The Contribution of Mixed and Concomitant Pathology to Dementia: Longitudinal data analysis of the Brains for Dementia Research programme

Abstract

Dementia is a leading cause of dependence and disability in older adults. Currently, there are over 55 million people living with dementia globally and, due to increasing life expectancy resulting in an ageing population, this is expected to triple by 2050. Neurodegenerative pathologies, such as Alzheimer’s disease, Lewy body disease and TDP-43 inclusions, and cerebrovascular disease are frequently associated with different clinical presentations of dementia. However, individuals often exhibit a combination of these pathologies, resulting in heterogenous and overlapping clinical phenotypes, complicating diagnosis, prognosis, and treatment. Examining these clinicopathological correlations may provide useful insights into how mixed and concomitant pathology contribute to the clinical manifestation of dementia. Longitudinal statistical methods, including latent class and multistate models, were used to analyse clinicopathological data from the Brains for Dementia Research programme, aiming to examine how co-existing pathologies contribute to cognitive decline and disease trajectory in dementia in comparison to cognitively healthy controls. A preliminary analysis indicated a high prevalence of mixed and concomitant pathology across the entire cohort, with poor concordance between study diagnosis and postmortem neuropathology. Mixed pathology was consistently associated with more severe cognitive impairment and faster decline in cognitive function, and greater risk of transition between cognitive states of dementia. Concomitant Alzheimer’s disease neuropathology, specifically neurofibrillary tangle pathology, appears to drive cognitive decline in other age-related neurodegenerative diseases, including Lewy body disease and limbic-predominant age-related TDP-43 encephalopathy (LATE), frequently associated with dementia. These findings highlight the importance of considering and accounting for mixed and concomitant pathology in dementia research and clinical management, providing supporting evidence for the application of comprehensive biomarker screening and personalised treatment strategies tailored to individual pathological profiles. The consistent association between mixed and concomitant pathology and more severe cognitive trajectories suggests that there may be shared pathways and processes underlying cognitive decline across the dementia spectrum.