Association of Serum Docosahexaenoic Acid With Cerebral Amyloidosis

Yassine, Hussein N.; Feng, Qingru; Azizkhanian, Ida; Rawat, Varun; Castor, Katherine; Fonteh, Alfred N.; Harrington, Michael G.; Zheng, Ling; Reed, Bruce R; DeCarli, Charles; Jagust, William J.; Chui, Helena C.

doi:10.1001/jamaneurol.2016.1924

Cited by 74 publications

(73 citation statements)

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“…Cell membrane fluidity also influences the processing of APP and cellular phagocytosis, both of which might affect Aβ generation and clearance. A high dietary intake of polyunsaturated fatty acids such as docosahexaenoic acid, which maintain membrane fluidity, have a beneficial effect on cognition in patients with AD 91,92 . The study of membrane fluidity in AD might provide insights into the alteration of membrane-dependent biological functions related to Aβ, such as phagocytosis, endocytosis, macropinocytosis and autophagy.…”

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confidence: 99%

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

et al. 2017

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The global burden of Alzheimer disease (AD), already the most common type of dementia, is expected to increase still further owing to population ageing. AD not only causes severe distress for patients and caregivers, but also results in a large economic burden on society. Current major challenges in AD include the lack of reliable biomarkers for its early diagnosis, as well as the lack of effective preventive strategies and treatments 1,2 . Thus, increased understanding of the molecular patho genesis of AD could lead to the development of improved diagnostic and therapeutic strategies.AD is conventionally regarded as a CNS disorder. However, increasing experimental, epidemiological and clinical evidence has suggested that manifestations of AD extend beyond the brain. These systemic alterations might not be simply secondary effects of the cerebral degeneration seen in AD, but could reflect under lying processes linked to progression of the disease. AD pathogenesis is complex, involving abnormal amyloid-β (Aβ) metabolism, tau hyperphosphorylation, oxidative stress, reactive glial and microglial changes, and other pathological events. Given that Aβ is a major hallmark of AD and a fertile area of research in this disease, this Review focuses on the systemic role of Aβ in AD. We discuss the communication between peripheral and central pools of Aβ, and describe interactions between systemic abnormalities and AD pathogenesis in the brain. We review emerging findings of associations between systemic abnormalities and Aβ metabolism, and describe how these associations might interact with or reflect on the central pathways of Aβ production and clearance. On the basis of these findings, we suggest that interactions between the brain and the periphery might have a crucial role in the development and progression of AD. Aβ biogenesis and catabolismA steady accrual of data from laboratories and clinics is providing increasing support for the concept that an imbalance between the production and clearance of Aβ is a very early (and often initiating) factor in AD 3 . Normal metabolism of Aβ and maintenance of the homeostatic balance between Aβ production and clearance is, therefore, essential to maintain brain health. In fact, physiological metabolism of Aβ occurs not only in the brain but also in the periphery, and communication between these regions is possible (FIG. 1). Central and peripheral production of AβAβ is derived from the proteolytic cleavage of amyloid precursor protein (APP), which is expressed not only in brain cells, including neurons, astrocytes and microglia, but also in peripheral organs and tissues, such as the Abstract | Alzheimer disease (AD) is the most common type of dementia, and is currently incurable; existing treatments for AD produce only a modest amelioration of symptoms. Research into this disease has conventionally focused on the CNS. However, several peripheral and systemic abnormalities are now understood to be linked to AD, and our understanding of how these alterations contribute to AD is becom...

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A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

et al. 2017

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“…The brain also requires DHA for maintenance of neuronal membranes, production and clearance of β-amyloid 42, modulation of inflammation [10, 11], and cerebrovascular health [12]. We previously reported a direct association between lower serum DHA levels and greater cerebral amyloidosis in cognitively healthy older adults [13]. The lowest quartile of serum DHA was associated with significantly greater cerebral amyloid deposition, smaller entorhinal and hippocampal volumes, and worse nonverbal memory scores [13].…”

Section: Introductionmentioning

confidence: 99%

“…We previously reported a direct association between lower serum DHA levels and greater cerebral amyloidosis in cognitively healthy older adults [13]. The lowest quartile of serum DHA was associated with significantly greater cerebral amyloid deposition, smaller entorhinal and hippocampal volumes, and worse nonverbal memory scores [13]. …”

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confidence: 99%

DHA brain uptake and APOE4 status: a PET study with [1-11C]-DHA

et al. 2017

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BackgroundThe apolipoprotein E ɛ4 (APOE4) allele is the strongest genetic risk factor identified for developing Alzheimer’s disease (AD). Among brain lipids, alteration in the ω-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) homeostasis is implicated in AD pathogenesis. APOE4 may influence both brain DHA metabolism and cognitive outcomes.MethodsUsing positron emission tomography, regional incorporation coefficients (k*), rates of DHA incorporation from plasma into the brain using [1-11C]-DHA (J in), and regional cerebral blood flow using [15O]-water were measured in 22 middle-aged healthy adults (mean age 35 years, range 19–65 years). Data were partially volume error-corrected for brain atrophy. APOE4 phenotype was determined by protein expression, and unesterified DHA concentrations were quantified in plasma. An exploratory post hoc analysis of the effect of APOE4 on DHA brain kinetics was performed.ResultsThe mean global gray matter DHA incorporation coefficient, k*, was significantly higher (16%) among APOE4 carriers (n = 9) than among noncarriers (n = 13, p = 0.046). Higher DHA incorporation coefficients were observed in several brain regions, particularly in the entorhinal subregion, an area affected early in AD pathogenesis. Cerebral blood flow, unesterified plasma DHA, and whole brain DHA incorporation rate (J in) did not differ significantly between the APOE groups.ConclusionsOur findings suggest an increase in the DHA incorporation coefficient in several brain regions in APOE4 carriers. These findings may contribute to understanding how APOE4 genotypes affect AD risk.

