Brain tocopherols related to Alzheimer's disease neuropathology in humans

Abstract

Randomized trials of α-tocopherol supplements on cognitive decline are negative, whereas studies of dietary tocopherols have shown benefit. We investigated these inconsistencies by analyzing the relations of α- and γ-tocopherol brain concentrations to Alzheimer's disease (AD) neuropathology among 115 deceased participants of the prospective Rush Memory and Aging Project. Associations of amyloid load and neurofibrillary tangle severity with brain tocopherol concentrations were examined in separate adjusted linear regression models. γ-Tocopherol concentrations were associated with lower amyloid load (β = -2.10, P = .002) and lower neurofibrillary tangle severity (β = -1.16, P = .02). Concentrations of α-tocopherol were not associated with AD neuropathology, except as modified by γ-tocopherol: high α-tocopherol was associated with higher amyloid load when γ-tocopherol levels were low and with lower amyloid levels when γ-tocopherol levels were high (P for interaction = 0.03). Brain concentrations of γ- and α-tocopherols may be associated with AD neuropathology in interrelated, complex ways. Randomized trials should consider the contribution of γ-tocopherol.

Keywords: Alzheimer's disease; Amyloid beta; Cohort studies; Neurofiibrillary tangles; Nutritional; Tocopherols; Vitamin E.

Figure 1

Two cases, one with low (A and C) and the other with high (B and D) Alzheimer’s pathology. A and B: Hippocampal neurofibrillary tangles, Braak score 2 (A) and Braak score 5 (B); Bielschowsky silver stain, at original magnification 10X. D and C: Dorsolateral prefrontal cortex amyloid, low(C) vs. high(D) at magnification 4X.

Figure 2

Statistical interaction effect between α-tocopherol and γ-tocopherol on amyloid load based on an age-adjusted linear regression model with log₁₀ (α-tocopherol) and log₁₀ (γ-tocopherol) modeled as continuous variables in pmol/mg protein and their multiplicative term (p-value for interaction=0.03). The lines reflect the association between amyloid load and alpha tocopherol at three different values of gamma tocopherol: log₁₀ =1.7 at the 33^rd percentile (grey), log₁₀ =1.8 at the 50^th percentile (dotted), and log₁₀ =1.9 at the 67^th percentile (black). Higher levels of α-tocopherol were associated with increased amyloid load except when the levels of γ-tocopherol were also high, at which point higher levels of α-tocopherol were associated with lower amyloid levels.