View source for ApoE ε4 and health conditions besides (or maybe contributing to) Alzheimer’s

== Introduction ==
The ε4 variant of the ApoE gene is mostly associated with Alzheimer’s Disease but other conditions have also been linked to it.

Do remember that this gene variant alone does not cause a medical condition.  Environmental, dietary, lifestyle, and other factors play strong epigenetic roles, and all those factors cannot be controlled in studies. 

This wiki article attempts to address conditions that have been identified, although not necessarily confirmed, as associated with ApoE ε4.  Don’t look at the list and think, “All this and Alzheimer's too? I’m doomed!”  These conditions are interconnected and some may be contributory subsets to a diagnosis of Alzheimer's.  

Remember, what's good for the body is good for the brain and vice versa.  The diet/lifestyle strategies suggested for an ApoE ε4 carrier in our [https://www.apoe4.info/forums/viewtopic.php?f=33&t=1418 PRIMER: An introduction to ApoE4, biochemistry, and possible prevention strategies], other articles contained within this ApoE4.info wiki, and in the ApoE4.info discussion threads can positively influence all of these conditions. 

Lastly, read the findings carefully, with some of the listed conditions the association with ApoE ε4 is weak, conflicted, and/or in need of further research.

== High Cholesterol (Hypercholesterolemia) ==

Cholesterol is a complex subject with multiple expert opinions, this subheading discussion strictly addresses that ApoE ϵ4s tend to have higher cholesterol numbers, for more information on the subject of lipids and cholesterol first read the lipid section in the [https://www.apoe4.info/forums/viewtopic.php?f=33&t=1418 PRIMER: An introduction to ApoE4, biochemistry, and possible prevention strategies], then see the ApoE4.info wiki article, [[Cholesterol, Lipids and Treatments, including statins]]

Hypercholesterolemia is a type of hyperlipidemia that refers to higher than normal levels of low-density lipoprotein (LDL) cholesterol, the so-called "bad cholesterol" or total cholesterol, but does not include triglycerides.

There is at least one study that suggests that the relationship between APOE4 and lipids may be beneficial for pathogen-driven immune responses and unlikely to increase cardiovascular risk in an active subsistence population. (Source:  [https://elifesciences.org/articles/68231 APOE4 is associated with elevated blood lipids and lower levels of innate immune biomarkers in a tropical Amerindian subsistence population] (Angela R Garcia et al, 29 Sep 2021).

Studies supporting hypercholesterolemia in ApoE ϵ4s (not a complete list):
* [https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1399-0004.1990.tb03579.x '''''Association of hypercholesterolemia and apolipoprotein E4 in school children'''''](Hisako Yanagi, et al., Oct 1990):
::APOE4 was present in 21 of 51 hypercholesterolemic children (41.2%), and in nine of 51 control subjects (17.6%). The difference was significant (p<0.01). This finding indicates that APOE4 is associated with hypercholesterolemia in children.

* [https://link.springer.com/article/10.1007/s00109-016-1427-y '''''Apolipoprotein E: from cardiovascular disease to neurodegenerative disorders'''''] (Robert W. Mahley, 09 Jun 2016)
::ApoE2 and apoE4 increase the risk for heart disease: apoE2 increases atherogenic lipoprotein levels (it binds poorly to LDL receptors), and '''apoE4 increases LDL levels''' (it binds preferentially to triglyceride-rich, very low density lipoproteins, leading to downregulation of LDL receptors).

* [https://www.sciencedirect.com/science/article/pii/S0021915000005700 '''''Apolipoprotein E genotype and cardiovascular disease in the Framingham Heart Study'''''] (CarlosLahoz, et al., 15 February 2001):
::The apo E4 (Arg112-Cys) polymorphism has been associated with dementia and hypercholesterolemia.

== Hypertriglyceridemia  ==
[[File:ApoE4 triglycerides.jpg|thumb|Graph showing that triglycerides were higher in APOE4s vs APOE3s after eating a meal (post-prandial) Source: '''''APOE Alleles and Diet in Brain Aging and Alzheimer’s Disease''''' https://www.frontiersin.org/articles/10.3389/fnagi.2020.00150/full  (Hussein N. Yassine and Caleb E. Finch,  10 June 2020) ]]

Hypertriglyceridemia is when there are too many triglycerides in the blood.  Often caused by excess sugar, refined carbs and alcohol, ApoE4 is associated with higher levels of triglycerides.  

From [https://www.frontiersin.org/articles/10.3389/fnagi.2020.00150/full '''''APOE Alleles and Diet in Brain Aging and Alzheimer’s Disease'''''](Hussein N. Yassine and Caleb E. Finch,  10 June 2020) 
::APOE4 carriers display both hypertriglyceridemia and hypercholesterolemia (Dallongeville et al., 1992; Carvalho-Wells et al., 2012).  
and
::The mechanism for hypertriglyceridemia in APOE4 may involve its stronger binding to VLDL, which decreases lipoprotein lipase mediated lipolysis (Li et al., 2013).

Higher triglyceride levels are associated with impaired cognitive function.  (source: [https://www.mdpi.com/2072-6643/13/6/2118 '''''The Role of High Triglycerides Level in Predicting Cognitive Impairment: A Review of Current Evidence'''''] (Alina Mihaela Dimache et al, 20 June 2021)

== Saturated Fat Sensitivity ==
ApoE4 carriers are well documented to hyper-absorb dietary fat. (Source: [https://link.springer.com/article/10.1007/s13668-013-0065-z '''''What We Know About Diet, Genes, and Dyslipidemia: Is There Potential for Translation?''''' ](Toni I. Pollin & Michael Quartuccio, 15 Oct 2013).  ApoE4s often see higher total cholesterol and LDL-C (low density lipoprotein cholesterol) levels with saturated fat intake.


From the discussion section 4.1 of this paper, [https://www.sciencedirect.com/science/article/pii/S0197458014003558?fbclid=IwAR3bI9-SIjrzrkZxnkRzHPfcZJ0Ue8azB4Ffn2bl3KNQnu0zEy2fNHuUMZQ '''Saturated and trans fats and dementia: a systematic review'''] (Neal D. Barnard et al, Sept 2014)
::Mechanisms Some studies have suggested that the effect of saturated fat intake on Alzheimer's risk may be most evident in (or even limited to) carriers of the APOE ε4 allele. The ApoE protein produced by the APOE gene is a major plasma apolipoprotein and the primary cholesterol carrier in the brain (Puglielli et al., 2003). As a group, APOE ε4 carriers have higher plasma total and LDL concentrations compared with APOE ε3 homozygotes (Bennett et al., 2007). Moreover, APOE status may influence the relationship between dietary intake and plasma lipid concentrations; a greater effect of dietary saturated fat on LDL cholesterol concentrations has been observed among APOE ε4 carriers (Rubin and Berglund, 2002). In a substudy of the European Prospective Investigation of Cancer and Nutrition (EPIC), saturated fat intake correlated significantly with serum LDL cholesterol concentrations only in individuals carrying the ε4 allele (Loktionov et al., 2000).


[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3828889/?fbclid=IwAR3QTSqHRppRnsUsTkLAkL1dvGFjvpA_U7H4V2Dh-vpax7X4DbnfsvSIBMU '''Apolipoprotein E ε4 magnifies lifestyle risks for dementia: a population-based study'''] (Miia Kivipelto et al, Dec 2008) this study found that high saturated fat diets are associated with a greater risk (7-fold increase) of Alzheimer’s disease for e4 carriers than non-e4 carriers in a northern European population. Additional risks were also found for e-4 carriers that were sedentary, drank alcohol, and smoked. 
::Furthermore, low–moderate intake of polyunsaturated, and moderate–high intake of saturated fats were associated with an increased risk of dementia/AD more pronouncedly among apoE ε4 carriers.


[https://jamanetwork.com/journals/jamaneurology/fullarticle/1697444?fbclid=IwAR23CHEVsPebiXhey4D6KRr-qoJoO7L9IG5dwSiADEekLgGKm8IS0L4eqFI '''Effect of Apolipoprotein E Genotype and Diet on Apolipoprotein E Lipidation and Amyloid Peptides''' Randomized Clinical Trial] (Angela J. Hanson, MD, et al, Aug 2013) The results of this study suggest that the lipidation states of apolipoproteins and amyloid peptides might play a role in Alzheimer’s pathology as influenced by saturated fats decreasing ApoE’s ability to remove beta-amyloid from the brain and that these AD pathological processes are influenced by APOE genotype, thus explaining the higher incidences in ApoE4s.
::Herein we provide preliminary evidence that E4+ adults have higher basal levels of LD [Lipid-depleted] ApoE and that adults with mild cognitive impairment (MCI), particularly E4+ adults, have higher levels of LD Aβ. We also show that a High diet [45% of energy from fat (>25% saturated fat), 35%-40% from carbohydrates with a mean glycemic index >70, and 15%-20% from protein] increases LD Aβ levels and that a Low diet [25% of energy from fat (<7% saturated fat), 55%-60% from carbohydrates with a mean glycemic index <55, and 15%-20% from protein] has opposing effects. Furthermore, diet-induced changes in LD Aβ levels inversely correlate with changes in CSF insulin levels. These findings may provide insight into the mechanisms through which ApoE4 and unhealthy diets impart risk for developing AD.

This paper [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3828889/ '''Apolipoprotein E ε4 magnifies lifestyle risks for dementia: a population-based study'''](Miia Kivipelto et al, 4 Mar 2008) found that high saturated fat diets are associated with a greater risk (7-fold increase) of Alzheimer’s disease for e4 carriers than non-e4 carriers in a northern European population. 

[https://pubmed.ncbi.nlm.nih.gov/16710090/ '''Fat intake at midlife and risk of dementia and Alzheimer's disease: a population-based study'''] (M H Laitinen et al, 2006)  
::CONCLUSION: Moderate intake of unsaturated fats at midlife is protective, whereas a moderate intake of saturated fats may increase the risk of dementia and AD, especially among ApoE epsilon4 carriers. Thus, dietary interventions may potentially modify the risk of dementia, particularly among genetically susceptible individuals.


