Inclusion-body myositis and Alzheimer disease

Inclusion-body myositis (IBM) is an age-related, slowly progressive degenerative disorder of the skeletal musculature with no effective treatment. Clinically, the disease is characterized by the atrophy of both proximal and distal muscle groups, leading to a gradually advancing weakness.¹ The muscle fibers from IBM patients display characteristic vacuolizations and contain heterogeneous, filamentous inclusions.² Although initially characterized as a form of polymyositis, the disease is only weakly responsive to corticosteroid treatment or other forms of immunomodulation and is now recognized as a distinct disease entity.

Aspects of IBM pathology share intriguing similarities to that of Alzheimer disease (AD), the most common form of elderly dementia. The severe cognitive dysfunction in AD is brought about by massive neurodegenerative changes to the brain. The bulk of available evidence implicates a small protein fragment, the amyloid-β peptide (Aβ), as the major causative element in the neurodegenerative process.^3,4 In the AD brain, Aβ is deposited extracellularly as amyloid, and is the major proteinaceous component of the neuritic plaques that can be found throughout the cortex. For over a decade, it has been known that Aβ—or larger protein fragments that contain it—also accumulate as part of the characteristic intracellular lesions of IBM.^2,5,6 What is unknown is whether or not this is important for IBM pathogenesis.

Strong evidence for a role of the amyloid β-protein precursor (APP), APP fragments, Aβ, or all three, in the pathogenesis of IBM comes from several sources.^6,7 The appearance of Aβ-positive, noncongophilic deposits precedes vacuolization in IBM muscle fibers.⁸ Further, APP mRNA is increased in the disease state,⁹ suggesting that the over expression of the precursor protein may be sufficient to cause pathology. As expected, the in vitro over expression of APP in muscle cells leads to a range of degenerative changes resembling various facets …