Thread by @dantawfik

1) Hi all, @healthspanmed did a write up on @foundmyfitness paper on how DHA in the Phospholipid Form Confers Preventative Benefits Against Alzheimer's Disease:
gethealthspan.com/blog/research/…
Here's a full synopsis of Dr. Patrick's hypothesis 👇👇

2) What is Alzheimer’s Disease? Alzheimer's Disease is a neurodegenerative disorder. Key Characteristics: memory loss, spatial disorientation, cognitive dysfunction, and behavioral changes.

3) Alzheimer's Disease and Age: Risk for AD doubles every 5 years, following the age of 65, and around 1/3 of people over 85 have AD.

4) Genetic Risks: Three common isoforms of the APOE(2, 3, 4) gene, each associated with different AD risks. In regard to AD, APOE4 is what we are concerned about.

5) We carry two alleles of one single gene, meaning we can carry either one or two APOE4 alleles. About 1/4 of the population has at least one APOE4 allele. ~65–80% of people with AD have at least one APOE4 allele.

6) ⚠️⚠️APOE4 allele increases your risk for AD ~2–3-fold

⚠️⚠️ APOE4 alleles increases your risk for AD ~15-fold

However, APOE4 does not guarantee you will get AD and not having APOE4 doesn’t mean you won’t get AD.

7) What is APOE? 🤔

The APOE gene codes for the APOE protein. This protein is made in the brain and peripheral tissues but plays similar roles for both in lipid and cholesterol transport.

8) In peripheral tissue, APOE is synthesized in the liver and regulates lipid and cholesterol transport to tissues and reverse cholesterol transport (from peripheral tissues back to the liver first via the lymphatic system, then the bloodstream).

9) In the Brain, APOE is synthesized by astrocytes and regulates lipid and cholesterol transport to neurons. APOE2 and APOE3 are expressed 2–4 times more in neurons than APOE4, therefore APOE4 has reduced lipid and cholesterol transport to neurons.

10) The three primary pathological hallmarks of Alzheimer's Disease are: a) Extracellular Amyloid-ß Plaques, b) Intracellular Neurofibrillary Tangles, c) and Reduced Brain Glucose Uptake.

11) As we age, reactive oxygen species (ROS) and inflammation accumulates in the brain and this is taken care of via the activation of microglial cells (brain’s immune cells). Acutely, microglial cell activation is good, chronic activation is bad.

12) In AD, they are chronically activated by a protein called amyloid-ß42, which is a product of full-length amyloid-ß cleavage. This triggers a vicious cycle because microglial activation leads to further production of amyloid-ß plaques, and thus more amyloid-ß42 product.

13) When amyloid-ß plaques form these aggregations, they interfere with neuronal communication, disrupting or destroying it. Two ways we clear amyloid-ß plaques from the brain:

14) Glymphatic System: activated when we sleep and removes waste products from the brain, including amyloid-ß plaques. A lack of sleep = less glymphatic activation = less amyloid-ß plaque clearance.

15) APOE-mediated Mechanism: APOE binds amyloid-ß42 and removes it from the cell. The APOE4 isoform, besides producing less APOE protein, also binds amyloid-ß42 with a 20-fold lower affinity than APOE3. This mechanism is therefore very ineffective for APOE4 carriers.

16) ⚠️⚠️Sleep matters more for APOE4 carriers since they must rely on only one clearance system⚠️⚠️ (glymphatic **system**) In short: chronic activation of our brain’s immune cells leads to amyloid-ß plaque build-up, and clearance is impaired in APOE4 carriers.

17) Next up: Intracellular Neurofibrillary Tangles: These are also referred to as tau tangles, because they are aggregates of tau proteins. These are inside the neurons of patients with AD, whereas the amyloid-ß plaques are outside the cell.

18) Tau tangles interfere with how cellular components are transferred inside neurons, and therefore limits energy to the cell needed to form new synapses and maintain those previously formed.

19) Eventually, neurons succumb to this energy deficit resulting in long-term memory loss and neuronal cell death. In short: aggregates of tau proteins form tau tangles inside neurons and result in long-term memory loss and neuronal cell death.

20) Between our blood and the brain is the blood brain barrier (BBB). Within the BBB are transporters that shuttle glucose into our brain, these are called GLUT transporters). Neurons rely on GLUT transporters because they cannot store or produce glucose themselves.

21) APOE4 carriers typically have downregulation of GLUT transporters, and therefore reduced brain glucose uptake is more prevalent in these individuals.

22) A lack of glucose to the brain also contributes to the formation of tau tangles. After a tau protein is translated (produced from its associated mRNA), it is modified in a glucose-dependent manner, and once modified, negatively regulates its phosphorylation.

23) Without this modification, which occurs with reduced brain glucose uptake, tau proteins are hyperphosphorylated (since it has nothing negatively regulating this now), and this renders tau proteins pretty useless and promotes their aggregation and formation of tau tangles.

24) In short: APOE4 carriers have reduced brain glucose uptake (which is more pronounced as we age) because APOE4 downregulates the transport of glucose into the brain.

25) How DHA acts on all three of these pathologies? Docosahexaenoic acid (DHA) is one of the essential omega-3 fatty acids (the other important one is EPA and to a lesser extent, ALA).