And with respect to the effects of '''saturated fat''' on '''Cardiovascular Disease in E4s''', this paper, [https://www.jstor.org/stable/41466520 '''Effect of Apolipoprotein E Genotype and Saturated Fat Intake on Plasma Lipids and Myocardial Infarction in the Central Valley of Costa Rica'''] (Yadong Yang et al, Dec 2007) found that while a high saturated fat intake was associated with a 49% increased risk of a heart attack in the e3/e3 genotype, e4/e4 was associated with a '''110% increased risk of a heart attack'''.

== Cardiovascular Disease (CVD) ==

First some terms used in the cited references:

'''Cardiovascular Disease''' - Heart conditions that include diseased vessels, structural problems, and blood clots.  Includes:  Coronary Artery Disease, High Blood Pressure, Cardiac Arrest, Congestive Heart Failure, Arrythmia, Peripheral Artery Disease, Stroke. 

'''Coronary Heart Disease''' - Plaque buildup in the wall of the arteries that supply blood to the heart (called coronary arteries) resulting in blockage or interruption of the heart muscle's blood supply.

'''Atherosclerosis''' - When plaque buildup causes the inside of the arteries to narrow over time.

'''Atherogenesis''' - The process of forming plaques in the intima layer of arteries.

'''Coronary Artery Disease''' - Also known as ischemic heart disease or "hardening of the arteries."

'''Myocardial infarction (MI)''' - More commonly known as a heart attack.

Some studies/findings:

* [https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.123.323921 '''Apolipoprotein E-ε2 and Resistance to Atherosclerosis in Midlife—The PESA Observational Study'''] (Raquel Toribio-Fernández et al, 23 Jan 2024):
::Conclusions:  This work sheds light on the role of APOE in cardiovascular disease development with important therapeutic and prevention implications on cardiovascular health, especially in early midlife.

* [https://www.frontiersin.org/articles/10.3389/fnagi.2020.00150/full '''''APOE Alleles and Diet in Brain Aging and Alzheimer’s Disease'''''] (Hussein N. Yassine and Caleb E. Finch,  10 June 2020):
::APOE4 is associated with greater levels of atherosclerosis, potentially through increased LDL-C levels from defective VLDL remnant clearance as described above. Correspondingly, APOE4 carriers have shown a higher incidence of ischemic heart disease (Xu et al., 2016). The increased use of statins may have attenuated this adverse impact of APOE4 (Nieminen et al., 2008).

* [https://link.springer.com/article/10.1007/s00109-016-1427-y '''''Apolipoprotein E: from cardiovascular disease to neurodegenerative disorders'''''](Robert W. Mahley, 09 Jun 2016): 
::'''ApoE4 increases plasma LDL levels and the risk for atherosclerosis''' [11, 12, 25]. The lipoprotein-binding preference of apoE4 to large (30–80 nm), triglyceride-rich VLDL, is associated with elevated LDL levels. (ApoE3 and apoE2 preferentially bind to small, 9–16-nm spherical HDL particles enriched in phospholipids and surface proteins, primarily apoAI.) [Bold font added to quote.] [See link for referenced footnotes.]

*[http://www.jlr.org/content/50/Supplement/S183.full.pdf&sa=U&ei=nw9uU9vAMZXJsQSbjIHADA&ved=0CCIQFjAB&usg=AFQjCNGpkPmKGD5TpkZ7WilR0Pw13hKL-Q '''''Apolipoprotein E: structure determines function, from atherosclerosis to Alzheimer's disease to AIDS'''''] (Robert W. Mahley, et al, Dec 22, 2008). 
::APOE AND CARDIOVASCULAR DISEASE '''ApoE2 and apoE4 increase the number of atherogenic lipoproteins and accelerate atherogenesis''' (1, 3, 6). Understanding structural differences in apoE isoforms helped establish the molecular mechanism responsible for the associated pathology. First, the altered structure and impaired function of the receptor binding region of apoE2 increase triglyceride and cholesterol levels caused by delayed clearance of hepatic and intestinal remnant lipoproteins (β-VLDL), resulting in type III HLP (3, 22). Cys-158 in apoE2 affects the receptor binding region by altering salt bridges and lowering the positive potential (25). Second, the increase in plasma cholesterol, LDL, and apoB associated with apoE4 appears to reflect the influence of Arg-112 (1–3). Arg-112 alters the lipid binding region of apoE4 and changes the lipid binding preference from small phospholipid-rich HDL (apoE2 and apoE3) to large triglyceride-rich VLDL (apoE4). This difference is due to apoE4 domain interaction, in which the N- and C-terminal domains interact, resulting in a more compact structure.-Cys) polymorphism has been associated with dementia and hypercholesterolemia. [Bold font added to quote for emphasis.][See link for referenced footnotes.]

* [https://www.sciencedirect.com/science/article/pii/S0021915002003350 '''''A prospective study of the association between APOE genotype and the risk of myocardial infarction among apparently healthy men'''''](Simin Liu, et al., Feb 2003).  
::Conclusions: These data from a prospective study of apparently healthy men '''do not support the simple view of E2 as a protective factor and E4 as a susceptibility factor in predicting future risk of MI''' independent of lipid parameters. '''Nor did we observe any interaction between smoking and apoE4 allele on MI risk'''. [Bold font added to quote for emphasis.]

* [https://onlinelibrary.wiley.com/doi/full/10.1111/j.1529-8817.2005.00205.x '''''The Significant Increase in Cardiovascular Disease Risk in APOEɛ4 Carriers is Evident Only in Men Who Smoke: Potential Relationship Between Reduced Antioxidant Status and ApoE4'''''] (P. J. Talmud, et al., 26 Jul 2005):
::These results provide '''strong confirmation that in men, the ɛ4 association with CVD risk is essentially confined to smokers'''. Since ɛ4 non‐smokers show no major CVD risk, i.e. when the environmental insult is not present, this has important public health implications. '''No studies to date have examined this ɛ4: smoking effect in women, so it is not clear whether these effects are gender specific.''' The multifactorial nature of CHD/CVD implies not only independent effects of genes and environmental factors but also their interaction on risk. Thus our study of ɛ4: smoking interaction and association with measures of ROS [Reactive Oxygen Species] confirms and extends our understanding of the multifactorial basis of CHD/CVD risk. [Bold font added to quote for emphasis.]

* [https://www.sciencedirect.com/science/article/pii/S0021915000005700 '''''Apolipoprotein E genotype and cardiovascular disease in the Framingham Heart Study'''''] (Carlos Lahoz, et al., 15 Feb 2001): 
:::The apo E4 (Arg112-Cys) polymorphism has been associated with dementia and hypercholesterolemia. We investigated the relation of APOE genotype to cardiovascular disease (CVD) in the Framingham Offspring Study. 
::Conclusions: The '''presence of the apo E2 or apo E4 alleles in men is associated with significantly greater CVD risk'''. This genotypic information may help to identify individuals at increased risk for CVD events. [Bold font added to quote for emphasis.]

* [https://www.sciencedirect.com/science/article/pii/S0002934300006392 '''''Is the apoE4 allele an independent predictor of coronary events?'''''] (Angelo Scuteri, et al., Jan 2001):
::Purpose: Although the apolipoprotein E genotype ϵ4 (apoE4) has been associated with high cholesterol levels, whether it is an independent predictor of coronary events is not certain.
:::Conclusion: '''The apoE4 genotype is a strong independent risk factor for coronary events in men, but not women. The association does not appear to be mediated by differences in total cholesterol levels.''' [Bold font added to quote.]

== Heightened Immune response/ Infectious disease susceptibility ==
While ApoE ϵ4's pro-inflammatory state helped early man survive wounds, walk on dung, and other insults, that may have been of benefit against the endemic diseases of Africa, where ApoE ϵ4 originated.  As man migrated, one theory is that new infectious diseases (the plague, small pox) placed ApoE ϵ4s at a disadvantage as compared to ϵ3s and this may be the primary reason ApoE ϵ3s outnumber ApoE ϵ4s. That's just a theory, there's still much to be learned in this area.  

Some findings: 

*[https://www.frontiersin.org/articles/10.3389/fnagi.2020.00150/full '''''APOE Alleles and Diet in Brain Aging and Alzheimer’s Disease'''''](Hussein N. Yassine and Caleb E. Finch,  10 June 2020):
::-As the ancestral human isoform, APOE4 may be beneficial in infectious environments with high pathogen loads (Trumble and Finch, 2019). Children carrying APOE4 in Brazilian slums, are more resistant to diarrhea and have better cognitive development (Oriá et al., 2010), while adult Tsimane farmer-foragers in Bolivia with APOE4 have better cognition during high parasitemia (Trumble et al., 2017). Moreover, in the highly infectious environment of rural Ghana, APOE4 carriers showed survival advantage as older adults and children, suggesting reproductive advantage (van Exel et al., 2017). APOE4 was also protective of HCV [hepatitis C virus] infection (Price et al., 2006). These findings are shown for APOE-TR mice in a model of infection by Cryptosporidium parvum: the APOE4-TR mice had faster recovery than E3 for intestinal inflammatory responses and mucosal damage (Azevedo et al., 2014).
::-In humans, APOE4 increased serum interleukin (IL)-1β, IL-6, IL-8, IL-10, IL-17, and tumor necrosis factor-α (TNF-α) responses to LPS (endotoxin) using in vivo and ex vivo assays. APOE4 carriers with severe sepsis had more thrombocytopenia. Correspondingly, APOE4-TR mice had greater responses IL-6 and TNF-α (the only cytokines assayed). In a murine monocyte-macrophage cell line stably transfected to produce equal amounts of human apoE3 or apoE4, LPS stimulation in apoE4-macrophages showed higher and lower concentrations of TNF-α (pro-inflammatory) and IL-10 (anti-inflammatory), for mRNA and protein levels. Furthermore, apoE4-macrophages had enhanced the transactivation of the key redox-sensitive transcription factor NF-κB (Jofre-Monseny et al., 2007). One mechanism for APOE4 associated higher inflammatory responses may relate to the increase in TLR4 activity by greater cell membrane cholesterol distribution from lower ABCA1 activity (Westerterp et al., 2013), as discussed above.
::-Chronic inflammation increases AD risk with APOE4. Data from 2,656 members of the Framingham Heart Study offspring cohort examined longitudinal measures of serum C-reactive protein (CRP) in relation to the diagnoses of incident dementia, including AD, and brain volume. APOE4 coupled with chronic low-grade inflammation, defined as a CRP level of 8 mg/L or higher, was associated with an increased risk of AD compared to APOE4 without inflammation, and APOE2 and APOE3 with chronic inflammation (Tao et al., 2018).
  
