Reply: Selected cryptic exons accumulate in hippocampal cell nuclei in Alzheimer’s disease with and without associated TDP-43 proteinopathy

Sir,

Pascual Torres and colleagues (2020) provide new and interesting information about biochemical phenomena relevant to common age-related brain diseases—Alzheimer’s neuropathological changes (ADNC) and limbic-predominant age-related TDP-43 encephalopathy neuropathological changes (LATE-NC). In their experiments, evaluating 11 ADNC and six ADNC + LATE-NC samples, they found that specific cryptic exons accumulated in ADNC, but they report no evidence that LATE-NC was associated with increased cryptic exon splicing. Additional topical experiments were performed in cultured clonal tumour cells. This report provides added information about the complexity of the pathogenetic changes occurring in the aged brain. I agree emphatically with one of their concluding points:’ the presented data emphasize the complexity of TDP-43 proteinopathy, which almost certainly extends beyond one mechanistic factor—multiple toxic gains and losses of function being present for this protein in CNS diseases’.

I do have a quibble with their sentence: ‘As TDP-43 proteinopathy was already described in Alzheimer’s disease, other opinions casted doubt on whether this is a novel entity or not’. The consensus working paper on LATE (Nelson et al., 2019) did not lay claim that LATE-NC represents a ‘novel different entity’. Instead, that paper documented exhaustively that many researchers have published evidence of LATE-NC features in various cohorts and contexts, over the past several decades. One researcher worthy of note is Dr Dennis Dickson, who made groundbreaking observations about pathological and clinical manifestations of this disease in the early 1990s (Crystal et al., 1993; Dickson et al., 1994), often with co-morbid ADNC, and who was second author on the consensus working group paper. However, for clinicians (neurologists and neuropathologists) and bench researchers alike, there were previously no consensus-based or universally applied nomenclature or staging system. There also had been no prior gathering of experts to discuss these common and impactful clinical-pathological phenomena.

Regarding the combination of ADNC and LATE-NC, this is a fast-developing research domain that defies simplistic discussion. There is evidence of pathological synergies between ADNC and LATE-NC (Smith et al., 2017), as there is between ADNC and Lewy body disease (Chornenkyy et al., 2019). However, ∼80% of the ‘oldest-old’ have some degree of ADNC (and these are yet more enriched in many dementia research cohorts) (Braak et al., 2011), and ∼30% of subjects in that population have LATE-NC (Nelson et al., 2019), so it is extremely likely that many aged brains will have co-morbid pathologies. On the other hand, many brains have very severe ADNC on autopsy and lack LATE-NC; certainly, LATE-NC is not an obligate feature of ADNC. Another key point is that the presence of LATE-NC (with or without co-morbid ADNC—and usually they are together) is associated strongly with additive clinical impairment (Nelson et al., 2010; Murray et al., 2014; Nag et al., 2017). Thus, it is important to have a neuropathological diagnosis, and, it is correspondingly important to have that diagnosis standardized, as is the case for any other prevalent and clinically impactful condition. The consensus working group, in a 2-day meeting, with a multidisciplinary group of experts that have published extensively in this area, made suggestions to achieve this key goal. The resulting paper has successfully catalysed and helped to focus substantial new research efforts. Obviously, there is a lot of work to be done in this scientific area, and I’m glad that excellent researchers such as this group from the University of Barcelona are actively contributing.

Data availability

Data sharing is not applicable to this article as no new data were created or analysed in this work.

Funding

NIH grants P30 AG028303.

Competing interests

The author reports no competing interests.