TDP-43 Aggregation is Present in Many Older People, Overlapping with Alzheimer's Pathology

TDP-43 is one of the small number of proteins that can misfold in ways that lead to aggregates and pathology. It is involved in a number of age-related neurodegenerative conditions, notably ALS. Like other aggregates found in the aging brain, such as amyloid-β, α-synuclein, and tau, TDP-43 aggregates are present in many older people. The decline into neurodegeneration is a sliding scale of pathology, in which some people, for reasons yet to be fully explored, develop much larger amounts of one or another protein aggregate than their peers. There is good reason to think that all protein aggregates are at least somewhat harmful and should be cleared, but as is the case in Alzheimer's disease, the damage done by some aggregates may be obscured by other, more severe forms of pathology that arise as the condition progresses.

The largest study to date on the prevalence of limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) finds that this type of neuropathology is strikingly common among those who survive well into their 80s. The study integrated autopsy and cognitive data across 13 community cohorts that comprised more than 6,000 participants. Roughly half of people with amyloid-β plaques and tau tangles also had evidence of LATE-NC, whereas a quarter of people with little to no AD pathology had LATE-NC. Either neuropathological scourge alone was tied to cognitive impairment, but people who harbored both AD pathology and LATE-NC suffered the strongest cognitive blow.

About 40 percent of participants across the cohorts were cognitively normal at their last clinical visit, and roughly the same proportion had dementia. Fifteen percent reportedly had mild cognitive impairment. Across all of the cohorts, 39.4 percent of participants had evidence of LATE-NC. For cohorts that staged LATE-NC, about two-thirds had stage 2 or 3 pathology. In other words, about a quarter of all participants had stage 2/3 LATE-NC, which has been tied to cognitive impairment in previous studies.

How did LATE-NC relate to Alzheimer's disease pathology? Regardless of how the latter was measured, the main finding was the same: People with more severe Alzheimer's disease pathology, such as those with higher CERAD neuritic plaque scores or Braak stages, were more likely to also have LATE-NC. For example, while only a quarter of people with a CERAD score of "none" had LATE-NC, half of people with a CERAD score of "frequent" had this co-pathology. Notably, even among people without Aβ plaques, those with LATE-NC tended to have more extensive primary age-related tauopathy (PART).



Could Intellia's platform that targets transthyretin amyloidosis be repurposed to target TDP-43(and other protein aggregates)?

Posted by: erasmus at June 27th, 2022 8:15 AM
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