Multiple comorbid neuropathologies in the setting of Alzheimer's disease neuropathology and implications for drug development

Abstract

Dementia is often characterized as being caused by one of several major diseases, such as Alzheimer's disease (AD), cerebrovascular disease, Lewy body disease, or a frontotemporal degeneration. Failure to acknowledge that more than one entity may be present precludes attempts to understand interactive relationships. The clinicopathological studies of dementia demonstrate that multiple pathologic processes often coexist. How overlapping pathologic findings affect the diagnosis and treatment of clinical AD and other dementia phenotypes was the topic taken up by the Alzheimer's Association's Research Roundtable in October 2014. This review will cover the neuropathologic basis of dementia, provide clinical perspectives on multiple pathologies, and discuss therapeutics and biomarkers targeting overlapping pathologies and how these issues impact clinical trials.High prevalence of multiple pathologic findings among individuals with clinical diagnosis of AD suggests that new treatment strategies may be needed to effectively treat AD and other dementing illnesses.

Keywords: Alzheimer's disease (AD); Cerebrovascular disease; Frontotemporal degeneration; Lewy body disease; TDP-43; Tau; α-Synuclein; β-amyloid.

Fig. 1

Multiple pathologic findings when AD is present. A total of 1242 brains were included: all Braak stage IV or greater and Thal phase 3 or greater. Eighty-six percent of patients had a primary clinical diagnosis of dementia and 14% were diagnosed with parkinsonism. “Tau” indicates argyrophilic grain disease, an age-associated medial temporal tauopathy. Abbreviations: AD, Alzheimer's disease; VaD, vascular dementia; LBD, Lewy body disease; HS, hippocampal sclerosis.

Fig. 2

Ten-year paths of global cognitive decline in 130 participants from the Religious Order Study with varying levels of TDP-43 pathology, adjusted for age at death, amyloid, tangles, and hippocampal sclerosis. Black line, no TDP-43; green line, 10th percentile; blue line, 50th percentile; and red line, 90th percentile TDP-43 .