Memory Loss / Dementia / Alzheimer's

MediaFanatic

[Login to see the link] recently posted excellent citations on blue light & sleep.

If I recall, you are a neurologist. I'm interested in his take on the following topics. I thought some other members might also be interested.

I've read that certain genes have been identified as risk factors for Alzheimer's.

For instance, having one copy of the ApoE4 gene variant can increase your risk 2-3 times, while having two copies (one from each parent) can increase your risk 12-fold.

Additionally, early-onset Alzheimer's is often associated with specific genetic mutations in the APP, PSEN1, or PSEN2 genes, which are inherited in an autosomal dominant fashion, meaning that each child of a person with one of these mutations has a 50% chance of inheriting it.

Are there other genetic markers that you're aware of, or indications to watch out for?

Thank you.

thebuzzard

The genetics of Alzheimer Disease - like most degenerative neurological disorders - is a complex interaction of genetic and epigenetic (which are external, influencing agents which may impact an individual's genes, without affecting the underlying genome - tobacco smoke, air pollution, radiation, drugs, industrial chemicals & pesticides, starvation, and simple aging are known examples ). I have heard genetic/epigenetic influence described as a board of flip-switches (which represent individual genetic markers/sequences), where you will not develop a disease/disorder unless an extraordinarily complex combination of "on-off " switches are coordinated & realized on or off.

Be aware that the National Library of Medicine ("PubMed" - NCBI) maintains the Online Mendelian Inheritance in Man ([Login to see the link]),which is a searchable "catalog of human genes and genetic disorders and traits, with particular focus on the molecular relationship between genetic variation and phenotypic expression." You can search and download by disease/disorder, symbol, phenotype, etc., and simply searching on "alzheimer" results in 405 references, including primary genes and contributory genes and processes.

One interesting example of pursuing the genetic influences of Alzheimer's Disease is to focus on the discovery of the gene responsible for the "beta-amyloid protein" in 1984 (which is identified by the symbol APP, cytogenic location 21q21.3, and genomic coordinates 21:25,880,550-26,171,128). This is responsible for the formation of the twisted plaque core that characterizes what we know as primary "Alzheimer' Disease 1, familial" (and interestingly enough, this amino acid composition, molecular mass, etc. is "nearly identical" to what is found in Down's Syndrome). You can find this presentation here: [Login to see the link]

Finally, I like this citation, specifically related to "early-onset" Alzheimer's Disease, but a good review of the core science.

Cacace, R., Sleegers, K., Van Broeckhoven, C. Molecular genetics of early-onset Alzheimer's disease revisited. Alzheimer's & Dementia Volume 12, Issue 6, June 2016, Pages 733-748, [Login to see the link].

Abstract

As the discovery of the Alzheimer's disease (AD) genes, APP, PSEN1, and PSEN2, in families with autosomal dominant early-onset AD (EOAD), gene discovery in familial EOAD came more or less to a standstill. Only 5% of EOAD patients are carrying a pathogenic mutation in one of the AD genes or a apolipoprotein E (APOE) risk allele ε4, most of EOAD patients remain unexplained. Here, we aimed at summarizing the current knowledge of EOAD genetics and its role in ongoing approaches to understand the biology of AD and disease symptomatology as well as developing new therapeutics. Next, we explored the possible molecular mechanisms that might underlie the missing genetic etiology of EOAD and discussed how the use of massive parallel sequencing technologies triggered novel gene discoveries. To conclude, we commented on the relevance of reinvestigating EOAD patients as a means to explore potential new avenues for translational research and therapeutic discoveries.

[Login to see the link]

crickety

thebuzzard I concede your aversion to AI but it seems necessary for any complete prediction of outcomes, if ever fully possible. Thank you for taking the time to enlighten. Don't forget to joke once in awhile. But of course not here.

thebuzzard

crickety For the record, I'm not averse to AI in the least. It constitutes the amzaing future of research, clinical trials, development of effective therapies, and as you say, outcome prediction. What I am averse to is the fundamental lack of theoretical & practical ethics to guide machine learning. If you say this is, generally, a technology developed and maintained by private enterprise, and to impose rules & guidelines would be censorship & interference with privacy rights and business development, I would offer the example of genetic manipulation through

CRISPR (Login to see the link

There are international restrictions on its use (and, obviously, abuse), and sanctions, censoring (which cut off research funding to individuals, universities, and independent labs), and serious fines have been imposed (e.g. the Chinese lab that attempted to cross-breed across species - parabiosis - of a human embryo and a pig, and when discovered, unapologetically stated that it had been immediately destroyed - sure...). Obviously we don't know what we don't know, but the rules and sanctions are at least in place and have been applied. CRISPR is, theoretically, an amazing technology that predicts the end of many genetically influenced disease, but is also capable of great destruction (e.g. a Chinese scientist indicated that he intended to experiment on mitochondrial DNA -mtDNA [Login to see the link] went to jail). Similar ethical sanctions should guide AI as well.

