Alzheimer’s disease is a progressive neurodegenerative disease estimated to affect six million Americans and thirty-three million people worldwide. One of the big issues is the lack of diagnosis in people with Alzheimer’s disease because it prevents early intervention and therapy in these patients. Pathologic hallmarks in the brain are extracellular amyloid-β deposits and intracellular tangles of tau filaments, inflammation, and atrophy(1).
Alzheimer’s disease is a multifactorial process which essentially increases oxidative stress and correlates with
cognitive impairment(2).
Current models of pathogenesis focus on mitochondrial dysfunction, disrupted autophagy
(removal of dysfunctional components) of aged or damaged organelles, particularly mitochondria, protein misfolding or production of inflammatory cytokines and reactive oxygen species around amyloid plaques or neurofibrillary tangles(3).
Neurons are highly susceptible to oxidative damage because of their high
metabolic rates, tissue oxygen levels, stores of redox metals, and high membrane content of easily oxidized polyunsaturated fatty acids which together represent 20% of brain lipids.
Because the brain operates in a delicate balance between its modest antioxidant reserve and the constant generation of damaging reactive species during normal functions, brain survival requires multiple forms of antioxidants.
When there is a disruption in this balance, whether increased oxidation or deficiency in brain antioxidants, there is an enhanced potential to for Alzheimer’s disease pathogenesis(4).
Dietary xanthophylls and other carotenoids suppress key aspects of Alzheimer’s disease pathogenesis, including oxidation and inflammation. In fact, low plasma levels of xanthophylls in Alzheimer’s’ disease have been attributed to significantly lower concentrations of HDL in Alzheimer’s’ disease subjects who also have vascular complications(5).
Dietary tocopherols are important antioxidants that also inhibit oxidative stress and modulate proinflammatory pathways, apoptosis, and neuroprotective functions that are implicated in risk for Alzheimer’s’ disease.
Higher intake of total carotenoids or lutein/zeaxanthin over more than a decade was associated with almost 50% lower risk for an Alzheimer’s’ disease diagnosis and less global brain pathology. Lutein/zeaxanthin intake was inversely correlated with Alzheimer’s’ disease diagnostic score, neuritic plaque severity, as well as neurofibrillary tangle density and severity(6).
Higher circulating levels of lutein and/or zeaxanthin and/or lycopene were associated with lower risk for dementia and lower risk for Alzheimer’s’ disease mortality in the NHANES study(7).
Greater dietary intake of carotenoids was correlated with
better cognitive performance, lower risk for Alzheimer’s’ disease, and less severity of brain pathology(6).
These observations are consistent with reports that those with higher levels of total carotenoids in diet, serum or plasma had slower cognitive decline, fewer white matter lesions, less brain atrophy, and lower risk for Alzheimer’s’ disease diagnosis or less brain pathology(6).
In addition, higher gamma-tocopherol levels in Alzheimer’s’ disease brains were associated with lower Aβ and lower severity of neurofibrillary tangles; higher levels were also associated with higher levels of six presynaptic proteins(8).
Despite its obvious relevance, little is known about carotenoid levels in brains with dementia or Alzheimer’s’ disease. Healthy elderly human brains contain more than 16 carotenoids and 66–77% of them are xanthophylls, dominated by β-cryptoxanthin, lutein, anhydrolutein, and zeaxanthin(9).
Lutein and β-carotene concentrations were significantly lower in brains of elderly donors with mild cognitive impairment than in those with normal cognition(10).
Considering these facts, a recent study investigated the hypothesis that concentrations of lutein and zeaxanthin, carotenoid, and tocopherols are lower in brains with confirmed Alzheimer’s’ disease than in healthy elderly brains of comparable age(1).
Results of this research indicated that concentrations of lutein, zeaxanthin, lycopene, retinol, and α-tocopherol are profoundly lower in brains with documented Alzheimer’s’ disease, that lycopene and zeaxanthin were the two most deficient antioxidants, and that Alzheimer’s’ disease brains had significantly higher levels of XMiAD, a yet unidentified xanthophyll.
Figure: Lutein and zeaxanthin concentrations in grey and white matter of Healthy Elderly (HE) and Alzheimer’s Disease (AD) brains. In AD brains, lutein exceeded zeaxanthin (* above bars); zeaxanthin in grey matter was lower in AD than in HE brains (*in bars) (1)
Inadequate levels of brain carotenoids would reduce the
potential neuroprotection offered by their antioxidant, anti-inflammatory, and anti-amyloidogenic activities. Reduced levels would increase risk of lipid peroxidation, protein nitration, and mitochondrial dysfunction that contribute to neuronal death(1).
