Alzheimer’s delayed 4.7 years by high Omega-3 index (7.6 years if also have APOE-4) June - 2022

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Red Blood Cell DHA Is Inversely Associated with Risk of Incident Alzheimer’s Disease and All-Cause Dementia: Framingham Offspring Study

Nutrients 2022, 14(12), 2408; https://doi.org/10.3390/nu14122408
by Aleix Sala-Vila 1,2,*,†ORCID,Claudia L. Satizabal 3,4,5,6,†,Nathan Tintle 1,7,Debora Melo van Lent 3,4,5,6ORCID,Ramachandran S. Vasan 8,Alexa S. Beiser 9,Sudha Seshadri 3,4,5,6 andWilliam S. Harris 1,10ORCID

High DHA, reduces incidence of dementia

High Omega-3 index: delays Alz 7.6 years, Dementia 7.3 years

Docosahexaenoic acid (DHA) might help prevent Alzheimer’s disease (AD). Red blood cell (RBC) status of DHA is an objective measure of long-term dietary DHA intake. In this prospective observational study conducted within the Framingham Offspring Cohort (1490 dementia-free participants aged ≥65 years old), we examined the association of RBC DHA with incident AD, testing for an interaction with APOE-ε4 carriership. During the follow-up (median, 7.2 years), 131 cases of AD were documented. In fully adjusted models, risk for incident AD in the highest RBC DHA quintile (Q5) was 49% lower compared with the lowest quintile (Q1) (Hazard ratio [HR]: 0.51, 95% confidence interval [CI]: 0.27, 0.96). An increase in RBC DHA from Q1 to Q5 was predicted to provide an estimated 4.7 additional years of life free of AD. We observed an interaction DHA × APOE-ε4 carriership for AD. Borderline statistical significance for a lower risk of AD was observed per standard deviation increase in RBC DHA (HR: 0.71, 95% CI: 0.51, 1.00, p = 0.053) in APOE-ε4 carriers, but not in non-carriers (HR: 0.85, 95% CI: 0.65, 1.11, p = 0.240). These findings add to the increasing body of literature suggesting a robust association worth exploring dietary DHA as one strategy to prevent or delay AD.
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Discussion