As for joking, I actually twice did 15-minutes of open-mic stand-up at the Comedy Club in SoCal. Now imagine a psychiatrist with stage fright...

crickety

thebuzzard No thanks, just imagining doing stand-up keeps me still. I applaud your bravery and hope you won your bet. I definitely agree with your estimate of human's ability to "play" with the unknown, ignoring the possibilities of bad outcomes. Frankenstein was a warning. I crossbred treefrogs in H.S. just to "see". No more. My conversations with the Bard seem hopeful or at least more positive than not. Bard assures me that different routes are tried and then the most right is kept until changed. But? I tend to trust machine more than human. Vonnegut wrote well of our big-brainess succumbing to stupidity in the final decision. I have hope for CRISPR but it is so easy just "see" what will happen without thought of . . . I'll admit to being naive, I still hope there's a way to instill a conscience in AI to keep us from just "seeing" what will happen. But will we listen AND obey. What happened to the use of ethics committees? We know what not to do (mostly) and always want to anyway. Pandora's box is opened and makes me seek divine interference. Good luck in your endeavors. My path is near ending. But as others have offered: somehow we survive. As a psychiatrist, how do you keep your cool from freaking out knowing the potential catastrophes around every corner?

thebuzzard

crickety When I was in medical school, I had the opportunity to hear several lectures by Irvin Yalom, MD, who was a professor of psychiatry at UC Berkley, and author of a number of what have become classics of instruction for practicing clinicians. One of the volumes is _Principles & Practices and of Group Psychotherapy _- which, obviouslis of little interest to non-clinicians - but he devotes a full chapter to the issue of "Healing Factors." At the very top of the list, he enphasizes the "instillation of hope," and the necessity for clinicians to immediately set that goal. The entire chapter was not only instructive, but this insistence of offering and encouraging hope was a dramatic revelation to me. Most importantly, in order to "instill" hope, you need to have hope, and I began pursuing it. I ended up training and working in forensics, and was hired by the medical school in my community to travel to state prisons - for men and for women - preparing those approved for parole who had a mental health and/or substance use disorder. I vowed to myself that no patient would leave without receiving the message of hope; hope in the ability to change. hope in the ability to suceed, and hope to enjoy a different way of life. I can't tell you how amazed & grateful I felt when I went with my wife to Target for something, and as we were checking out, there was loud banging & crashing from the men's bathroom nearby, and suddenly the door opened, and it was a patient I had seen prison, trying with limited success to navigate a bucket w mops & and a cart with cleaning supplies out the door. He came over to me and he said this was his new job - which he basically enjoyed - he still was taking his meds, and he was living in a small halfway house. I told him I was proud of him, and he went back to work. These, crickety, are a whole lotta words to make one simple point: I keep my cool by hope. I also quit watching the news, and quit listening to liars,politicians (same outfit as liars), conspiracy theorists, and peddlers of misinformation. In any case, hope enriches, enlightens, comforts, and calms me.

abluesboy

err , what are we talking about again ?

MediaFanatic

[Login to see the link] - Excellent details, thank you very much for the reply.

I also don't think that anyone here disagrees that for every bit of promise behind deep-learning, there is just as much to be concerned about. If there is someone that disagrees, I hope you will allow us to disavow you of that notion.

Funny anecdote - Speaking of epigenetics, I was providing support for a friend who recently debated Steve Kirsch a few days back. Kirsch is now back on the "vaccines cause ASD" nonsense, because he's done a few "studies" (surveys - yes, he refers to his social media surveys as "studies" that he believes will pass peer rigor).

In that debate, a Dr. Ben Tapper (Chiropractor) jumped-in and started lecturing everyone on epigenetics as if no one understood such a cursory topic generally introduced in highschool.

With each exchange among the anti-science group, particularly when they go against things so easily disproven, I'm becoming more worried for our world. I've invested hundreds upon hundreds of hours on Quora & Twitter debunking insane claims and with each year, they become worse.

[Login to see the link] - I see what you did there 😉

abluesboy

MediaFanatic With each exchange among the anti-science group, particularly when they go against things so easily disproven, I'm becoming more worried for our world. I've invested hundreds upon hundreds of hours on Quora & Twitter debunking insane claims and with each year, they become worse.

This , confuses me and instills a fear for the future 🙁

We appear to be rushing headlong back to the dark ages and some who will profit from this are hastening the decent .

being well on the way to my 3 score and 10 is a blessing .........

crickety

thebuzzard Excellent. Hope and healing are the highest calling. I thank you for your reply and saving souls. Most of society prefers to ignore those living in hell. As you well know. But a slight bit of humor: I walk the Sonoran Desert in AZ, and the vultures circling make me nervous, though serving their purpose. Your chosen handle of buzzard, is there a hidden meaning? Just curious. And silence is a satisfactory answer. Peace be always with you, brother. 🪶

thebuzzard

abluesboy I suspect that, like the CRISPR controversies I noted above, an "incident" of AI action literally causing direct harm (e.g. the US armed forces have approved experiments with trained machines making their own "kill shot" decisions without a human approving/consenting to the decision) will result in social backlash, and ultimately lead to ethical standards and regulation. One of the biggest concerns of scientist in the field is that only wealthy conglomerates will be able to absorb the cost of massive data mining required for AI, thereby monopolizing the technology to the exclusion of smaller, independent users. Monopolies tend to isolate themselves from "transparency" and independent evaluation of their methods & activity, and reject voluntary accountability despite utilizing a potentially volatile technology. Nevertheless, it seems likely that - relying on the history of business ethics in the US (see The Moral Background: An Inquiry into the History of Business Ethics by Gabriel Abend ) - the paradoxical case that when social ethics wane, business leaders seem to step in to fill the void (e.g. John Maxwell's Ethics 101 and There's No Such Thing as "Business" Ethics: There's Only One Rule for Making Decisions; The Righteous Mind: Why Good People are Divided by Politics and Religion by Jonathan Haidt).

Work on acquiring hope in the few years you have left bro' [crickety: this was a joke].

crickety

thebuzzard duly noted and greatly appreciated, and that remaining time is wrong.