The importance of inadequate levels of lutein and zeaxanthin in Alzheimer’s’ disease brains are emphasized by reports that those with highest levels of lutein and zeaxanthin have a 50% lower risk for an Alzheimer’s’ disease diagnosis, and higher cognitive performance. The observation that lutein and zeaxanthin were selectively lower in brain white matter aligns with previous reports associating better white matter integrity with higher serum concentrations of lutein and zeaxanthin, and increased risk for white matter lesions with low serum carotenoids.
Presence of white matter lesions are a risk factor for greater progression from mild cognitive impairment to Alzheimer’s’ disease. Lutein and zeaxanthin may slow cognitive decline and reduce risk for Alzheimer’s’ disease by helping to preserve white matter connectivity.
Given the vulnerability of the brain to oxidative damage, constant generation of reactive species through normal brain functions, and limited antioxidant resources, it is plausible to consider that brains with 40–50% lower levels of α-tocopherol and four carotenoids, and marginally lower levels in three of the four remaining brain carotenoids would be more vulnerable to oxidative damage and inflammation.
This new evidence of selective carotenoid and tocopherol deficiencies in the brains of subjects with Alzheimer’s’ disease add further support to the growing evidence that greater dietary intake of lutein, zeaxanthin, lycopene as well as α- and γ-tocopherols may slow cognitive decline prior to— and possibly following— a diagnosis with Alzheimer’s’ disease.
This is a landmark study that demonstrated for the first time that brain levels of dietary lutein, zeaxanthin, lycopene, and vitamin E in individuals with Alzheimer’s disease are 50% less compared to age-matched normal brains.
This is the first evidence showing deficits in important dietary antioxidants in Alzheimer’s brains and these findings are consistent with large population studies that show risk for Alzheimer’s disease was significantly lower in those who consumed diets rich in carotenoids, or had high levels of lutein and zeaxanthin in their blood.
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References:
1. Dorey CK, Gierhart D, Fitch KA, et al: Low Xanthophylls, Retinol, Lycopene, and Tocopherols in Grey and White Matter of Brains with Alzheimer's Disease. J Alzheimers Dis 94:1-17, 2023
2. Polidori MC, Stahl W, Griffiths HR: Nutritional cognitive neuroscience of aging: Focus on carotenoids and cognitive frailty. Redox Biol 44:101996, 2021
3. Serrano-Pozo A, Mielke ML, Gómez-Isla T, et al: Reactive glia not only associates with plaques but also parallels tangles in Alzheimer's disease. Am J Pathol 179:1373-84, 2011
4. Ionescu-Tucker A, Cotman CW: Emerging roles of oxidative stress in brain aging and Alzheimer's disease. Neurobiol Aging 107:86-95, 2021
5. Dias IH, Polidori MC, Li L, et al: Plasma levels of HDL and carotenoids are lower in dementia patients with vascular comorbidities. J Alzheimers Dis 40:399-408, 2014
6. Yuan C, Chen H, Wang Y, et al: Dietary carotenoids related to risk of incident Alzheimer dementia (AD) and brain AD neuropathology: a community-based cohort of older adults. Am J Clin Nutr 113:200-208, 2021
7. Min JY, Min KB: Serum lycopene, lutein and zeaxanthin, and the risk of Alzheimer's disease mortality in older adults. Dement Geriatr Cogn Disord 37:246-56, 2014
8. de Leeuw FA, Honer WG, Schneider JA, et al: Brain γ-Tocopherol Levels Are Associated with Presynaptic Protein Levels in Elderly Human Midfrontal Cortex. J Alzheimers Dis 77:619-627, 2020
9. Craft NE, Haitema TB, Garnett KM, et al: Carotenoid, tocopherol, and retinol concentrations in elderly human brain. J Nutr Health Aging 8:156-62, 2004
10. Johnson EJ, Vishwanathan R, Johnson MA, et al: Relationship between Serum and Brain Carotenoids, α-Tocopherol, and Retinol Concentrations and Cognitive Performance in the Oldest Old from the Georgia Centenarian Study. J Aging Res 2013:951786, 2013
11. Sommerburg O, Keunen JE, Bird AC, van Kuijk FJ. Fruits and vegetables that are sources for lutein and zeaxanthin: the macular pigment in human eyes. Br J Ophthalmol. 1998 Aug;82(8):907-10
