Association between self-reported multimorbidity and longitudinal brain Aβ deposition in Alzheimer’s disease

Introduction

Alzheimer’s disease (AD), the most common type of dementia in older adults, is clinically characterized by progressive memory loss and cognitive and behavioral abnormalities. It is estimated that at least 55 million people worldwide suffer from AD or other dementias¹. The pathological hallmarks of AD include the accumulation of the abnormal proteins beta-amyloid (Aβ) and phosphorylated tau, as well as the degeneration of neurons in the brain. Aβ is the molecular driver of AD pathogenesis and is considered a promising target for disease-modifying therapies^2,3.

AD is conventionally regarded as a brain-specific disease that is independent of the peripheral system or body. Nevertheless, previous studies have reported that the multimorbidity burden is heavy in patients with AD and dementia^4,5. Recent large epidemiological studies have demonstrated the associations of systemic multimorbidity with AD and dementia risk^{6, 7–8}, suggesting that multimorbidity may exacerbate the development and progression of AD. Thus, it is speculated that AD may be not only a brain disorder but also a systemic disease involving morbidity in multiple systems beyond the brain^9,10. However, the potential mechanism underlying the associations between AD and multimorbidity remains unclear. Recent evidence from our groups and others revealed that abnormalities in non-brain organs and tissues contributed to brain Aβ deposition and cognitive impairment in AD model mice^{11, 12, 13, 14, 15–16}. However, whether AD patients with increased multimorbidity experienced faster Aβ accumulation in the brain is unclear.

In this study, we investigated the impact of the multimorbidity burden on longitudinal brain Aβ deposition in the AD continuum among brain Aβ-positive older adults from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) for whom baseline and longitudinal ¹⁸F-florbetapir (FBP) Aβ positron emission tomography (PET) scans and medical records were available. The ultimate goal of this study is to obtain evidence from human tissues to clarify the mechanism underlying the increased risk of AD in individuals with a high multimorbidity burden. These findings will help to improve the interventions available for AD patients by incorporating management of multimorbidity, of the brain as well as the peripheral systems.

Results

Characteristics of study participants

A total of 435 brain Aβ-positive participants (153 cognitively unimpaired (CU) and 282 cognitively impaired (CI) participants, CI...