TDP-43: a newly-recognized route to cognitive decline

Both in people with Alzheimer’s Disease (AD) and in those without AD, TDP-43 pathology is related to cognitive decline, dementia, and progressive hippocampal degeneration (and ultimately sclerosis), Julie Schneider (Rush Alzheimer’s Disease Center, Chicago, Illinois, USA) told the AAT-AD/PD Focus meeting.

According to data she presented, 32% of the association between age and dementia is accounted for by vascular pathology.¹ The remaining 68% can be attributed to neurodegeneration. Probably less than 5% is due to Lewy bodies, and around 25% to neuritic plaque/tau pathology. Around 40%, however, can be traced to the hippocampal sclerosis/TDP-43 pathway.

TDP-43 patholgy is common, mimics AD but is independent of it, and could account for 40% of age-related dementia

New disease defined

Transactive response DNA-binding protein 43 (TDP-43) is present in the nucleus but may translocate and become phosphorylated. The presence of hyperphosphorylated inclusions is now recognized as a feature of common dementias.

In Brain in 2019, a consensus working group described a new disease entity --  limbic-predominant age-related TDP-43 encephalopathy (LATE) – and proposed diagnostic criteria.²

TDP-43 and AD often occur together, but this is not always the case: it can be a distinct cause of amnestic dementia in people without AD.³ In people with AD, TDP-43 proteinopathy adds to cognitive impairment, particularly of episodic and working memory; and the presence of multiple pathologies lowers the threshold for the diagnosis of AD.⁴ 

TDP-43 inclusions at autopsy are strongly associated with a history of cognitive decline and dementia

Large autopsy studies

Interestingly, while the frequency of isolated AD does not increase with age (according to data presented by Professor Schneider), the frequency of TDP-43 pathology does. That is also true of vascular pathology.

Many of these insights into a major new etiology for cognitive decline and dementia derive from two large longitudinal studies. The Religious Orders Study assesses cognition annually in elderly nuns, priests and monks, and relates changes to pathology evident at autopsy. The Rush Memory and Aging Project follows a similar methodology in a lay population drawn from retirement communities. Both series have an autopsy rate greater than 80%.

An early study found TDP-43 pathology in the brains of almost half of those investigated.⁵ TDP-43 pathology was associated with amyloid plaques, tangles, and hippocampal sclerosis. But TDP-43 was linked to particularly rapid cognitive decline and – after controlling for other pathologies -- had an effect size similar to that of tangles.