Gerontology & Geriatric Research

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A One-Drug Strategy is Needed to Attenuate the Multi-Proteinopathy that Leads to Age-Related Diseases

Ben A. Bahr

Alzheimer’s disease (AD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS) are age-related protein accumulation disorders. They exhibit multi-proteinopathy involving tau and TAR DNA-binding protein 43 (TDP43), and the latter two disorders can also accumulate fused in sarcoma protein (FUS). AD is the most common multi-proteinopathy with an additional and perhaps key pathogenic contributor being the Aβ42 peptide. AD can also exhibit the accumulation of α-synuclein, a key protein that accumulates in Parkinson’s disease (PD) and related Lewy body diseases. The specific disorders that constitute FTD have a high proportion of familial or inherited cases, whereas less than 5% of AD cases and 5-10% of ALS cases are the familial inherited form, and the cause of the remaining 90-95% of sporadic AD and ALS cases is not fully understood. Many of the molecular and cellular features related to combinations of protein accumulation events are observed in both sporadic and familial forms of these disorders, often occurring for many years before symptoms arise. The multiple protein accumulation/aggregation events may elicit separate degenerative pathways in distinct age-dependent manners, culminating with the enhanced risk of developing one of several protein accumulation disorders (AD, FTD, ALS, PD, Huntington’s disease, multiple system atrophy, multisystem proteinopathy).