26) It accounts for just shy of 1/3 of the brain’s lipids, so it’s presence is pretty critical. Unfortunately, the body cannot produce DHA on its own, and it must be acquired through the diet. Low levels of DHA promote all three pathological hallmarks of AD

27) Normal/high levels of DHA prevent or reverse all three pathological hallmarks of AD

- DHA has been shown to reduce amyloid-ß plaques and their associated toxicity
- DHA has been shown to promote amyloid-ß plaque clearance from the brain

28) - DHA has been shown to decrease tau tangles
- DHA regulates GLUT transporters; high levels upregulate GLUTs and low levels downregulate GLUTs

29) Regardless of APOE status, dietary fish and seafood intake slows AD progression and improves all three pathological characteristics of AD. Interestingly, DHA supplementation does not show these effects in APOE4 carriers, but does in non-carriers.

30) Why would fish improve cognitive function in APOE4carriers but supplementing with DHA does not? Dr. Rhonda Patrick suggests that the reason for this is because DHA in fish is in phospholipid form, whereas in a DHA supplement it is not.

31) Phospholipid form of DHA (found in fish) is metabolized to lysophosphatidylcholine (DHA-lysoPC) Non-phospholipid form of DHA (found in DHA supplements) is metabolized to non-esterfied DHA (free DHA)

32) The transport of these two types of DHA use different transport mechanisms for entry into the brain. Therefore, Dr. Patrick suggests that the transport of free DHA into the brain of APOE4 carriers is impaired, but the transport of DHA-lysoPC, is not.

33) Dr. Rhonda Patrick’s proposal: Providing the brain of APOE4 carriers with DHA-lysoPC may be a way to bypass defective free DHA transport into the brain.

34) DHA-lysoPC may in fact be the brain’s preferred source of DHA and it’s been reported that those with low levels of the precursor to DHA-lysoPC can predict mild dementia and AD with 90% accuracy, regardless of APOE4 status.

35) In short: the type of DHA found in fish, fish roe, and krill oil has a better chance of getting into the brain of APOE4 carriers.

36) How APOE4 Impacts Free DHA Transport: APOE4 in the brain breaks down the integrity and permeability of the BBB through multiple different mechanisms ultimately rendering free DHA transport into the brain very limited. It also decreases cerebral vascularization

37) Specifically, APOE4 degrades the tight junctions of the BBB which disrupts the outer membrane leaflet used by free DHA to enter the brain.

38) Free DHA improves cognitive function in young APOE4 carriers, but not in older individuals, indicating that age is a factor in the APOE4-mediated deterioration of the BBB.

39) In short: the type of DHA in fish oil supplements can not adequately enter the brain in APOE4 carriers, especially in older individuals.

40) How APOE4 Impacts DHA-LysoPC Transport. It doesn’t. DHA-LysoPC bypasses the tight junctions of the BBB and enters the brain via the inner membrane leaflet, therefore regardless of APOE status, DHA-LysoPC should enter the brain despite any degradation caused by APOE4.

41) The form of DHA becomes very critical for APOE4 carriers, because this dictates DHA’s entry into our brain. Fish contain ~1–1.5% of their omega-3 fatty acids in phospholipid form but fish oil

42) Fish roe from salmon, herring, pollock, and flying fish contain high amounts (~38–75%) of their omega-3 fatty acids in phospholipid form (mostly as phosphatidylcholine). Krill oil contains ~35% of DHA in phospholipids.

43) In phospholipid form, whether DHA is attached to the first or second carbon of the glycerol backbone dictates its break down.

44) DHA at carbon 2 (sn2)
- Metabolized by pancreatic enzyme PLA2 which releases DHA as a free fatty acid
- This free fatty acid (DHA) is resecreted into both LDL and HDL
- Only the portion that binds to HDL generates DHA-LysoPC
- The portion in LDL will generate free form DHA

45) DHA at carbon 1 (sn1)
- Bypasses pancreatic enzyme PLA2 therefore retaining its phospholipid form
- This has a much greater chance of accumulating in HDL than LDL, therefore a much greater chance of generating DHA-lysoPC

46) These forms are broken down by pancreatic lipases in the intestines and can both generate free DHA and DHA-lysoPC depending on whether it is resecreted into LDL or HDL, respectively.

47) Compared to the fate of DHA at the sn1 position in phospholipid form, these forms do not generate DHA-lysoPC (the end product we want!) to the same extent.

48) Dr. Patrick suggests the possibility that high dose DHA supplementation could increase the generation of DHA-lysoPC. Phospholipid form ends up in circulation as DHA-lysoPC more rapidly than consumption in triglyceride form

49) DHA is delivered to the brain in greater abundance when consumed in phospholipid form versus triglyceride

50) In summary, APOE4 limits the transport of free DHA (from DHA supplements) into the brain, therefore consuming DHA in phospholipid form to generate DHA-lysoPC (e.g. fish, fish roe, and krill oil) may bypass this faulty transport in APOE4 carriers.

51) That's it for the tweetstorm. Thank you @foundmyfitness! To see the full article on @healthspanmed, see here: gethealthspan.com/blog/research/…