In this prospective study conducted in a community-based sample of Americans over age 65 who were followed for a median of 7.2 years for incident dementia, we found that an increasing proportion of DHA in RBCs was related to a lower risk of AD and all-cause dementia. Of note, participants at the top quintile of RBC DHA had roughly half the risk of developing AD during follow-up compared to those at bottom quintile. We also detected a possible interaction between RBC DHA x APOE-e4 carriership, with a stronger inverse association between RBC DHA and risk of AD in e4 carriers—individuals at increased genetic risk of late-onset AD—than non-carriers. This suggests that carriers may benefit more from higher DHA levels than non-carriers [6].
Three of our findings are important. First, this study supports the hypothesis of a link between diet and brain health, since the most effective way to raise RBC DHA levels is to consume more preformed DHA. Thus, DHA, a fatty acid also known to have cardiovascular benefits [25], might also slow the progression of AD. Second, based on our estimations, changing from the lowest quintile (<3.8% of DHA in RBC membranes) to the top quintile (>6.1%) could translate into an estimated gain of 4.7 years free of AD. This was roughly half of the apparent benefit gained from not carrying an APOE-e4 allele. Given that estimated health-care payments in 2021 for all patients with AD or other dementias amount to $355 billion in US (not including caregiving by family members and other unpaid caregivers) [26], any cost-effective strategy for delaying the onset of AD is of utmost public health interest. Delaying AD by 5 years leads to 2.7 additional years of life, and 4.8 additional AD-free years for an individual who would have acquired AD, and is worth over $500,000 [27]. Third, after excluding e2/e4 participants (because of the known protective effects of the e2 allele), we observed an interaction DHA x APOE-e4 carriership on incident AD and all-cause dementia, with a trend towards a greater benefit of DHA in e4 carriers than in non-carriers. A plausible explanation for this finding is that APOE-e4 carriers might need more DHA to overcome their lower status of DHA (secondary to accelerated liver catabolism of DHA) coupled to impaired delivery of DHA to the brain [6]. This exploratory finding, which should be confirmed in more prospective studies with adequate statistical power, suggests that the APOE genotype modulates the associations between DHA and incident AD, and reinforces the need to target these particular individuals for supplementation, as expanded upon below.
Our study is in line with that of Tan et al., who reported cross-sectional associations with RBC DHA on cognitive performance and brain volume measurements (with higher DHA being associated with beneficial outcomes) in the same cohort as studied here [28]. Most interestingly, 15 years ago, similar findings were reported by Schaefer et al. in the parents of the individuals who were the focus of this present investigation (i.e., the Original Framingham Heart Study cohort). Schaefer et al. reported that participants in the top quartile of plasma phosphatidylcholine DHA experienced a significant, 47% reduction in the risk of developing all-cause dementia compared with those with lower levels [13]. Similar findings a generation apart in a similar genetic pool provide considerable confirmation of this DHA-dementia relationship.
Despite mounting evidence on the association between circulating DHA and preserved brain structure [9,10], blood-brain barrier integrity [29], and lower cerebral amyloidosis [30], several longitudinal studies on circulating DHA and incident AD/dementia failed to report statistically significant associations for DHA [11,12,17,18], while reporting significant inverse associations for DHA + EPA [12,15] or EPA alone [17,18]. In our study, using RBC EPA + DHA (i.e., the omega-3 index) or RBC EPA as the exposures of interest resulted in weaker and non-significant associations than for DHA alone. Future research is warranted to better delineate the extent to which EPA and/or DHA is the better marker of risk for dementia, and whether plasma concentrations vs. percent composition vs. RBC is the optimal sample type to analyze for omega-3 content when evaluating patients with respect to dementia.
In terms of clinical relevance, the lack of benefits in cognitive performance in randomized controlled trials involving DHA [31-35] urges to improve the design of future trials. Other study designs to elucidate causation (e.g., Mendelian Randomization) may also be valuable, though identifying a good quality genetic instrument for DHA may prove challenging [36,37]. Our results imply that certain people might benefit more from DHA-based interventions than others. This perspective is aligned with the 21st century shift towards "precision nutrition" and "personalized medicine." Specifically, two patient characteristics would be of interest. First, those with low DHA status, as suggested by results from the Multidomain Alzheimer Preventive Trial (MAPT), in which 3-year supplementation with 800 mg DHA + 225 mg EPA showed no significant effect on cognitive decline overall in older people with memory complaints [34], but benefits were observed in a subgroup of individuals with low omega-3 status at baseline [38]. This finding spawned the ongoing "low-omega (LO)-MAPT" trial (18-month intervention in older adults with omega-3 index < 4.83%; [39]), which will hopefully shed light on this issue. The second group that might benefit from DHA supplementation is individuals who are genetically at risk of AD (i.e., APOE-e4 carriers). In these people, subclinical structural and functional brain changes associated with AD take place years (even decades) before AD is present. There is increasing evidence for cognitive benefit from dietary DHA in cognitively healthy e4 carriers (consistent with our findings), but not in those with AD or mild cognitive impairment [6]. Therefore, there may be a window of opportunity to identify cognitive healthy e4 carriers and manage their associated elevated dementia risk with a dietary intervention (i.e., dietary DHA, but requiring doses close to 2 g/d [40]).
The strengths of this study are the inclusion of a large sample of older adults living in a community setting, with comprehensive cognitive assessments, continuous dementia surveillance, and collection of multiple health measures that can be included as potential confounders in statistical models. Furthermore, we used objective measurements of DHA and EPA from RBC, which reflect their long-term intake more accurately than dietary intake questionnaires. However, our study has several limitations. First, given its observational nature, it cannot address causality, and it is not possible to establish the directionality of associations. Second, the low number of e4 carriers resulted in a less precise effect estimates; therefore, our exploratory finding should be replicated in larger studies with greater statistical power. Third, we could not exclude the possibility that uncaptured environmental or other genetic factors may have influenced or caused the observed associations. Fourth, there is no information on whether a single measurement of RBC DHA is appropriate to estimate the risk of AD over long-term follow up when compared to repeated measurements. Finally, additional studies are needed to replicate these results in more diverse populations.

