Alzheimer’s disease (AD) is identified by the development of two hallmark changes in the brain: beta-amyloid plaques and tau neurofibrillary tangles. Yet, this is only part of the story. Most patients also develop other age-related pathologies that impact the severity and progression of AD. One such example is the buildup of TDP-43 (TAR DNA-binding protein 43), a protein essential for normal cellular function, that, like beta-amyloid, can misfold and form toxic aggregates. Pathological TDP-43 defines several neurodegenerative diseases, including ALS, frontotemporal dementia, and limbic-predominant age-related TDP-43 encephalopathy (LATE). And when TDP-43 co-occurs with AD pathology, patients experience greater hippocampal tissue loss and more severe cognitive decline.
The presence of such mixed pathologies complicates efforts to understand AD’s root causes and develop targeted treatments. Despite this clinical reality, surprisingly few studies have attempted to determine which co-pathologies are most common in AD patients or to identify the factors that predispose certain individuals to their development. Researchers suspect that genetic differences may make some individuals more vulnerable or more resistant to particular types of brain damage, but this remains poorly understood. A major barrier to addressing these questions has been the limited availability of large, well-characterized postmortem brain collections that capture the full spectrum of pathology presentation in Alzheimer’s. However, Dr. Petrucelli’s team has access to the Mayo Clinic Brain Bank, which contains over 3,000 brains from individuals with autopsy-confirmed AD. We know these brains have amyloid and tau pathology – the Petrucelli lab aims to comprehensively map the other co-pathologies present in each case alongside these AD hallmarks, starting with samples from the amygdala, a brain region especially vulnerable to mixed pathologies. Amyloid plaques, tau tangles, TDP-43, and α-synuclein (characteristic of Parkinson’s disease and Lewy body dementia) pathologies have all been found in the amygdala, and the convergence of multiple pathologies in this single anatomical region suggests that they may interact in harmful ways, making the amygdala an ideal location for understanding how co-pathologies worsen AD.
The team has already generated preliminary findings that point to these complex relationships amongst pathologies present in brains from the Mayo Clinic Brain Bank. Their analyses confirmed that AD cases with TDP-43 pathology show worse cognitive decline and more severe hippocampal shrinkage than those without TDP-43. Moreover, they found that AD patients who lived to older ages were less likely to have advanced amyloid plaques and tau tangles and had fewer instances of α-synuclein co-pathology – but were more likely to have TDP-43 and vascular changes. This pattern suggests that, under conditions where traditional Alzheimer’s brain changes may be less severe, other co-pathologies like TDP-43 may play a key role in triggering cognitive decline. This observation also highlights just how important it is to consider the full range of possible brain pathologies when studying and treating AD.