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“…AD risk is closely linked to changes in lipid metabolism and plasma DHA levels were inversely associated to the brain Ab load (Yassine et al, 2016). Some suggest that the E4 allele induce a decrease in levels of apoE protein in the brain (i.e.…”

Section: Evidence Of Effective Prevention Strategiesmentioning

confidence: 99%

“…This higher uptake was particularly emphasized in the entorhinal region, an area affected early in AD pathogenesis and it was suggested by the authors it might represent a compensatory mechanism in younger E4 carriers to cope with increased brain DHA loss thus to maintain brain DHA levels (Yassine et al, 2017). Therefore, at younger ages, E4 carriers might require more DHA than non-carriers to support brain DHA turnover and prevent accumulation of Ab peptide since it was shown that higher plasma DHA levels were inversely associated to the brain Ab load (Yassine et al, 2016). However, Abdullah et al showed that a fish oil supplement modulate the ARA: DHA ratio in carriers and non-carriers of E4 suggesting that E4 carrier could somehow benefit from a fish oil supplement in rebalancing the ARA: DHA ratio but this may be conditional to higher doses and longer duration than what has currently been published yet on the topic.…”

Section: Evidence Of Effective Prevention Strategiesmentioning

confidence: 99%

Aging, cognitive decline, apolipoprotein E and docosahexaenoic acid metabolism

Plourde

2018

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-In Canada, ∼17 millions of adults between 30-64 years old could benefit from a prevention strategy to lower the risk of Alzheimer's disease (AD). My group is working on a population that is particularly at risk of AD, the carriers of an epsilon 4 allele of apolipoprotein E (E4), a genetic risk. Around 20% of the population in industrial countries have this genetic risk but not all carriers will develop AD, suggesting that environmental factors modulate the clinical manifestation and risk of AD in the carriers. My group has discovered that the metabolism of docosahexaenoic acid (DHA) is disrupted during aging and in E4 carriers, a finding replicated in homozygous mice knocked-in for human E4 allele (hAPOE4). We recently showed that a diet containing DHA prevented behavioral deficits in hAPOE4 mice. Another group reported in E4 carriers that the ratio of arachidonic acid (ARA): DHA is disrupted in the plasma and constitute a preclinical marker of mild cognitive impairment/AD in E4 carriers. Using our kinetics approaches with uniformly labelled carbon 13 fatty acids, we showed that the kinetics of 13 C-DHA is modified by age and E4 carriage. The kinetics of 13 C-arachidonic acid was however not modified by age conversely to that of 13 C-eicosapentaenoic acid (EPA). We also reported that the synthesis of 13 C-DHA from 13 C-EPA started 2 h after the tracer intake in older adults conversely to 7 d in young men. Whether old men needs in DHA is higher or whether their ability to use it is lower remains to be established. These differences in the DHA and EPA metabolism seems, however related to physiological modifications occurring during aging and in E4 carriers and obscure the relationship between plasma DHA and EPA levels, dietary fatty fish intake and cognitive status.Keywords: docosahexaenoic acid / arachidonic acid / eicosapentaenoic acid / aging / cognitive decline / apolipoprotein E / kinetics Résumé -Vieillissement, déclin cognitif, apolipoprotéine E et métabolisme de l'acide docosahexaénoïque. Au Canada, 17 millions d'adultes âgés entre 30-64 ans pourraient bénéficier d'une intervention en prévention pour diminuer leur risque de développer la maladie d'Alzheimer (MA). L'un des groupes les plus à risque de développer la MA, les porteurs de l'allèle epsilon 4 de l'apolipoprotéine E (E4), est au centre des recherches menées par mon groupe. Environ 20 % de la population des pays industrialisés sont porteurs d'E4 mais ce ne sont pas tous les porteurs qui développeront la MA, ce qui suggère que des facteurs environnementaux puissent moduler l'expression clinique et le risque de la MA chez les porteurs. Nous avons découvert que le métabolisme de l'acide docosahexaénoïque (DHA) est débalancé pendant le vieillissement et chez les porteurs de l'E4. Ces découvertes ont été répliquées dans un modèle de souris transgénique dont l'apolipoprotein de souris a été remplacé par de l'E4 humaine (hAPOE4). Nous avons récemment montré qu'une diète riche en DHA prévenait les déficits comportementaux chez la souris hAPOE4. U...

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Association of Serum Docosahexaenoic Acid With Cerebral Amyloidosis

Cited by 74 publications

References 53 publications

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

DHA brain uptake and APOE4 status: a PET study with [1-11C]-DHA

Aging, cognitive decline, apolipoprotein E and docosahexaenoic acid metabolism

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