*[http://www.jlr.org/content/50/Supplement/S183.full.pdf&sa=U&ei=nw9uU9vAMZXJsQSbjIHADA&ved=0CCIQFjAB&usg=AFQjCNGpkPmKGD5TpkZ7WilR0Pw13hKL-Q '''''Apolipoprotein E: structure determines function, from atherosclerosis to Alzheimer's disease to AIDS'''''](Robert W. Mahley, et al, December 22, 2008) discusses the roles of ApoE beyond lipoprotein metabolism.
::-ApoE also influences susceptibility to parasitic, bacterial, and viral infections. '''In HIV-positive patients, apoE4 homozygosity hastens progression to AIDS and death and increases susceptibility to opportunistic infections'''. [Bold font added to quote]
::-ApoE also modulates susceptibility to infectious disease and possibly immunoregulation (1, 3). ApoE4 enhances the infectivity of HIV in vitro and hastens progression to AIDS and death in HIV-positive subjects (23). [See link for referenced footnotes.]
::-HSV1 [[Herpes simplex virus type 1 or oral herpes] infection is associated with increased risk of AD, and '''apoE4 is overrepresented in HSV-infected subjects''' (51). In HIV-positive patients, apoE4 homozygosity hastens progression to AIDS and death and increases susceptibility to opportunistic organisms (23). Cultured cells are more susceptible to infection with HIV in the presence of apoE4 than apoE3, reflecting enhancement of viral attachment and fusion. The structural differences between apoE4 and apoE3 may shed light on the mechanism by which apoE4 modulates infectivity and fusion.[Bold font added to quote for emphasis.][See link for referenced footnotes.]

*[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2782461/ '''''APOE genotype-specific differences in the innate immune response'''''] (Michael P. Vitek, et al, Sep 2009): 
::Apolipoprotein-E protein is an endogenous immunomodulatory agent that affects both the innate and the adaptive immune responses. Since individuals with the APOE4 gene demonstrate worsened pathology and poorer outcomes in many neurological disorders, we examined isoform specific differences in the response of microglia, the primary cellular component of the brain’s innate immune response, in detail. '''Our data demonstrate that microglia derived from APOE4/4 targeted replacement mice demonstrate a pro-inflammatory phenotype that includes altered cell morphology'''

== Issues of the Brain ==
Among its pleiotropic effects on aging, ApoE4’s strongest effects are arguably on the brain. (Source: [https://www.frontiersin.org/articles/10.3389/fnagi.2020.00150/full '''''APOE Alleles and Diet in Brain Aging and Alzheimer’s Disease'''''](Hussein N. Yassine and Caleb E. Finch, 10 June 2020)
:::

=== Slowed brain glucose uptake ===
The body’s primary source of energy is glucose, also known as [[Blood Sugar]].  The brain wants unimpaired glucose passage, because the brain needs fuel and lots of it. The brain uses more energy than any other human organ. While the brain constitutes only about 3% of the body's mass, it uses approximately 20%-25% of the body's energy and it needs that energy 24 hours a day.

ApoE4s have impaired cerebral glucose uptake which is one of the reasons ketosis (see the ApoE4.info wiki article [[Ketosis and Ketogenic Diet]]) can be of benefit, as ketones provide unimpaired fuel to the brain thus aiding its function.  While ketones can provide significant help with cognition, note that they cannot entirely replace glucose for brain fuel.

There is a significant link between Alzheimer’s disease (AD) and impaired fuel metabolism, (see the ApoE4.info wiki article [[Insulin Resistance in the brain]]) specifically disturbed cerebral glucose metabolism. (Sources:  [https://journals.co.za/doi/10.4102/jir.v1i1.15 '''''Insulin resistance and reduced brain glucose metabolism in the aetiology of Alzheimer’s disease'''''](Berger A.L., 30 Dec 2016) and [https://www.sciencedirect.com/science/article/pii/S0301008213000531?via%3Dihub '''''Decoding Alzheimer's disease from perturbed cerebral glucose metabolism: Implications for diagnostic and therapeutic strategies'''''] (Chen, Z, et al., Sep 2013))

ApoE4 carriers show reduced cerebral glucose metabolism by positron emission testing and reduced uptake of glucose into astrocytes. (Source: [https://www.sciencedirect.com/science/article/pii/S0969996120300176 '''''APOE alters glucose flux through central carbon pathways in astrocytes'''''](Holden C. Williams et al, Mar 2020))

Some findings:

*[https://www.frontiersin.org/articles/10.3389/fnagi.2020.00150/full '''''APOE Alleles and Diet in Brain Aging and Alzheimer’s Disease'''''](Hussein N. Yassine and Caleb E. Finch,  10 June 2020)
::APOE4 is associated with glucose hypometabolism in the brain of older adults (Wolf et al., 2013), and with both markers of astrocytosis and microgliosis (Fernandez et al., 2019). In the Mayo Clinic study, older APOE4 carriers demonstrate greater glucose hypometabolism in AD-affected brain areas than non-carriers. These changes are not associated with fibrillary amyloid detected by PET imaging (Knopman et al., 2014), but smaller aggregates and oligomers may still be a factor. In the subgroup of participants between the ages of 30 and 60 years from this study (n = 62), there were no significant regional differences between APOE4 carriers and noncarriers (Knopman et al., 2014). The effect of APOE4 on glucose hypometabolism in younger (middle aged) cognitively normal adults is more evident in APOE4 homozygotes than heterozygotes (Mosconi et al., 2004; Reiman et al., 2004). Proposed mechanisms include changes in apoE protein expression levels, qualitative differences in apoE proteins (for example, aggregated vs. lipidated ApoE), a direct effect of apoE on nuclear transcription, and complex interactions with Aβ (Fernandez et al., 2019). Another mechanism involves apoE’s effect on endosomal trafficking. Brain endosomes are enlarged decades before the onset of cognitive decline in APOE4, particularly in pyramidal neurons in the inferior frontal lobe (Cataldo et al., 2000; Nixon, 2005). APOE-TR [transgenic] mice corroborate these postmortem findings, with enlarged endosomes and increased endosomal trafficking proteins in APOE4 vs. APOE3-TR brains in the entorhinal cortex area of APOE-TR mice (Nuriel et al., 2017b; Peng et al., 2019).

=== Vascular Dementia ===
This paper, [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4128964/ '''''Is apolipoprotein E4 an important risk factor for vascular dementia?''''' ] (Troy T Rohn 2014) analyzed 24 studies from 1994 to 2012 which examined the potential association of APOE polymorphism in Vascular Dementia (VaD). Fourteen of these studies showed a positive association but 9 found that the ApoE4 allele did not confer risk for VaD.  Of the negative findings, 5 of the 9 were of Asian populations, the other 4 were from European populations, so environmental and/or genetic factors may have played a role in these studies. 

From this paper’s Concluding Remarks:
::Clearly, vascular risk factors including hypertension, stroke, atherosclerosis may increase the risk for VaD and it follows that harboring the APOE4 allele may also lead to enhanced vulnerability. However, conflicting reports on APOE polymorphism and enhanced VaD risk have been documented although '''the preponderance of data suggest the presence of the APOE4 allele does increase risk albeit to a lower extent to what has been found in AD'''…. Further studies are warranted to examine more clearly the potential connection between VaD and the APOE polymorphism. [Bold font added to quote for emphasis.]

=== Lewy Body Dementia ===

The research paper [https://www.nature.com/articles/s41588-021-00785-3 '''''Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture'''''](Ruth Chia et al, 15 Feb 21) is behind a paywall, but this article [https://neurosciencenews.com/genetics-lbd-parkinsons-alzhimers-17787/ '''''Genetic Study of Lewy Body Dementia Supports Ties to Alzheimer’s and Parkinson’s Diseases'''''] is a report on the research in this paper and says that five genes, including APOE may play a critical role in determining whether a person will suffer from Lewy body dementia.

This paper, [https://jamanetwork.com/journals/jamaneurology/fullarticle/1391953 '''''APOE ε4 increases risk for dementia in pure synucleinopathies''''' ],(Debby Tsuang, MD, MSc, et al., Feb 2013) identifies that the APOE ϵ4 allele is a strong risk factor across the Lewy Body Dementia (LBD) spectrum: 
-Pure Lewy body dementia   
-Alzheimer’s with Lewy bodies (a coexistence of Lewy bodies with Alzheimer’s but not pure Lewy Body Dementia) 
-Parkinson’s Disease Dementia (a dementia that occurs many years after diagnosis of Parkinson’s.  Those with Parkinson’s often have Lewy bodies in their brain, however, PDD is also not pure Lewy Body Dementia) 
However, any ApoE ϵ4 genetic risk for Dementia with Lewy Bodies may be related to the frequent coexistence with Alzheimer’s Disease.  How and '''if ApoE ϵ4 contributes to the development of Lewy Bodies is unclear'''.  The above referenced paper discusses how several studies have examined ApoE in Dementia with Lewy Bodies (DLB) without making a distinction between pure Dementia with Lewy Bodies (pDLB) and Lewy Body Disease with coexisting levels of Alzheimer’s Disease neuropathologic changes (LBD-AD).  From the paper:
::Therefore, it is possible that all genetic risk for DLB [Dementia with Lewy bodies] associated with the APOEϵ4 allele is related to its frequent comorbidity with ADNCs [Alzheimer disease (AD) neuropathologic changes (NCs)] and is unrelated to LBDNCs [Lewy body disease (LBD) neuropathologic changes (NCs)] Furthermore, no studies have directly compared genetic risk factors between pDLB [pure Dementia with Lewy Bodies) and PDD [Parkinson’s Disease Dementia].

