosomal-recessive inclusion-body myopathy, and 16 normal and disease controls. Seventy to eighty percent of the vacuolated muscle fibers of both s-IBM and autosomal-recessive inclusion-body myopathy had inclusions that were strongly PS1-immunoreactive, which by immunoelectron microscopy localized mainly to paired helical filaments and 6- to 10-nm filaments. None of the control biopsies had PS1-positive inclusions characteristic of the s- and h-IBM abnormal muscle fibers. Mutations of the newly discovered PS1 gene are responsible for early-onset familial Alzheimer disease (AD), and PS1 is abnormally accumulated in sporadic and familial AD brain. Our study provides the first demonstration of PS1 abnormality in non-neural tissue and in diseases other than AD and suggests that the cytopathogenesis in AD brain and IBM muscle may share similarities.