Review: A multi-hit hypothesis for an APOE4-dependent pathophysiological state

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BrianR
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Review: A multi-hit hypothesis for an APOE4-dependent pathophysiological state

Post by BrianR »

Open access. A review which discusses 9 methods (hits) by which APOE4 can damage brains. Extensive references if you want to dig deeper into any of those methods. (neurodegeneration, neurovascular dysfunction, neuroinflammation, oxidative stress, endosomal trafficking impairments, lipid and cellular metabolism disruption, impaired calcium homeostasis and altered transcriptional regulation)

https://onlinelibrary.wiley.com/doi/full/10.1111/ejn.15685

A multi-hit hypothesis for an APOE4-dependent pathophysiological state
Oliver George Steele, Alexander Cameron Stuart, Lucy Minkley, Kira Shaw, Orla Bonnar, Silvia Anderle, Andrew Charles Penn, Jennifer Rusted, Louise Serpell, Catherine Hall, Sarah King
First published: 05 May 2022
European Journal of Neuroscience
https://doi.org/10.1111/ejn.15685

Abstract
The APOE gene encoding the Apolipoprotein E protein is the single most significant genetic risk factor for late-onset Alzheimer's disease. The APOE4 genotype confers a significantly increased risk relative to the other two common genotypes APOE3 and APOE2. Intriguingly, APOE4 has been associated with neuropathological and cognitive deficits in the absence of Alzheimer's disease-related amyloid or tau pathology.

Here, we review the extensive literature surrounding the impact of APOE genotype on central nervous system dysfunction, focussing on preclinical model systems and comparison of APOE3 and APOE4, given the low global prevalence of APOE2. A multi-hit hypothesis is proposed to explain how APOE4 shifts cerebral physiology towards pathophysiology through interconnected hits.

These hits include the following: neurodegeneration, neurovascular dysfunction, neuroinflammation, oxidative stress, endosomal trafficking impairments, lipid and cellular metabolism disruption, impaired calcium homeostasis and altered transcriptional regulation.

The hits, individually and in combination, leave the APOE4 brain in a vulnerable state where further cumulative insults will exacerbate degeneration and lead to cognitive deficits in the absence of Alzheimer's disease pathology and also a state in which such pathology may more easily take hold. We conclude that current evidence supports an APOE4 multi-hit hypothesis, which contributes to an APOE4 pathophysiological state. We highlight key areas where further study is required to elucidate the complex interplay between these individual mechanisms and downstream consequences, helping to frame the current landscape of existing APOE-centric literature.
ejn15685-fig-0008-m.jpg
FIGURE 8: The multihit hypothesis. APOE4 genotype promotes a pathophysiological state of vulnerability to further damage through multiple interacting hits. Cellular stress, ageing and an altered transcriptional landscape act as key moderators of many of the hits described and are thus highlighted in their own box (top right). There are multiple points of crosstalk between APOE4-mediated hits (as described in Section 10). Including the following: lipid and metabolic homeostasis and neuronal maintenance; calcium homeostasis and transcriptional regulation; neuroinflammation, oxidative stress and neurovascular dysfunction; and endosomal trafficking, lipid homeostasis and neurodegeneration. Abbreviations: ApoE4, apolipoprotein E4; CNS, central nervous system.
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Re: Review: A multi-hit hypothesis for an APOE4-dependent pathophysiological state

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I suspect this research is fundamentally flawed in some way and have previously posted about the other hypothesis that divide the population into different cultural populations of APOE4. Instead of finding them now I found quickly other recent research that supports this idea. The implications of looking at the negative hits is that it sets us a looks to the negative aspects of APOE4 when it can also pointed out that certain cultural practises of the most dominate segment of defect holders the European subset one does have many people living to and beyond 100.
The more research we have the better we all can understand that there is hope in the future so please do not think it is critical but to draw attention to other positive aspects of research.

APOE ε4 is not associated with increased risk for Alzheimer’s disease and dementia in American Indians
https://www.nia.nih.gov/news/apoe-e4-no ... an-indians
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Re: Review: A multi-hit hypothesis for an APOE4-dependent pathophysiological state

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Greyhound wrote: Tue Jun 21, 2022 2:42 pm APOE ε4 is not associated with increased risk for Alzheimer’s disease and dementia in American Indians
I wish they broke up the Native Americans by life style and/or location...

It could be that with the VERY limited initial gene pool that make up the current population, I wonder if they developed a separate gene mutation that ameliorates the negative affects of a carb-rich lifestyle.
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Re: Review: A multi-hit hypothesis for an APOE4-dependent pathophysiological state

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Greyhound wrote: Tue Jun 21, 2022 2:42 pm APOE ε4 is not associated with increased risk for Alzheimer’s disease and dementia in American Indians
mike wrote: Tue Jun 21, 2022 4:30 pmI wish they broke up the Native Americans by life style and/or location...
Your wish is granted! For some background for others reading this, the current study used multiple cognitive and imaging tests, very similar to what is currently used on studies to clearly and accurately identify those with early signs of neuropathology and impaired cognition. The complete article is available for $10. for 48-hour online access here: https://alz-journals.onlinelibrary.wile ... /alz.12573