==== Parkinson's Disease Dementia ====
Parkinson's Disease Dementia (PDD) occurs many years after diagnosis of Parkinson’s.  Those with Parkinson’s often have Lewy bodies in their brain, however, PDD is also not pure Lewy Body Dementia.  From this paper [https://jamanetwork.com/journals/jamaneurology/fullarticle/1391953 ''A'''POE ε4 increases risk for dementia in pure synucleinopathies''''' ](Debby Tsuang, MD, MSc, et al., Feb 2013):

::Data from genomewide association studies indicate that APOE is not a susceptibility gene for PD.<sup>30-32</sup> While PD is clinically defined by motor symptoms, more than 50% of patients develop dementia within 10 years of diagnosis.<sup>33,34</sup> '''Whether APOE acts as a modifier gene by influencing the manifestation of cognitive dysfunction in PD is still a matter of debate.''' [Bold font added to quote for emphasis.] [See link for referenced footnotes.]

=== Brain Arterial Disorders === 

Cerebral atherosclerosis (AS), small vessel disease (SVD), and cerebral amyloid angiopathy (CAA) are the most prevalent arterial disorders in the aged brain.  The three are different, but ApoE is involved in all three disorders.  All three disorders can lead to infarction (obstruction of the blood supply) and hemorrhage (bleeding) in the brain.

==== Cerebral atherosclerosis (AS) ====
Cerebral atherosclerosis (AS) is the thickening and hardening of the walls of the arteries in the brain.  From this paper 
[https://link.springer.com/article/10.1007/s00401-010-0652-7 '''''Vascular pathology in the aged human brain'''''] (Grinberg, L.T. & Thal, D.R. Acta, Feb 2010)
::ApoE and its receptors are critically involved in the pathogenesis of AS.  ApoE-knockout mice and low-density lipoprotein (LDL) receptor knockout mice develop AS [8, 156]. Dysfunctional uptake of LDLs may, thereby, lead to the accumulation of oxidized LDLs in the atherosclerotic vessel wall [9]. Thus, oxidized LDLs may be candidates to trigger the development of atherosclerotic plaques. ApoE and LDL receptors [e.g. LDLR and A2M receptor/LDL receptor-related protein (LRP = CD91)] were found in AS plaques (Fig. 1c) [8, 43]. '''The apoE ε4 allele is controversially discussed as a possible genetic risk factor for AS''' [64, 75, 116]. [Bold font added to quote for emphasis.] [See link for referenced footnotes.]

==== Small Vessel Disease (SVD) ====
Small Vessel Disease (SVD) is a condition found in older adults which can contribute to cognitive decline and vascular dementia.  SVD encompasses degenerative alterations in the vessel wall of the small arteries and arterioles (a small branch of an artery leading into capillaries).  

*From this comprehensive review article [https://www.frontiersin.org/articles/10.3389/fphys.2019.01317/full '''''Cerebral Small Vessel Disease (CSVD) – Lessons From the Animal Models'''''] (Muzaimi Mustapha et al, Oct 2019):
::APOE gene polymorphisms have been associated with amyloidogenic CSVD [Cerebral Small Vessel Disease] and serve as the strongest genetic factor for the disease including AD. Two main types of APOE genes are involved in CVSD: APOE ε4 and APOE ε2

*[https://link.springer.com/article/10.1007/s00401-010-0652-7 '''''Vascular pathology in the aged human brain'''''](Grinberg, L.T. & Thal, D.R. Acta, Feb 2010):
::Genetically, an association between SVD and the apoE ε4 allele has been reported [154].

*The above 154 footnote refers to this paper: [https://www.ncbi.nlm.nih.gov/pubmed/16043796 '''''APOE, vascular pathology, and the AD brain''''' ] (Yip AG, et al., Jul 2005), which says:
::Conclusion:  APOE-epsilon4 is associated with small vessel arteriolosclerosis, microinfarcts of the deep nuclei, neuritic senile plaque density, and amyloid angiopathy in patients with autopsy-proven Alzheimer disease (AD). '''These results suggest a role for epsilon4 in some of the microvascular changes commonly found in AD''' and are consistent with a potential amyloidogenic role for epsilon4. [Bold font added to quote for emphasis.]

But Small Vessel Disease is not an ultimate destiny for ApoE4s.  According to this article [https://www.neurologyadvisor.com/topics/alzheimers-disease-and-dementia/cerebral-small-vessel-disease-severity-progression-predict-dementia-risk/ '''Cerebral Small Vessel Disease Severity, Progression May Predict Dementia Risk'''] (Sheila Jacobs, ''Neurology Advisor'' 16 May 2023)  

::"Agents improving endothelial dysfunction, blood-brain barrier integrity, and anti-inflammatory effects, but also preventive strategies for managing vascular risk factors earlier in life, have been proposed as potentially promising therapeutic targets for SVD and thus dementia,” the researchers wrote. They concluded, “A delay in disease onset by merely a few years could reduce the devastating burden of dementia substantially.”

You can read more about Small Vessel Disease including prevention strategies in this comprehensive article by Dr Rhonda Patrick [https://www.foundmyfitness.com/topics/small-vessel-disease '''Small vessel disease'''].

==== Cerebral amyloid angiopathy (CAA) ====
 
Cerebral amyloid angiopathy (CAA) is a condition in which proteins (amyloid) build up on the walls of the arteries in the brain. CAA increases the risk for stroke caused by bleeding and dementia.

*[https://link.springer.com/article/10.1007/s00401-010-0652-7 '''''Vascular pathology in the aged human brain'''''] (Grinberg, L.T. & Thal, D.R. Acta, Feb 2010):
::'''CAA, especially capillary CAA, is associated with the apoE ε4 allele''' [37, 100, 103, 126, 130, 132]. This finding points to an important role of apoE for the development of CAA because apoE4 is less effective in the receptor-mediated clearance of Aβ [Amyloid Beta] when compared to apoE3 [19]. This property of apoE4 presumably results in capillary Aβ deposition in apoE ε4 carriers as soon as alterations in the perivascular drainage occur. In addition, the apoE ε4-genotype promotes Aβ aggregation in vascular smooth muscle cell cultures [85]. Finally, CAA-related hemorrhage is reported to be associated with the apoE ε2 and ε4 allele [37, 88, 95, 97]. [See link for referenced footnotes.]

*[https://pubmed.ncbi.nlm.nih.gov/23457231/ '''''Genetics of cerebral amyloid angiopathy: systematic review and meta-analysis'''''](Kristiina Rannikmäe, et al, Mar 2013)
::Conclusions: There is '''convincing evidence for a dose dependent association between APOE ε4 and sporadic CAA'''. Further work is needed to better understand the mechanism of this association and to further investigate other genetic associations with CAA. (Bold font added to quote for emphasis.)

=== Blood Brain Barrier (BBB) Breakdown/Leakage ===

[[File:Blood Brain Barrier.jpg|frame|right|	Source: https://www.christopherreeve.org/blog/research-news/blood-brain-barrier-the-spinal-cord]]
The blood–brain barrier (BBB) provides a barrier between circulating blood and the brain.  It protects the brain from pathogens the blood may carry.  When the blood–brain barrier becomes leaky, bacteria and viruses are allowed to infiltrate the brain thus producing a toxic, neuroinflammatory effect.  Breakdown of the BBB likely contributes to APOE4-associated cognitive decline independently of Alzheimer’s disease pathology. 

*[https://www.frontiersin.org/articles/10.3389/fnagi.2020.00150/full '''''APOE Alleles and Diet in Brain Aging and Alzheimer’s Disease'''''](Hussein N. Yassine and Caleb E. Finch,  10 June 2020):
::There is evidence supporting BBB breakdown in older APOE4 carriers. In APOE-TR [transgenic mice] models, activation of the cyclophilin A (CypA)–matrix metalloproteinase 9 (MMP-9) pathway leads to enzymatic degradation of the BBB tight junction and basement membrane proteins, resulting in BBB breakdown followed by neuronal uptake of multiple blood-derived neurotoxic proteins (e.g., thrombin, fibrin), perivascular deposition of erythrocyte-derived hemosiderin, and microvascular and cerebral blood flow reductions. The vascular defects in APOE4-TR mice appear to precede neuronal dysfunction and may initiate neurodegenerative changes. Also, this study showed that the astrocyte secreted apoE3 and apoE2, but not apoE4, suppressed the CypA–MMP-9 pathway in pericytes via low-density lipoprotein receptor-related protein 1 (LRP1; Bell et al., 2012). '''In humans, postmortem brain tissue analysis support BBB breakdown in patients with AD, which is more pronounced in APOE4 carriers compared with APOE3 or APOE2''' (Zipser et al., 2007). The CSF plasma albumin quotient, a marker of BBB breakdown, is greater in older (above 65) cognitively normal APOE4 carriers compared to persons carrying the other genotypes (Halliday et al., 2013). Ongoing studies are examining whether more subtle vascular changes at the BBB appear in younger cognitively normal APOE4 carriers. (Bold font added to quote for emphasis.)

*Axel Montagne has researched the blood brain barrier for years.  He is the lead author of the paper [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250000/ '''''APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline'''''](Axel Montagne et al, 29 Apr 2020).  From the abstract:  
::Recent studies have suggested that breakdown of the blood–brain barrier (BBB) is an early biomarker of human cognitive dysfunction[7], including the early clinical stages of Alzheimer’s disease[5,8,9,10]. The E4 variant of apolipoprotein E (APOE4), the main susceptibility gene for Alzheimer’s disease[11,12,13,14], leads to accelerated breakdown of the BBB and degeneration of brain capillary pericytes[15,16,17,18,19], which maintain BBB integrity[20,21,22]. ...Our findings suggest that breakdown of the BBB contributes to APOE4-associated cognitive decline independently of Alzheimer’s disease pathology, and might be a therapeutic target in APOE4 carriers.  
*A comprehensive interview with Dr Montagne as conducted by Dr Rhonda Patrick and posted on Feb 28, 2023 can be found here [https://www.youtube.com/watch?v=lChdNK0I8bw '''Axel Montagne, PhD, on Solving Alzheimer’s and Dementia with Blood-Brain Barrier Repair'''].  ApoE4 is addressed multiple times in this interview.  