Conclusions

In conclusion, in a cohort of dementia-free participants from the Framingham Heart Study aged 65 years and older, we observed that those with a baseline RBC DHA proportion above 6.1% (top quintile) had nearly half the risk of developing AD (and all-cause dementia), and had an estimated 4.7 extra years of life free of AD compared to those with an RBC DHA below 3.8% (bottom quintile). In addition, we observed a trend for a stronger association in between RBC DHA and risk for dementia in e4 carriers than non-carriers, a finding that needs further research. Our results, which concur with a growing experimental research foundation, suggest that an increased DHA intake may be a safe and cost-effective strategy in preventing AD in specific populations.

VitaminDWiki - Omega-3 helps many health problems

407 Omega-3 items in category Omega-3 helps with: Autism (7 studies), Depression (28 studies), Cardiovascular (34 studies), Cognition (52 studies), Pregnancy (44 studies), Infant (34 studies), Obesity (14 studies), Mortality (7 studies), Breast Cancer (5 studies), Smoking, Sleep, Stroke, Longevity, Trauma (12 studies), Inflammation (18 studies), Multiple Sclerosis (9 studies), VIRUS (12 studies), etc
CIlck here for details

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VitaminDWiki - 52 studies in both categories Cognitive and Omega-3

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VitaminDWiki - Overview Alzheimer's-Cognition and Vitamin D contains

• FACT: Cognitive decline is 19X more likely if low vitamin D
• FACT: Dementia is associated with low vitamin D levels.
• FACT: Alzheimer’s Dementia 2.3X more likely in elderly if low vitamin D – Dec 2022
• FACT: Dementia is associated with low vitamin D - many studies
• FACT: Alzheimer's Disease is 4X less likely if high vitamin D
• FACT: Every single risk factor listed for Alzheimer's Disease is also a risk factor for low vitamin D levels
• FACT: Elderly cognition gets worse as the elderly vitamin D levels get even lower (while in senior homes)
• OBSERVATION: Reports of increased vitamin D levels result in improved cognition
• OBSERVATION: Alzheimer’s patients 3X more likely to have a malfunctioning vitamin D receptor gene – 2012
• OBSERVATION: Alzheimer's Disease has been seen to halt when vitamin D was added.
• OBSERVATION: Alzheimer’s is associated with all 7 of the genes which restrict vitamin D
• OBSERVATION: 39 vitamin D and Alz. or Cognition intervention trials as of Sept 2018
• OBSERVATION: 2 Meta-analysis in 2012 agreed that Alzheimer's Disease. associated with low vitamin D
• OBSERVATION: 50X increase in Alzheimer's while decrease in vitamin D
• OBSERVATION: Vitamin D reduces Alzheimer’s disease in 11 ways
• OBSERVATION: Alzheimer’s cognition improved by 4,000 IU of vitamin D
• OBSERVATION: Plaque removed in mice by equiv. of 14,000 IU daily
• OBSERVATION: DDT (which decreases Vit D) increases risk of Alzheimer's by up to 3.8X
• OBSERVATION: 2% of people have 2 copies of the poor gene reference: Alz Org
• OBSERVATION: Genes do not change rapidly enough to account for the huge increase in incidence
• OBSERVATION: End of Alzheimer's videos, transcripts and many studies protocol has been very successful
  • It adjusts Vitamin D, B-12, Iron, Omega-3, food, etc, and can now be done at home.
• FACT: Vitamin D is extremely low cost and has very very few side effects
• CONCLUSION: Everyone concerned about cognitive decline or Alzheimer's Disease should take vitamin D
• PREDICTION MET: By 2024 Omega-3 and high dose Vitamin D will be found to reverse Alzheimer's in humans
  There are 13+ Alzheimer’s meta-analyses in VitaminDWiki
  There are 97+ Alzheimer’s studies in VitaminDWiki
  Dementia is associated with low vitamin D - many studies 50+ studies
  16+ studies in both categories Cognitive and Omega-3

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VitaminDWiki pages with ALZHEIMER in title (78 as of June 2022)

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VitaminDWiki pages with DEMENTIA in title (41 as of June 2022)

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