Alzheimer’s Disease, heart failure, and musculoskeletal defects and their relationship to clinical co‐morbidities

Abstract

Alzheimer’s Disease represents a significant threat to the health of the US population. The most common causes of morbidity and mortality in AD patients are associated with muscle function (swallowing), bone and muscle strength (hip fractures), and heart failure severity used in advanced dementia prognostic tools. AD patients experience an underlying sarcopenia and decreased strength increasingly present with AD disease progression after adjusting for multiple covariates, and differentially affected women more than men. This reduced muscle strength did not parallel the rate of decline in global cognitive function tests, with underlying mechanisms currently unknown. New conceptual frameworks are needed to address this issue to allow a better understanding of the complexity of aging diseases so that therapeutics targeting multiple systems can be developed. The association with AD and heart failure patients have linked the presence of amyloid beta (Ab) protein aggregates in the hearts of patients with a primary diagnosis of AD. An increase in cardiac Ab protein and the degree of diastolic dysfunction before death were correlated, indicating a possible mechanistic link between Ab protein and cardiac dysfunction. Subsequent echocardiographic studies of AD patients and age‐matched controls with AD‐mutations (i.e., PSEN1, PSEN2, APP, and APOE genes) and ECG analysis have found multiple echocardiographic abnormalities, including diastolic dysfunction and a low voltage QRS complexes and cardiac hypertrophy by electrocardiography (ECG), together illustrating a link between subclinical cardiac Disease and Abamyloid deposition in AD patients. These findings have led to a concerted effort to phenotype the cardiac and musculoskeletal system in both animal and human models of AD disease in our research group. We focus on both clinically relevant and diverse animal models for muscle, bone, and cardiac alterations driven by multiple known mechanisms, including mutations in Ab and the microtubule‐associated protein tau (MAPT) and the role of endogenous tau protein and microtubule function throughout the body. We’ve identified a spectrum of pathologic changes in cardiac, muscle, and bone is seen in almost all AD models we’ve investigated to date, with deficits getting worse with age. These unexpected findings will allow us to determine both the underlying mechanisms and to test therapeutic interventions for both brain and the musculoskeletal system disease in AD patients. Our goal is to improve the AD patient’s quality of life as it relates to the musculoskeletal system while attenuating brain disease as part of a systemic protein quality control disease throughout the body. These will allow us to translate our limited knowledge and fledging understanding of AD patients’ musculoskeletal disease, which is not a critical concern clinically today, given our limited knowledge and fledging understanding of its expression.Support or Funding InformationLilly Foundation/Indiana Center for Musculoskeletal Health/ IU School of Medicine, Physician Scientist Initiative, Scientific Research Initiative