*[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5600438/ '''''The blood-brain barrier in Alzheimer's disease'''''](Elena Zenaro, et al., Nov 2017): 
::Previous studies have shown that lack of murine Apoe and expression of APOE4 gene, a major genetic risk factor for AD, but not APOE2 and APOE3, leads to BBB dysfunction by activating a proinflammatory cyclophilin A (CypA)–nuclear factor-κ B–matrix-metalloproteinase-9 pathway in mouse pericytes (Bell et al., 2012). Interestingly, Apoe−/− and APOE4 mice also show a reduction of TJ proteins and develop vascular defects before neuronal and synaptic changes occur (Bell et al., 2012). In support of these data, recent studies using postmortem human brain tissues have shown that APOE4 compared with APOE3 accelerates pericyte loss in AD, which correlates with the magnitude of BBB breakdown to plasma proteins immunoglobulin G and fibrin (Halliday et al., 2016). APOE4 compared with APOE3 leads to a higher accumulation of CypA and MMP-9 in pericytes and endothelial cells in AD suggesting a role for LRP1-dependent CypA–MMP-9 BBB degrading pathway in accelerated BBB breakdown in AD APOE4 compared with AD APOE3 carriers (Halliday et al., 2016).

*The abstract of the paper cited above [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4758554/ '''''Accelerated pericyte degeneration and blood–brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer’s disease'''''](Matthew R Halliday et al, Jan 2016) says:
::The blood–brain barrier (BBB) limits the entry of neurotoxic blood-derived products and cells into the brain that is required for normal neuronal functioning and information processing. Pericytes maintain the integrity of the BBB and degenerate in Alzheimer’s disease (AD). The BBB is damaged in AD, particularly in individuals carrying apolipoprotein E4 (APOE4) gene, which is a major genetic risk factor for late-onset AD. The mechanisms underlying the BBB breakdown in AD remain, however, elusive. Here, we show accelerated pericyte degeneration in AD APOE4 carriers >AD APOE3 carriers >non-AD controls, which correlates with the magnitude of BBB breakdown to immunoglobulin G and fibrin. We also show accumulation of the proinflammatory cytokine cyclophilin A (CypA) and matrix metalloproteinase-9 (MMP-9) in pericytes and endothelial cells in AD (APOE4 >APOE3), previously shown to lead to BBB breakdown in transgenic APOE4 mice. The levels of the apoE lipoprotein receptor, low-density lipoprotein receptor-related protein-1 (LRP1), were similarly reduced in AD APOE4 and APOE3 carriers. Our data suggest that APOE4 leads to accelerated pericyte loss and enhanced activation of LRP1-dependent CypA–MMP-9 BBB-degrading pathway in pericytes and endothelial cells, which can mediate a greater BBB damage in AD APOE4 compared with AD APOE3 carriers.

*[https://www.sciencedirect.com/science/article/pii/S0197458006001758?via%3Dihub '''''The blood-brain barrier in Alzheimer's disease'''''](B.D.Zipser, et al., Jul 2007):
::These studies provide evidence that in advanced AD (Braak stage V–VI), plasma proteins like prothrombin can be found within the microvessel wall and surrounding neuropil, and '''that leakage of the blood–brain barrier may be more common in patients with at least one APOE4 allele'''. [Bold font added to quote for emphasis.]

== Mitochondrial dysfunction susceptibility ==
Mitochondria produce energy for our bodies. The energy they produce is called ATP (adenosine triphosphate). Mitochondrial dysfunction is a major determinant in how we age.  It is a key factor in a myriad of diseases, and in particular is one of the earliest and most prominent features of Alzheimer’s Disease.  Neurons, the fundamental units of the brain and nervous system, require massive amounts of energy to function and can die if they don’t have a constant supply of ATP.  Anything that disrupts or impairs the brain’s ability to fuel itself has implications on cognition. The first priority of the mitochondria is to keep your cells oxygenized and blood pumping, other functions such as cognitive thinking, is a secondary task, so cognition will suffer in order for mitochondria to keep up with all their demands.

Studies indicate that the E4 allele is more susceptible to mitochondrial dysfunction, that ApoE4 is more sensitive than E3s or E2s to damaging free radicals. (Sources: [https://academic.oup.com/ajcn/article/71/2/621S/4729317 '''''Oxidative stress and Alzheimer disease''''' ](Yves Christen, Feb 2000) see below and [https://www.sciencedirect.com/science/article/pii/S0969996120300176 '''''APOE alters glucose flux through central carbon pathways in astrocytes'''''](Holden C. Williams et al, Mar 2020)).

For more information on mitochondria and factors that degrade or can improve mitochondrial function see the ApoE4.info wiki article on [[Mitochondria]].

*[https://pubs.aip.org/aip/acp/article/2589/1/020024/2830327/'''Intertwined-relationship-among-ROS-mitochondria Intertwined relationship among ROS, mitochondria and APOE4 during the onset of Alzheimer's disease'''](Sihan Wang, 19 Dec 2022). From the link you can download the PDF paper. 
::Multiple biomarkers have been detected in relation to AD, with a current emphasis in figuring out how the accumulation of Aβ can be affected by the interplay of ROS [Reactive Oxygen Species], mitochondria, and APOE4. While ROS arises from highly chemicals formed by oxygen and mitochondria being the energy center of human body, APOE4 is a newly-targeted gene connected with AD. This review tries to go through the mechanisms mediated by the three potential factors mentioned above. As the mechanisms count considerably in the cause of AD, the related drugs and therapeutic methods aimed to mitigate the influence brought by the three factors will also be summarized.

*[https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-022-02478-y?fbclid=IwAR0AfyKHk10HernO6Eb8QKWGA-BbGvM0stPhsT619S3MRX2IE9gAy-Vd_pQ '''''Regular proton pump inhibitor use and incident dementia: population-based cohort study'''''](Peidong Zhang et al, 1 Sep 2022) Proton Pump Inhibitors (Prilosec, Prevacid, Nexium, Losec) are often used with conditions caused by excess stomach acid.  But proton pumps aren’t limited to the stomach; they are present in every cell that has mitochondria, in other words every cell in the body except red blood cells. 
::The finding of this large population-based cohort study indicates that the use of proton pump inhibitors is associated with an increased risk of incident dementia, particularly among APOE ε4 heterozygotes.

*Neurons are extremely sensitive to attacks by destructive free radicals and according to this paper, [https://academic.oup.com/ajcn/article/71/2/621S/4729317 '''''Oxidative stress and Alzheimer disease'''''](Yves Christen, Feb 2000) APOE is also sensitive to attacks by free radicals, with E4 being more sensitive than E3s or E2s. As stated in this paper:
:::Poirier (80) maintains that apo E has a beneficial effect for neuronal protection but that the apo E4 isoform is less effective than are the apo E2 and E3 isoforms. (In other words, apo E4 may not be toxic, but simply capable of producing a less-favorable effect.) Miyata and Smith (81) showed that apo E has a beneficial effect against free radicals.

== Impaired Autophagy ==
Autophagy is the body's way of cleaning out damaged cells, in order to regenerate newer, healthier cells.  

*[https://inf.news/en/science/90d8242c042311bf2be39f32646d0252.html?fbclid=IwAR0McWJ8raGh0xmyKc9K7JytYVwh2nrFLF7oWC23o49_zE78bdGQmSibap4 '''''Effects of APOE4 expression on autophagy and mitochondrial dynamics and activity of astrocytes'''''](14 May 2023)
::These results point to a possible link between autophagy and β-amyloid clearance. Importantly, previous studies have shown that the expression of APOE4 may be related to impaired autophagy, especially in astrocytes. 

*[https://www.frontiersin.org/articles/10.3389/fnagi.2022.881239/full?fbclid=IwAR04XYRiXutM9z3swmMPlVce1r73xXF9NbQHlDx1aGWTZxvkDf1OTwKQzlw '''''A Review of ApoE4 Interference Targeting Mitophagy Molecular Pathways for Alzheimer's Disease'''''](Huiyi Chen et al, 20 May 2022)
::Mitophagy is selective autophagy through the clearance of aberrant mitochondria, specifically for degradation to maintain energy generation and neuronal and synaptic function in the brain. Accumulating evidence shows that defective mitophagy is believed to be as one of the early and prominent features in AD pathogenesis and has drawn attention in the recent few years. APOE ε4 allele is the greatest genetic determinant for AD and is widely reported to mediate detrimental effects on mitochondria function and mitophagic process. Given the continuity of the physiological process, this review takes the mitochondrial dynamic and mitophagic core events into consideration, which highlights the current knowledge about the molecular alterations from an APOE-genotype perspective, synthesizes ApoE4-associated regulations, and the cross-talk between these signaling, along with the focuses on general autophagic process and several pivotal processes of mitophagy, including mitochondrial dynamic (DRP1, MFN-1), mitophagic induction (PINK1, Parkin). These may shed new light on the link between ApoE4 and AD and provide novel insights for promising mitophagy-targeted therapeutic strategies for AD.

*[https://www.nature.com/articles/s41598-021-97117-6?fbclid=IwAR3kXC58jzhtSg7LL1tsnIvEAiyXWFYBAkjIH6NJBT9mQ1MDZWzowbtlZZQ '''''ApoE4 attenuates autophagy via FoxO3a repression in the brain'''''](Hee-Young Sohn et al, 02 Sep 2021)
::We investigated the effect of ApoE4 on autophagy in the human brains of ApoE4 carriers. Compared to non-carriers, the expression of FoxO3a regulating autophagy-related genes was significantly reduced in ApoE4 carriers, and the phosphorylation level of FoxO3a at Ser253 increased in ApoE4 carriers, indicating that FoxO3a is considerably repressed in ApoE4 carriers. As a result, the protein expression of FoxO3a downstream genes, such as Atg12, Beclin-1, BNIP3, and PINK1, was significantly decreased, likely leading to dysfunction of both autophagy and mitophagy in ApoE4 carriers. In addition, phosphorylated tau accumulated more in ApoE4 carriers than in non-carriers. Taken together, our results suggest that ApoE4 might attenuate autophagy via the repression of FoxO3a in AD pathogenesis. The regulation of the ApoE4-FoxO3a axis may provide a novel therapeutic target for the prevention and treatment of AD with the APOE4 allele.

== Gut Microbiota Differences ==
Gut microbiota, sometimes called gut flora or gut bugs refers to the microorganisms found in the gut (large and small intestines).  The microbiome can contain both beneficial microbes as well as undesirable pathogens. Ideally, the bad bugs don't dominate the microbiome and the good and bad bugs are in balance.  

