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Mutations in earls onset AD
Monti00
Posted: Thursday, June 11, 2020 6:13 AM
Joined: 8/12/2019
Posts: 38


Hello, recently i saw an article about psen mutations in eoad https://jamanetwork.com/journals/jamaneurology/fullarticle/783125

 

In they article they Said that if they used a cutoff age of 52 or younger they would detect 85% of the psen mutations, because most mutation carrier were younger than 52 but they wrote that „with the inclusion of a low number of patients without mutations“(specificity=25%) and with a cut off age of 58 they said that 44% of patients without mutations would be tested. Does it mean that 25% of patients below the age of 52 do not have a mutation? But that would be ilogical, because the average age at onset in the sporadic group was 49 years and the vast majority of them didn’t have a mutation, so what do they mean with 25% of patients without a mutation or 44% of patients without a mutation?
Lane Simonian
Posted: Thursday, June 11, 2020 1:19 PM
Joined: 12/12/2011
Posts: 4983


I am trying to parse through the language used by the authors:

"...if an age of 52 years or younger is used to select patients who will be tested, then 85% of PSEN mutations would have been detected with the inclusion of a low number of patients without mutations (1-specificity=25 percent).  If we had chosen a cutoff age of 58 years or younger, we would have detected 92 percent of PSEN mutations although with an increase in number of patients without mutations (44%) tested."

The authors seem to be saying that the percentage of people tested without mutations goes from 25 percent to 44% between age 52 and 58 (although this does not seem to match some of the other data presented in the article).

The more important question is why did 8 percent of people with PSEN not develop Alzheimer's disease before age 58.  Was there a counteracting genetic factors that delayed the age of onset and/or was their diet or some other non-genetic factor delaying the onset of Alzheimer's disease?


Monti00
Posted: Friday, June 12, 2020 5:19 PM
Joined: 8/12/2019
Posts: 38


So the authors try to say that below the age of 52, only 25% of the patients don’t have a mutation? And 44% of the patients below 58, but that would be very contradictory because they found one mutation in the familial non autosomal dominant group and one in the sporadic group what means that the vast majority of them do not have a mutation(more than 90%) and the average age of onset is 49 in the sporadic group what means it’s below the age of 52 and if 15 patients have onset before 52 and no mutation than there are definitely more than 50% without a mutation so why do they write 25%? And in the familial non autosomal dominant group the average age of onset is 54 years what’s also below the age of 58 and there are much more than 44% without a mutation. So is it possible that the authors try to say something else?and I think it’s normal That there are some carriers who develope the disease over the age of 58 because they are not all relatives and early onset Alzheimer’s usually occurs between 30-60 so it’s not that uncommon.
Lane Simonian
Posted: Friday, June 12, 2020 6:33 PM
Joined: 12/12/2011
Posts: 4983


I noticed a problem in the study: it does not indicate how many of the participants had amyloid precursor protein mutations.  Are we left to assume this is what accounts for the difference in the percentages between those with mutations and those without mutations for early onset Alzheimer's disease?  Hard to say.

There does not seem to be any definitive study indicating what percentage of early onset cases are due to determinant mutations.  My guess, too, is that the number of cases not due to mutations has increased over the years.


Monti00
Posted: Saturday, June 13, 2020 6:20 PM
Joined: 8/12/2019
Posts: 38


There are two headlines with results and in the second one, they said that the did not find any mutations in the app gene.
Lane Simonian
Posted: Saturday, June 13, 2020 8:30 PM
Joined: 12/12/2011
Posts: 4983


Thank you for pointing this out.  I picked this out in the first reading; did not pick it out in the second reading, and struggled to find it in the third reading:

"We did not find any mutations in the APP gene."

Still something seems wrong: "The frequency of [PSEN] mutations was 54.6% (6/11) among the autosomal dominant group."  

Which based on the following seems impossible if there were no APP gene mutations.

"The early-onset familial forms of AD have an autosomal dominant inheritance linked to 3 genes: APP, PSEN1, and PSEN2, whereas the most common sporadic form of AD, which occurs after the age of 60, has thus far been consistently, across numerous studies, associated with only 1 gene, the APOE gene."

More to your point, it seems like most of the early onset cases were not due to autosomal dominant genetic mutations based on table one, despite the authors assertions to the contrary.

 


Lane Simonian
Posted: Saturday, June 13, 2020 11:09 PM
Joined: 12/12/2011
Posts: 4983


I am looking for comparable studies.  This one is from 2002.  I will see if there is a more recent one.

Early onset familial Alzheimer’s disease

Mutation frequency in 31 families

 Objective: To determine the proportion of patients with early onset AD with a positive family history accounted for by mutations in these genes.

Methods: A mutational analysis of the amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) genes was performed in 31 probands with probable or definite AD from UK families with an age at onset (AAO) <61 years.

Results: The mean AAO was 46.9 years (median 45 years; range 33 to 60 years). The majority of patients (23 of 31; 74%) fulfilled recognized criteria for autosomal dominant inheritance. In 17 (55%) probands the authors identified eight novel PSEN1 sequence variants and eight recognized pathogenic mutations. In 4 (13%) probands the authors identified one novel APP sequence variant (H677R) and two recognized mutations. Thus in this series 21 of 31 (68%) probands were associated with a sequence variant in APP or PSEN1. Nine of the 11 (82%) probands with neuropathologically confirmed AD who additionally fulfilled recognized criteria for autosomal dominant inheritance were associated with a sequence variant in APP or PSEN1. The 10 patients in whom the authors were unable to identify a mutation in APPPSEN1, or PSEN2 were older than the probands with sequence variants (55.4 vs 44.7 years: p = 0.001).

Conclusions: Sequence variants in APP and PSEN1 accounted for the majority of neuropathologically confirmed autosomal dominant early onset AD; no mutations in PSEN2 were detected. There may be a further genetic factor involved in the etiology of autosomal dominant early onset AD.


Monti00
Posted: Sunday, June 14, 2020 11:53 AM
Joined: 8/12/2019
Posts: 38


I’ve already seen this study, but the authors concentrated on the familial(Autosomal dominant type) of eoad, were mutations are much more common. But I think there are more sporadic/familial without an autosomal Dominant inheritance cases. I looked for some more Studies and found an really interesting onehttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3332307/#!po=0.909091
Lane Simonian
Posted: Sunday, June 14, 2020 12:17 PM
Joined: 12/12/2011
Posts: 4983


This is a very interesting article: another aspect to consider at least. 

I wonder beyond this, how many cases of early onset Alzheimer's disease are due to non-genetic or epigenetic factors.  In comparison to late onset cases, the various causes of early onset Alzheimer's disease have not seemed to receive a great deal of attention.


Marcus1976
Posted: Saturday, June 20, 2020 9:24 AM
Joined: 5/22/2020
Posts: 9


In the article about psen mutations among early onset patients, they said that they found 11 families with an autosomal dominant inheritance 16 with a sporadic type and 25 without autosomal dominant inheritance but a family history. But later the wrote, that among the 11 families who presented with autosomal dominant inheritance there are 16 subjects and in the non autosomal dominant group with family history there were 28 subjects now. But the sporadic group didn’t change. Is that the cases, because in the familial and autosomal dominant were some of the patients relatives?