In the current study using data from 2010-2013, 72.5% of those ages 64-95 were ApoE 3/3; 21% ApoE 3/4; 5.1%
ApoE 2/3; 0.7% ApoE4/4 and 0.6% ApoE 2/4
Participants were mean 73 years, 67% female, and 54% had some college education. The majority were obese (>50%), hypertensive (>80%), and diabetic (>50%).Neither imaging findings nor multidomain cognitive testing showed any substantive differences between APOE ε4 carriers and non-carriers.
APOE genotype, hippocampus, and cognitive markers of Alzheimer's disease in American Indians: Data from the Strong Heart Study

Some digging found this information from the initial Strong Heart study, which began in 1989 with 8,670 participants, who comprised 62% of eligible participants--a truly amazing willingness to participate in a study of cardiovascular risk. An abstract of a 1990 article on the original study design notes that:
The study population consists of 12 tribes in three geographic areas: an area near Phoenix, Arizona, the southwestern area of Oklahoma, and the Aberdeen area of North and South Dakota....[including] a clinical examination of 4,500 tribal members aged 45-74 years in order to estimate the prevalence of cardiovascular disease and its associations with risk factors. Family history, diet, alcohol and tobacco consumption, physical activity, degree of acculturation, and socioeconomic status are assessed in personal interviews. The physical examination includes measurements of body fat, body circumferences, and blood pressure, an examination of the heart and lungs, an evaluation of peripheral vascular disease, and a 12-lead electrocardiogram. Laboratory measurements include fasting and postload glucose, insulin, fasting lipids, apoproteins, fibrinogen, and glycated hemoglobin. Also measured are serum and urine creatinine and urinary albumin. DNA from lymphocytes is isolated and stored for future genetic studies.
The Strong Heart Study. A study of cardiovascular disease in American Indians: design and methods

A second phase of the Strong Heart study looked at diet compared with national dietary guidance and national samples of other adults in the U.S. "to determine areas for improvement." Surprise, surprise: Native Americans were not eating diets "substantially different" than the people in other US studies of diet.
Results: Nutrient intakes varied little between centers... Carbohydrate and sodium intakes were higher among participants compared with NHANES III estimates, whereas intakes of several vitamins were lower....Conclusions: Dietary intakes of American Indians vary by age, sex, and geographic location, but do not differ substantially from national estimates of dietary intake...and are not consistent with the remarkably different rates of CVD and associated comorbidities that currently exist.
https://pubmed.ncbi.nlm.nih.gov/16321595

Because the the 2010 group only had 0.7% ApoE 4/4 carriers ( 6 out of 811) and only 0.6% of ApoE 2/4 carriers (5 out of 811) it seems possible that the original group was close to US prevalence of 2% each for ApoE 2/4 and 4/4 and a disproportionate 1.5% of each type died from cardiac, metabolic or Alzheimer's disease between 1991 and 2010. At an average age of 73, the ApoE 3/4 carriers seem unlikely to currently show MCI/AD cognitive impairment or MRI atrophy, given a risk to age 85 for those healthy at age 70-75 with ApoE 3/4 of about 15%. APOE-related risk of mild cognitive impairment and dementia for prevention trials: An analysis of four cohorts

My take-away: It's great news for Native Americans with risk factors including ApoE4: if they live to be in their 70's, they may continue to do well given access to excellent health care. The researchers suggest that access to traditional food source and "positive aging features" may provide resilience against genetic risk. They recommend further work on cultural, genetic and environmental protective factors, as well as study of amyloid and tau biomarkers.
4/4 and still an optimist!
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Re: Review: A multi-hit hypothesis for an APOE4-dependent pathophysiological state

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NF52 wrote: Sat Jun 25, 2022 12:23 pm Because the the 2010 group only had 0.7% ApoE 4/4 carriers ( 6 out of 811) and only 0.6% of ApoE 2/4 carriers (5 out of 811) it seems possible that the original group was close to US prevalence of 2% each for ApoE 2/4 and 4/4 and a disproportionate 1.5% of each type died from cardiac, metabolic or Alzheimer's disease between 1991 and 2010. At an average age of 73, the ApoE 3/4 carriers seem unlikely to currently show MCI/AD cognitive impairment or MRI atrophy, given a risk to age 85 for those healthy at age 70-75 with ApoE 3/4 of about 15%. APOE-related risk of mild cognitive impairment and dementia for prevention trials: An analysis of four cohorts

My take-away: It's great news for Native Americans with risk factors including ApoE4: if they live to be in their 70's, they may continue to do well given access to excellent health care. The researchers suggest that access to traditional food source and "positive aging features" may provide resilience against genetic risk. They recommend further work on cultural, genetic and environmental protective factors, as well as study of amyloid and tau biomarkers.
Thanks Nancy! I'm wondering if you can actually get any statistical relevant numbers with only 6 4/4 carriers... Also, what % of people die before age 73? It looks like you're saying that 2/3 of 4/4 native americans die before age 73 (.7/2)? Seems a bit high...
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Re: Review: A multi-hit hypothesis for an APOE4-dependent pathophysiological state

Post by BrianR »

mike wrote: Mon Jun 27, 2022 10:50 am ... Also, what % of people die before age 73? It looks like you're saying that 2/3 of 4/4 native americans die before age 73 (.7/2)? Seems a bit high...
Source: https://www.ihs.gov/newsroom/factsheets/disparities/
American Indians and Alaska Natives born today have a life expectancy that is 5.5 years less than the U.S. all races population (73.0 years to 78.5 years, respectively).
I wonder if some of the lower incidence of dementia may be a survivor bias effect.
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