The gut contains 500 million neurons and the gut and brain are strongly connected via the “gut-brain axis”.  Communication between the gut and brain is facilitated by biochemical communication from neurotransmitters through the vagus nerve.  The gut and its microbial inhabitants send signals via the axis to the brain and the brain also sends signals to the gut in two-way communication.  The digestive tract also contains the largest component of the body’s immune system so the gut-brain axis is also connected through the body’s immune system.  

Research shows that there is a difference in microbiota diversity and abundance between ApoE genotypes. The deficiencies ApoE4s hold could be a driver in our greater association with Alzheimer’s. [Source: [https://faseb.onlinelibrary.wiley.com/doi/10.1096/fj.201900071R?fbclid=IwAR0W0GztloDGrDOch8MWeTAuzuaURcFQJUvE6cXVUs2q7L0s0I4mdTH0QZM_ '''''APOE genotype influences the gut microbiome structure and function in humans and mice: relevance for Alzheimer's disease pathophysiology'''''](Tam T. T. Tran et al, 8 Apr 2019)]

For more understanding of the gut-brain axis, its importance, and how to improve the gut microbiome see the ApoE4.info wiki article on [[Gut-Brain Connection: Leaky Gut/Leaky Brain, Microbiome (gut bugs)]]

*[https://www.nature.com/articles/s41598-023-31730-5 '''''Genetic correlations between Alzheimer’s disease and gut microbiome genera'''''](Davis Cammann et al, 31 Mar 2023) 
::This study published in the journal Scientific Reports analyzed the gut microbes of 2,077 people with Alzheimer’s and 2,081 healthy controls. People with Alzheimer’s had higher levels of certain types of gut bacteria. '''Some of these bacteria were also found in higher levels in the guts of people who had the Alzheimer’s gene, APOE4. This suggests a relationship between the Alzheimer’s gene and gut bacteria that could be contributing to Alzheimer’s.''' [Bold font added to quote for emphasis.]

*[https://www.nature.com/articles/s41598-023-31730-5 '''''Genetic correlations between Alzheimer’s disease and gut microbiome genera'''''](Min Hou et al, 24 Feb 2021)
::Results: Apolipoprotein ε4 allele and rs744373 were risk loci for the AD among 12 genetic variants. Phylum Proteobacteria; orders Enterobacteriales, Deltaproteobacteria, and Desulfovibrionales; families Enterobacteriaceae and Desulfovibrionaceae; and genera Escherichia–Shigella, Ruminococcaceae_UCG_002, Shuttleworthia, Anaerofustis, Morganelia, Finegoldia, and Anaerotruncus were increased in AD subjects, whereas family Enterococcaceae and genera Megamonas, Enterococcus, and Anaerostipes were more abundant in controls (P < 0.05). '''Among the altered microbiota, APOE ε4 allele was positively associated with pathogens: Proteobacteria.''' [Bold font added to quote for emphasis.]

*[https://www.frontiersin.org/articles/10.3389/fnins.2021.619051/full '''''APOE-ε4 Carrier Status and Gut Microbiota Dysbiosis in Patients With Alzheimer Disease'''''](Tam T. T. Tran et al, 8 Apr 2019)
::Together, these findings indicate that APOE genotype is associated with specific gut microbiome profiles in both humans and APOE‐TR mice. This suggests that the gut microbiome is worth further investigation as a potential target to mitigate the deleterious impact of the APOE4 allele on cognitive decline and the prevention of AD.

== Sleep Apnea ==
Studies have shown ApoE4 increases the risk of sleep apnea, especially obstructive sleep apnea.   Many studies have also identified an association between sleep apnea (the cessation of breathing while asleep) and Alzheimer’s.  

In 2019, Dr Rhonda Patrick interviewed Matthew Walker, Phd [https://www.foundmyfitness.com/episodes/matthew-walker '''Dr. Matthew Walker on Sleep for Enhancing Learning, Creativity, Immunity, and Glymphatic System''']  Dr Walker is a professor of neuroscience and psychology at the University of California, Berkeley, and serves as the Director of the Center for Human Sleep Science. Formerly, Dr. Walker served as a professor of psychiatry at the Harvard Medical School.  From the transcript of the interview, Dr Walker said:

::What I would also say that's important for people, if you know your ApoE status, and if you are apoe-4, be mindful of snoring as well. '''Because people who are apoe-4-positive, they also have a significantly elevated risk of a sleep disorder that we call sleep apnea,''' which is sleep disordered breathing, which is heavy snoring and a cessation of breathing entirely. And then you gasp when you wake up again.

::But one of the other problems with sleep apnea is that you don't get the amount of deep sleep that you need. And you have hypoxic damage. Because you stopped breathing, your oxygen saturation goes down. You get hypoxia damage particularly in a region that is most sensitive to it in the brain, which is, drumroll, the hippocampus, the very same memory structure that is attacked in Alzheimer's disease.
::So now you can see why I appeal for this sensitivity in this danger to sleep apnea. Because if you are apoe-4, you're already at high risk of Alzheimer's disease, you need to pay attention to your sleep. If you start snoring, and you have sleep apnea untreated, you will get less deep sleep. So you're compromising the thing that you need to try and lower your amyloid risk to begin with, because you're going to build up that amyloid, because you're not going to get the amyloid clearance elsewhere in the body, for example, in the liver. And then worse still, the part of the brain that is attacked severely by Alzheimer's disease and atrophies, which is the hippocampus, which is why memory fades, is a part of the brain that is damaged when you stop breathing because of oxygen desaturation.
(Bold font added to quote for emphasis.)

Some papers on this subject:  

[https://onlinelibrary.wiley.com/doi/full/10.1111/jsr.13938 '''Obstructive sleep apnea and cognitive functioning in the older general population: The moderating effect of age, sex, ApoE4, and obesity'''] (Nicola Andrea Marchi et al, 13 June 2023)
::Apolipoprotein E4 and obesity appear to be vulnerability factors that strengthen the association between severe obstructive sleep apnea and lower performance in processing speed.


[https://link.springer.com/article/10.1186/s13195-022-00992-y '''APOE ε4, Alzheimer’s disease neuropathology and sleep disturbance, in individuals with and without dementia'''] (Jonathan Blackman et al, 30 March 2022)
::These findings lend weight to the hypothesis that APOE-ε4 affects sleep by mechanisms independent of AD pathological change. Evaluation of those mechanisms would enhance understanding of sleep disturbance pathways and potentially provide treatment targets.


[https://journals.sagepub.com/doi/abs/10.1177/0891988717720301 '''The Relationship Between Apolipoprotein ε4 Carrier Status and Sleep Characteristics in Cognitively Normal Older Adults'''] (Melike Kahya et al,  27 Jul 2017)  Behind a paywall, but from the abstract:
::The APOE ε4 carriers had a higher number of awakenings compared to the noncarriers (P = .02). ... This study provides evidence that individuals who are cognitively normal and genetically at risk of AD may have disrupted sleep. These findings are consistent with prior studies and suggest that sleep disruption may be present in the presymptomatic stages of AD.


[https://www.atsjournals.org/doi/full/10.1513/AnnalsATS.201701-052OC '''Greater Cognitive Deficits with Sleep-disordered Breathing among Individuals with Genetic Susceptibility to Alzheimer Disease. The Multi-Ethnic Study of Atherosclerosis'''] (Dayna A. Johnson et al, July 20, 2017)
::Our results (1) suggest that SDB [sleep-disordered breathing ] be considered among a group of modifiable dementia risk factors, and (2) highlight the potential vulnerability of APOE-ε4 risk allele carriers with SDB.


[https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0078655 '''Sleep Apnea and the Risk of Dementia: A Population-Based 5-Year Follow-Up Study in Taiwan'''] (Wei-Pin Chang et al, 24 Oct 2013)
::Recent studies have shown that the apolipoprotein epsilon 4 (APOE4) allele increases the risk of SA, particularly that which is obstructive in mechanism [14]. The APOE4 allele is associated with cognitive decline and the development of dementia in the general population. These findings suggest a shared genetic background between SA and dementia. In addition, O’Hara et al [15] showed that SA interacts with the APOE4 allele to affect memory negatively, suggesting that APOE4 carriers with SA may be at a higher risk of developing dementia. Fourth, it is conceivable that vascular risk factors are more prevalent in SA patients than in the general population [16,17], and that the incidence of dementia increases in SA patients.

== Reduced insulin-degrading enzyme (IDE) ==
In comparison with ApoE2 and ApoE3, ApoE4 significantly reduces levels of insulin-degrading enzyme (IDE), which is responsible for the cellular clearance of Aβ in neurons.  ApoE4 down-regulates IDE expression in neurons by binding to its receptor and stimulating the NMDA receptor pathway, which may account for its role in AD pathogenesis. (Source:  [https://www.sciencedirect.com/science/article/abs/pii/S0304394009009574?via%3Dihub '''ApoE 4 reduces the expression of Aβ degrading enzyme IDE by activating the NMDA receptor in hippocampal neurons'''] (Jing Du et al, 23 Nov 2009)




== Handles parasites well, at least in certain countries ==
According to this paper, [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5349792/ Apolipoprotein E4 is associated with improved cognitive function in Amazonian forager-horticulturalists with a high parasite burden] (Benjamin C. Trumble et al, Apr 2017) "We examined the interactions of E4, parasite burden, and cognitive performance in a traditional, nonindustrialized population of Amazonian forager-horticulturalists (N = 372) to test whether E4 protects against cognitive decline in environments with a heavy pathogen burden. Contrary to observations in industrial populations, older adult E4 carriers with high parasite burdens either maintained or showed slight improvements in cognitive performance, whereas non-E4 carriers with a high parasite burden showed reduced cognitive performance."

== Greater susceptibility to pesticides ==
DDE (dichlorodiphenyldichloroethylene) is a metabolite of the pesticide dichlorodiphenyltrichloroethane (DDT). From this paper [https://jamanetwork.com/journals/jamaneurology/fullarticle/1816015 '''Elevated Serum Pesticide Levels and Risk for Alzheimer Disease'''] (Jason R. Richardson et al, Mar 2014)"
::'''Conclusions and Relevance'''  Elevated serum DDE levels are associated with an increased risk for AD and carriers of an APOE4 ε4 allele may be more susceptible to the effects of DDE. Both DDT and DDE increase amyloid precursor protein levels, providing mechanistic plausibility for the association of DDE exposure with AD. Identifying people who have elevated levels of DDE and carry an APOE ε4 allele may lead to early identification of some cases of AD.

