LATE To The Game
LATE To The Game
Apo E4/E4, Male, Age 60
Re: LATE To The Game
A few more details at Science Daily: https://www.sciencedaily.com/releases/2019/04/190430121800.htm
My quick skim of the paper leads me to believe they don't yet have a reliable way to diagnose "LATE" in living people. But if you want to be obsessive, here is their guess regarding genetic indicators:
See the "Genetics of LATE" section in the paper for more details.
The open access paper is: Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report"We proposed a new name to increase recognition and research for this common cause of dementia, the symptoms of which mimic Alzheimer's dementia but is not caused by plaques and tangles (the buildup of beta amyloid proteins that Alzheimer's produces). Rather, LATE dementia is caused by deposits of a protein called TDP-43 in the brain," said Dr. Julie Schneider
...
The function of normal TDP-43 (transactive response DNA binding protein of 43 kDa) is related to how cells use DNA to make proteins. In disease, TDP protein becomes misfolded (abnormally structured) and moves from its normal location in the cell. Abnormal TDP-43 was first recognized in amyotrophic lateral sclerosis and frontotemporal lobar degeneration, relatively uncommon diseases.
Recent research shows that misfolded TDP-43 protein is very common in older adults. Roughly 25 percent of individuals more than 85 years of age have enough misfolded TDP-43 protein to affect their memory and/or thinking abilities.
...
Based on existing research, the authors suggested that LATE progresses more gradually than Alzheimer's. However, LATE combined with Alzheimer's -- which is common for these two highly prevalent brain diseases -- appears to cause a more rapid decline than either would alone.
My quick skim of the paper leads me to believe they don't yet have a reliable way to diagnose "LATE" in living people. But if you want to be obsessive, here is their guess regarding genetic indicators:
The following five genes (in the chronological order in which they were identified) have been reported to harbour risk alleles associated with pathological manifestations we refer to as LATE-NC: granulin (GRN) on chromosome 17q, transmembrane protein 106B (TMEM106B) on chromosome 7p, ATP-binding cassette sub-family member 9 (ABCC9) on chromosome 12p, potassium channel subfamily M regulatory beta subunit 2 (KCNMB2) on chromosome 3q, and apolipoprotein E (APOE) on chromosome 19q (Dickson et al., 2010; Pao et al., 2011; Beecham et al., 2014; Murray et al., 2014; Nelson et al., 2014, 2015b; Aoki et al., 2015; Katsumata et al., 2017; Yang et al., 2018). See Supplementary Table 1 for summary information on these genes and their associated phenotypes
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An important recent finding by several different groups is that the APOE ɛ4 allele, which is a risk factor for ADNC and Lewy body disease, is also associated with increased risk for TDP-43 proteinopathy in the elderly (Robinson et al., 2018c; Wennberg et al., 2018; Yang et al., 2018). Other studies did not find an association between APOE genotypes and risk for hippocampal sclerosis (Troncoso et al., 1996; Leverenz et al., 2002; Nelson et al., 2011b; Pao et al., 2011; Brenowitz et al., 2014; Hall et al., 2019; but see Farfel et al., 2016). Few subjects with the APOE ɛ4 allele survive into advanced old age without any amyloid-β plaques (Saunders et al., 1993; Schmechel et al., 1993), and it remains to be seen exactly how the APOE ɛ4 protein influences TDP-43 proteinopathy. Nevertheless, recent studies from large research cohorts have provided additional insights into the presence of pathogenetic mechanisms that are shared between neurodegenerative diseases.
See the "Genetics of LATE" section in the paper for more details.
Re: LATE To The Game
NewRon wrote:https://www.bbc.com/news/health-48092570
Here's another take on this news:When is Alzheimer's not Alzheimer's? Researchers characterize a different form of dementia. The researchers quoted in this article offer some very specific hypotheses, such as the possibility that the failure some drug trials on preventing or slowing Alzheimer's disease may have been due to the incorrect diagnosis of people with LATE, which affects the amygdala and hippocampus more than other regions typically affected by AD.BrianR wrote:A few more details at Science Daily: https://www.sciencedaily.com/releases/2 ... 121800.htm
. {Emphasis added.]Suggestions were provided for possible strategies to help guide future therapeutic interventions, including the importance of removing subjects with LATE from other clinical trials, which could significantly improve the chances of successful Alzheimer's breakthroughs. The researchers also discussed the importance of more epidemiological, clinical, neuroimaging and genetic studies to better characterize LATE, and the need for research in diverse populations.
And although the research is in early days, here's some associations of ApoE 4 and TDP-43 from autopsy studies of the Religious Orders Project and Rush Memory and Aging Project, published in 2018:
[Emphasis added.]APOE ε4 seems to increase TDP-43 burden, and this effect in turn was associated with higher odds of hippocampal sclerosis, a pathology potentially downstream of TDP-43 proteinopathy. TDP-43 proteinopathy contributes to the detrimental effect of APOE ε4 on late-life cognition through mechanisms independent of Alzheimer's disease pathology, and future research should consider that TDP-43 proteinopathy might be an integral component of APOE-related neurodegeneration.
Evaluation of TDP-43 proteinopathy and hippocampal sclerosis in relation to APOE ε4 haplotype status: a community-based cohort study
This is one of the areas in which funding from the National Institute of Aging and the Alzheimer's Association may make a significant difference in the ability to correctly diagnose, treat and or ameliorate the effects of this recently identified "bad actor".
4/4 and still an optimist!
Re: LATE To The Game
The emergence of LATE to refine the differential diagnosis of Alzheimer's had until late entirely escaped my attention.
However, it is of considerable importance that Alzheimer's be a clearly defined neuropathology, otherwise clinical
trials might wrongly conclude that treatments were ineffective. From what I understand now TDP-43 associated
dementing illness might rival the incidence of AD (especially at older ages).
LATE is a topic that all those on forum should become informed about. What is particularly exciting is that all of the dark matter
of the dementing universe might now have been discovered. A reasonable concern could have been that a large (possibly near infinite)
number of agglomerating proteins aside from beta-amyloid, tau, prions(?), and TDP-43 might have lurked in the brain making the discovery of all of these proteins a long term project. Yet, if TDP- 43 (LATE) comprises ~20% of dementias that had previously been typically diagnosed as AD, then we might already approaching an era in which Alzheimer's disease is a clear clinical entity and not merely a residuum of "other".
However, it is of considerable importance that Alzheimer's be a clearly defined neuropathology, otherwise clinical
trials might wrongly conclude that treatments were ineffective. From what I understand now TDP-43 associated
dementing illness might rival the incidence of AD (especially at older ages).
LATE is a topic that all those on forum should become informed about. What is particularly exciting is that all of the dark matter
of the dementing universe might now have been discovered. A reasonable concern could have been that a large (possibly near infinite)
number of agglomerating proteins aside from beta-amyloid, tau, prions(?), and TDP-43 might have lurked in the brain making the discovery of all of these proteins a long term project. Yet, if TDP- 43 (LATE) comprises ~20% of dementias that had previously been typically diagnosed as AD, then we might already approaching an era in which Alzheimer's disease is a clear clinical entity and not merely a residuum of "other".
