Docosahexaenoic acid (DHA) is the predominant omega-3 fatty acid in brain tissue¹ and a crucial nutrient for the management of Alzheimer’s disease (AD). It exerts anti-amyloidogenic effects,² modulates glial cell activity and reduces neuroinflammation in AD,³ helping to prevent and slow the progression of neurodegeneration. This predominantly occurs though its pleiotropic effects on the activity of secretases and lipid rafts in the brain, which are involved in amyloid production, aggregation and neurotoxicity.^2,4,5

It is important to distinguish between the two genetically distinct forms of AD: early-onset familial AD and late-onset sporadic AD, which generally occur before and after 60 years of age, respectively. Early-onset familial AD exhibits a certain pattern of inheritance and is rare, representing <1% of AD cases. In contrast, the most common form of the disease is late-onset sporadic AD, where both genetic and environmental risk factors are involved. Importantly, apolipoprotein E (ApoE) genotype heavily influences the risk of developing late-onset sporadic AD and the age in which onset occurs.⁶

Of the three major alleles of the ApoE gene, ε2 and ε4 are the most significant regarding AD.7 While the ApoE ε2 allele variant appears to be neuroprotective,⁸ strong evidence has linked the ApoE ε4 to cholesterol dysregulation and AD-associated pathology,^9,10 and is disproportionately found in approximately 40% of late-onset AD patients.11 ApoE ε4 also increases β-amyloid accumulation by encouraging ApoE (a major cholesterol transporter in the brain) to colocalise with β-amyloid in plaques and synapses.¹² Additionally, ApoE ε4 elevates β-amyloid 42 secretion and impairs its clearance in neural and glial cells.¹³ In turn, β-amyloid 42 causes neuronal dysfunction, since the pathological accumulation of oligomeric β-amyloid assemblies impairs excitatory transmission at the synaptic level and contributes to the destabilisation of neuronal networks.¹⁴

Further, research indicates that carriers of the ApoE ε4 allele are less effective at metabolising DHA,¹⁵ resulting in slower brain uptake and distribution of DHA.^16,17 As such, ApoE ε4 predisposes individuals to AD in two main ways, firstly by promoting neuronal dysfunction via its effects on β-amyloid metabolism and secondly by lowering the amount of dietary DHA delivered to brain cells. Strategies that block these effects may therefore serve to prevent cognitive decline with age in AD.¹⁴ Taken together, this highlights the increased need for dietary DHA supply for prevention of neurodegeneration in those at the greatest risk of developing AD.

Early DHA Intervention in Apolipoprotein E (ApoE) ε4-Positive AD

Clinical trials and population-based studies highlight the extent of ApoE ε4 genetic predisposition in AD. In a randomised, double-blind, placebo-controlled trial investigating the objective effects of DHA in mild to moderate AD, participants in the treatment group received 2000 mg DHA/day for 18 months. DHA significantly lowered the decline in AD assessment scale (ADAS-cog) and mini-mental state examination (MMSE) scores in the DHA-treated ApoE ε4-negative subgroup only.¹⁸

In contrast, 900 mg/day of DHA has been shown to significantly promote learning and memory function in those experiencing age-related cognitive decline (ARCD). While approximately 36% of this sample population had a family history of dementia, ApoE genotyping was not conducted in this double-blind, randomised, placebo-controlled trial.19 Additionally, data from a meta-analysis of 21 cohort studies demonstrated that 0.1 g/day increments of DHA intake also significantly lowered the risk of AD (37% relative risk reduction [RRR]) [p<0.001].²⁰ Separately, homozygous ApoE ε4 carriers

from the ALzheimer and FAmilies (ALFA) study displayed greater resilience to AD-related neurodegenerative pathology when consuming a higher dietary intake of DHA.²¹ This evidence suggests that increased dietary or prescribed supplemental DHA serves as an important and easily accessible strategy promoting neuroprotection in ApoE ε4 carriers at risk of AD.

DHA Influences Metabolism of β-Amyloid

Epidemiological evidence demonstrates an inverse association between serum DHA and the severity of cognitive impairment in AD.^22,23 Not only does DHA appear to reduce β-amyloid production but it simultaneously increases its clearance from the brain.

Demonstrating this, a 24-month study administering 2000 mg DHA/day was shown to enhance the effects of autophagy and metabolism of β-amyloid in elderly participants with mild cognitive impairment (MCI) in a randomised, double-blind, controlled trial. Results favoured DHA over placebo treatment with scores of full-scale intelligence quotient (IQ), verbal IQ, and subdomains of information (i.e., verbal comprehension) and digit span (i.e., working memory) significantly higher among the DHA group. Blood β-amyloid 42 level and expression of APP were also significantly decreased, while autophagy-related gene beclin-1 levels, and autophagosomal marker LC3-II levels and expression were significantly increased.²⁴ This study supports earlier in vitro findings showing DHA enhanced the removal of β-amyloid 42 by microglia and induced a shift away from pro-inflammatory M1 activation.²⁵

Overall, these findings illustrate that the way in which DHA modulates neuroinflammation is twofold: DHA reduces β-amyloid production and encourages its clearance from the brain, thereby deterring the progression of AD and preserving cognitive function.

DHA Helps Control Neurodegeneration

DHA is an essential structural and functional component of the brain that has also been shown to exert neuroprotective effects in AD. ApoE ε4 genotype is a strong genetic determinant of AD risk and progression, especially given its influence on β-amyloid accumulation and its association with DHA. Clinical studies reveal that consumption of ≤2000 mg DHA/day may be most beneficial during the preclinical stage of AD. In high-risk ApoE ε4 carriers specifically, early treatment with DHA may delay the onset of neurodegenerative changes associated with the development of AD and slow early memory decline in dementia.²⁶

References

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