== Post Operative Cognitive Decline (POCD) after General Anesthesia ==
The different types of anesthesia include:

::•	'''Local anesthesia'''. Local anesthesia stops pain (numbs) in one part of the body while the the patient is awake and alert.  An example is Novocain often used in dental procedures.

::•	'''Regional anesthesia'''. Regional anesthesia is used to numb only the part of the body that will have the surgery.  Local aesthetics are applied close to nerves, but at a distance from the surgical site. These include spinal blocks, nerve blocks, and epidurals.  The patient may remain awake, or be given a sedative.

::•	'''General anesthesia'''. A method of medically inducing loss of consciousness that renders a patient unarousable even with painful stimuli.  General anesthesia usually uses a combination of intravenous medicines and inhaled gasses.

It is general anesthesia that is of particular concern, although spinal anesthesia has been shown to be no better than general anesthesia in its risk for the subsequent development of dementia.  (Source: [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5213281/ Cognitive decline in the elderly after surgery and anaesthesia: results from the Oxford Project to Investigate Memory and Ageing (OPTIMA) cohort] (D Patel et al, Oct 2016). 

It is common, for all genotypes, not just ApoE4, to hear of cognitive decline beginning after general anesthesia, especially if the time under anesthesia was prolonged or there were multiple episodes.  According to '''''The End of Alzheimer’s Program''''' (Dale Bredesen, 2020) this is due to multiple mechanisms:

::•First is the overall burden of toxicity, with reduction of glutathione and stress on the detoxification systems (although it should be noted that anesthetic agents also have some neuroprotective effects).

::•Second is the hypoxia (poor oxygenation) and hypotension (low blood pressure) that occur commonly while under general anesthesia, thus compounding the toxicity from the anesthetic agents thus compounding the toxicity from the anesthetic agents.

::•Third is the severe stress that occurs with surgical procedures.

::•Fourth is the common use of antibiotics associated with surgical procedures, which alters the microbiome and may increase gut permeability.

::•Fifth is the inflammation that occurs with surgery and in general with healing.

Chapter 19 of '''''The End of Alzheimer’s Program''''' also contains a long list of issues to consider and discuss with your doctor if possibly facing general anesthesia.  The discussion includes strategies to prepare, supplements to avoid, and a post anesthesia administration clearing diet recommendation.


Specifically with respect to anesthesia’s effect on ApoE4s, some papers:


[https://link.springer.com/article/10.1007/s00101-021-00972-1 '''Effects of Apolipoprotein Ε ε4 allele on early postoperative cognitive dysfunction after anesthesia'''](Deng-feng Ding et al, 18 Jun 2021):
::The results of the study indicated that the ApoΕ ε4/ε4 genotype was a risk factor for early POCD [Postoperative cognitive dysfunction] in older patients undergoing sevoflurane anesthesia.


[https://www.frontiersin.org/articles/10.3389/fnagi.2021.658860/full?fbclid=IwAR32LSUEC3Pdr0uxztheVrQMY4O87qNs-qqf50s0jhwgCC_RT-p5jqxNetU '''Surgery Performed Under Propofol Anesthesia Induces Cognitive Impairment and Amyloid Pathology in ApoE4 Knock-In Mouse Model'''] (Jong-Ho Kim et al, 26 April 2021)
::Our findings may have clinical implications. Patients with mild cognitive impairment (MCI) or preclinical AD may be at greater risk of POCD [Postoperative cognitive dysfunction] than others, consistent with the clinical observation that elderly patients with higher brain Aβ levels (Fukumoto et al., 2004) and carriers of the gene encoding apolipoprotein E4 (Cao et al., 2014), are more likely to develop POCD (Moller et al., 1998).
and from the last sentence of the paper
::It is difficult to diagnose preclinical AD; however, in patients with risk factors for AD, such as a familial history, '''genetic predisposition''', and/or a history of stroke, diabetes, and/or MCI, clinicians should be careful when planning anesthesia and surgery.
(bold font added to quote for emphasis)


[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5213281/ '''Cognitive decline in the elderly after surgery and anaesthesia: results from the Oxford Project to Investigate Memory and Ageing (OPTIMA) cohort'''] (D. Patel et al, Oct 2016) 
::The median age at recruitment was 72.6 years (IQR 66.6–77.8 years). APOEε4 allele heterozygosity was present in 117 and homozygosity in 14 participants.We found that elderly people were at risk of more rapid cognitive decline after an episode of moderate or major surgery with general or regional anaesthesia (Fig. (Fig.3).3). On further analysis, we discovered that in our cohort this '''effect was limited to those who had already suffered cognitive impairment''' (Fig. (Fig.4),4), that is, either mild cognitive impairment or possible or probable Alzheimer's disease. A second episode of such surgery reversed that decline at borderline significance (Tables 1 and 2). We found no difference between men and women. '''We found no independent influence of the APOEε4 allele on the effects of surgery.'''
(Bold font added to quote for emphasis)


[https://www.tandfonline.com/doi/full/10.3109/00207454.2013.860601 '''Association between APOE epsilon 4 allele and postoperative cognitive dysfunction: A meta-analysis'''] (Liang Cao et al, 25 Nov 2013).  Behind a paywall, but from abstract:
::Conclusions: The '''APOEε4 allele was associated with a significantly increased POCD''' [post-operative cognitive dysfunction]  risk about 1-week postsurgery, but the association depended on one large study. No association was found 1–3 months and 1-year postsurgery.

== Greater incidence of postoperative delirium  ==
According to [https://www.hopkinsmedicine.org/health/conditions-and-diseases/delirium#:~:text=Delirium%20is%20an%20altered%20state,adults%20who%20are%20acutely%20ill. John Hopkins Medicine] delirium is an altered state of consciousness, characterized by episodes of confusion. Delirium is a syndrome, not a disease.  If you notice sudden changes in a loved one’s awareness, mood, attention, perception and thinking, they might be experiencing the symptom of delirium, especially if they are in the hospital or very ill.

According to the findings of this paper, [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7086383/ '''Apolipoprotein E Genotype and the Association between C-reactive Protein and Postoperative Delirium: Importance of Gene-Protein Interactions'''] ((Sarinnapha M. Vasunilashorn et al, 1 Mar 2021), the relationship between the inflammation marker C-reactive Protein (CRP) and delirium incidence, severity, and duration differed by APOE status. Among ε4 carriers, there was a strong relationship between high CRP (vs. low CRP) and delirium incidence (relative risk [RR] (95% confidence interval [CI]: 3.0(1.4-6.7)); however, no significant association was observed among non-ε4 carriers (RR(95% CI): 1.2(0.8-1.7)).
::In summary, we found that the relationship between CRP and postoperative delirium differs by APOE genotype. Specifically, '''among APOE ε4 carriers, high CRP was associated with a significantly increased delirium incidence, severity, and duration'''; however, no such associations were observed among APOE non-ε4 carriers. This suggests that the APOE ε4 allele may be associated with less reserve in the setting of high postoperative inflammation, and thereby increasing risk for delirium. Within the context of delirium and its association with AD, this work is innovative in its expansion from examining direct genetic effects toward examining indirect, gene-protein interactions, which may be more informative of the shared pathophysiology linking delirium and AD. Importantly, this work may inform the targeting of future interventions, such as anti-inflammatory treatments, to those with genetic susceptibility (ε4 carrier status) for prevention of postoperative delirium and its associated adverse long-term cognitive outcomes, including AD. (bold font added for emphasis)

This paper also supports a greater incidence of delirium,[https://pubs.asahq.org/anesthesiology/article/107/3/406/8183/'''Apolipoprotein-E-e4-Allele-Increases-the-Risk-of Apolipoprotein E e4 Allele Increases the Risk of Early Postoperative Delirium in Older Patients Undergoing Noncardiac Surgery'''] (Jacqueline M. Leung et al, Sep 2007)
::Apolipoprotein e4 carrier status was associated with an increased risk for early postoperative delirium after controlling for known demographic and clinical risk factors. These results suggest that genetic predisposition plays a role and may interact with anesthetic/surgical factors contributing to the development of early postoperative delirium.

However, there's this paper [https://link.springer.com/article/10.1007/s00540-012-1326-5 '''Apolipoprotein E e4 allele does not increase the risk of early postoperative delirium after major surgery'''](Fernando José Abelha et al, 1 Feb 2012)
::Apolipoprotein e4 carrier status was not associated with an increased risk for early postoperative delirium. Age, congestive heart failure, and emergency surgery were independent risk factors for the development of delirium after major surgery.

== Gallstones ==
Two papers from 1996 (the first two cited below) indicate a strong correlation between ApoE ε4 and gallstone formation/recurrence.  However, more recent papers (also below) have cited no ApoE ε4 genetic susceptibility.  

*[https://www.gastrojournal.org/article/S0016-5085(96)70023-9/pdf? '''''Apolipoprotein E polymorphism and gallstones''''' ] (Bertomeu A, et al., Dec 1996) 
::...apo E4 increases hepatic lipoprotein uptake; hence, apo E4 could promote gallstone formation by increasing hepatic and biliary cholesterol concentrations. This study was designed to evaluate whether apo E polymorphism is related to gallstone risk....
::Conclusions: '''Carrying the apo E4 isoform is a genetic risk factor for cholelithiasis''' [the formation of gallstones] '''in humans.'''[Bold font added to quote for emphasis.]

*[https://aasldpubs.onlinelibrary.wiley.com/doi/abs/10.1002/hep.510240320 '''''Apolipoprotein E polymorphism and gallstones'''''] (Portincasa P, et al., Sep 1996): 
::Apolipoprotein E (apoE) genotyping and gallbladder motility (sonography) were studied in a representative subgroup of patients (n = 50). 
::Recurrence rate [of gallstones] was higher (flog rank test, P = .037) in those patients who were homozygous and heterozygous for the E4 allele compared with the individuals who were not expressing the apoE4 allele. 
::The present '''study indicates that apoE4 genotype is associated with increased speed of gallstone clearance as well as a high risk of recurrence after ESWL''' [Extracorporeal shock‐wave lithotripsy – a gallstone treatment]. [Bold font added to quote for emphasis.]

Subsequent findings present a lack of correlation between ApoE ε4 and gallstones. 
*[https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.510310105 '''''Apolipoprotein E Genotype and the Risk of Gallbladder Disease in Pregnancy'''''] (Cynthia W. Ko, et al., Oct 1999)
::In contrast to previous studies,10,11 [the above cited studies] '''we found that apoE4 was not a risk factor for gallbladder sludge and stones in pregnancy''', even after adjusting for other known risk factors such as body mass index. Women who were heterozygous or homozygous for apoE4 were not at higher risk than women who did not carry any apoE4 allele. [Bold font added to quote for emphasis.]

*[https://www.ncbi.nlm.nih.gov/pubmed/17384433 '''''Genetic evidence that apolipoprotein E4 is not a relevant susceptibility factor for cholelithiasis in two high-risk populations'''''] (Mella JG, et al., Jun 2007) 
::In this study analyzing the largest sample set available, apoE4 genotype was not associated with an increased frequency of GD [cholesterol gallstone disease (GD)] in either population. Moreover, in the Chilean population after adjusting for risk factors such as gender, age, body mass index, serum lipids, and glucose, the odds ratio for the association of the apoE4 allele and GD was significantly (P < 0.05) <1. Also, genotypes were not correlated with cholesterol crystal formation time, CSI, or gallstone cholesterol content. '''In contrast to previous smaller studies, apoE polymorphisms were not associated with susceptibility to cholesterol GD in high-risk populations.'''[Bold font added to quote for emphasis.]

*[https://www.ncbi.nlm.nih.gov/pubmed/12873586 '''''Effect of apolipoprotein E polymorphism on bile lipid composition and the formation of cholesterol gallstone'''''] (Hasegawa K, et al., Jul 2003):  
::OBJECTIVE:  It remains a matter of controversy whether possession of the apolipoprotein E4 (apoE4) allele is a genetic risk factor for the formation of cholesterol gallstones. The aim of the present study was to test this hypothesis by investigating the effect of apoE4 on bile lipid composition in normal subjects and in patients with cholesterol gallstones and to evaluate the distributions of apoE alleles in these two groups.
::CONCLUSIONS: '''The apoE4 allele is not a contributory factor to cholesterol gallstone formation, at least in the Japanese population.''' [Bold font added to quote for emphasis.]

== Decreased Longevity ==

Some papers:


[https://www.frontiersin.org/articles/10.3389/fragi.2024.1359202/full?utm_source=F-NTF&utm_medium=EMLX&utm_campaign=PRD_FEOPS_20170000_ARTICLE '''How are APOE4, changes in body weight, and longevity related? Insights from a causal mediation analysis'''] (Rachel Holmes et al, 1 Mar 2024)
::Here, we explore the role of aging changes in weight in the connection between APOE4 and longevity using the causal mediation analysis (CMA) approach to uncover the mechanisms of genetic associations.  … '''This finding is in line with the idea that the detrimental effect of APOE4 on longevity is, in part, related to the accelerated physical aging of ε4 carriers'''. (bold font added for emphasis)


[https://www.nature.com/articles/s41598-023-41078-5 '''Lower mortality risk in APOE4 carriers with normal cognitive ageing'''] (Elizabeth Pirraglia et al, 12 Sep 2023)
::We conducted the first-ever study of APOE4’s opposing effects on cognitive decline and mortality using competing risk models considering two types of death—death with high-amounts versus low-amounts of autopsy-assessed Alzheimer’s neuropathology. We observed that APOE4 was associated with decreased mortality risk in people who died with low amounts of Alzheimer’s-type neuropathology, but APOE4 was associated with increased mortality risk in people who died with high amounts of Alzheimer’s-type neuropathology, a major risk factor of cognitive impairment.


[https://www.sciencedirect.com/science/article/pii/S0047637423000179?via%3Dihub '''Understanding Alzheimer’s disease in the context of aging: Findings from applications of stochastic process models to the Health and Retirement Study'''] (Konstantin G. Arbeev et al, Apr 2023)
::Highlights
::• Stochastic process model embeds aging-related traits into AD development.
::• Robustness component of stress resistance differs by APOE4 status in both sexes.
::• There is age-related decline in resilience to deviations of BMI from the optimum.
::• APOE affects BMI variability and there is accumulation of allostatic load with age.
::• The model can incorporate dynamics of risk factors in forecasting future AD trends.


[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330482/ '''Varying Effects of APOE Alleles on Extreme Longevity in European Ethnicities'''] (Anastasia Gurinovich et al, Nov 2019)
::•Using the PopCluster algorithm, we identified several ethnically different clusters in which the effect of the e2 and e4 alleles on EL changed substantially.
::•In all five clusters, the effect of APOE e4 is deleterious on longevity with worst effect in subjects of British ancestry (OR = 0.3, 95% CI: 0.21, 0.44) and slightly less severe effect in subjects with North Eastern Europeans ethnicities.


As discussed in this paper, [http://citation-needed.springer.com/v2/references/10.1038/s41467-019-11558-2?format=refman&flavour=citation  '''''A meta-analysis of genome-wide association studies identifies multiple longevity genes'''''] (Joris Deelen, et al., Aug 2019)  for over two decades there have been studies associating genetic variation in APOE with longevity and lifespan identifying ApoE ε4 at increased risk for several age-related diseases, such as cardiovascular disease and Alzheimer’s disease therefore decreased longevity.  The researchers in this paper took studies from all over the world to perform a genome-wide association (GWA) meta-analysis of over 13,000 long-lived individuals of diverse ethnic background, including European, East Asian and African American ancestry, to characterize the genetic architecture of human longevity and found:
::Consistent with previous reports, rs429358, defining ApoE ε4, was associated with decreased odds of becoming long-lived.


[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6471373/ '''The Genetic Variability of APOE in Different Human Populations and Its Implications for Longevity'''] (Paolo Abondio et al, Mar 2019)
::Isoform ε4 of APOE is involved in several cardiovascular and neural pathologies that become apparent at a post-reproductive age. Many studies in the last decade tried to find explanations as to why such a deleterious variant has been maintained at high frequency in many human groups, particularly in indigenous populations of Africa and Oceania [178]. The main collected findings suggest an association between isoform ε4 and a number of population-specific and environment-related beneficial effects that compensate for the damage induced by the same variant in later life [175,176,187,189,193].


[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6298189/ '''APOE Alleles and Extreme Human Longevity'''] (Paola Sebastiani et al, Jan 2019)  
::We assembled a collection of 28,297 participants from seven studies of longevity and healthy aging comprising New England Centenarian, Long Life Family, Longevity Gene Population, Southern Italian Centenarian, Japanese Centenarian, the Danish Longevity, and the Health and Retirement Studies to investigate the association between the APOE alleles ε2ε3 and ε4 and extreme human longevity and age at death. By using three different genetic models and two definitions of extreme longevity based on either a threshold model or age at death, '''we show that ε4 is associated with a substantially decreased odds for extreme longevity,''' and increased risk for death that persists even beyond ages reached by less than 1% of the population. (bold font added for emphasis)


[https://www.liebertpub.com/doi/10.1089/rej.2014.1605?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub++0pubmed  '''The ApoE gene is related with exceptional longevity: a systematic review and meta-analysis'''] (Nuria Garatachean et al, Feb 2018)
::The main result for all ethnic groups combined was that the likelihood of reaching EL  [exceptional longevity (i.e., reaching 100+ years)] was negatively associated with ε4 allele carriage [pooled odds ratio (OR)=0.43; 95% confidence interval (CI) 0.36, 0.50; p<0.001] and with ε4/ε4 (OR=0.18; 95% CI 0.08, 0.39; p<0.001), ε3/ε4 (OR=0.44; 95% CI 0.37, 0.53; p<0.001) and ε2/ε4 genotypes (OR=0.48; 95% CI 0.31, 0.74; p<0.001).


[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3907310/ '''Age, Gender, and Cancer but Not Neurodegenerative and Cardiovascular Diseases Strongly Modulate Systemic Effect of the Apolipoprotein E4 Allele on Lifespan'''] (Alexander M. Kulminski et al, Jan 2014)
::The results suggest a pivotal role of non-sex-specific cancer as a nonlinear modulator of survival in this sample that increases the risk of death of the ApoE4 carriers by 150% (p = 5.3×10−8) compared to the non-carriers. This risk explains the 4.2 year shorter life expectancy of the e4 carriers compared to the non-carriers in this sample. The analyses suggest the existence of age- and gender-sensitive systemic mechanisms linking the e4 allele to lifespan which can non-additively interfere with cancer-related mechanisms.


[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3653307/ '''Effect of the APOE Polymorphism and Age Trajectories of Physiological Variables on Mortality: Application of Genetic Stochastic Process Model of Aging'''] (Konstantin G. Arbeev et al, 2 Jul 2012)
::We evaluated effects of the APOE polymorphism (carriers versus noncarriers of the e4 allele) and age trajectories of total cholesterol (CH) and diastolic blood pressure (DBP) on mortality risk in the Framingham Heart Study (original cohort).  …  Such observations strongly indicate the presence of a genetic component in respective aging-related mechanisms. Such differences may contribute to patterns of allele- and sex-specific mortality rates.


[https://pubmed.ncbi.nlm.nih.gov/21332925/ '''Trade-off in the effects of the apolipoprotein E polymorphism on the ages at onset of CVD and cancer influences human lifespan'''] (Alexander M. Kulminski et al, Jun 2011)
::We focus on the well-studied apolipoprotein [sic] E (APOE) e2/3/4 polymorphism and on lifespan and ages at onset of cardiovascular diseases (CVD) and cancer, using data on 3,924 participants of the Framingham Heart Study Offspring cohort. Kaplan-Meier estimates show that the e4 allele carriers live shorter lives than the non-e4 allele carriers (log rank=0.016).


[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3352324/ '''Evaluation of genotype-specific survival using joint analysis of genetic and non-genetic subsamples of longitudinal data'''] (Konstantin G. Arbeev et al, Apr 2011)
::Application of this method to analysis of the effect of common apolipoprotein E (APOE) polymorphism on survival using combined genetic and non-genetic subsamples of the Framingham Heart Study original cohort data showed that female, but not male, carriers of the APOE e4 allele have significantly worse survival than non-carriers, whereas empirical analyses did not produce any significant results for either sex.