Poor folate status is associated with cognitive decline and dementia in older adults. Although impaired brain methylation activity and homocysteine toxicity are widely thought to account for this association, how folate deficiency impairs cognition is uncertain. To better define the role of folate deficiency in cognitive dysfunction, we fed rats folate-deficient diets (0 mg FA/kg diet) with or without supplemental L-methionine for 10 wk, followed by cognitive testing and tissue collection for hematological and biochemical analysis. Folate deficiency with normal methionine impaired spatial memory and learning; however, this impairment was prevented when the folate-deficient diet was supplemented with methionine. Under conditions of folate deficiency, brain membrane content of the methylated phospholipid phosphatidylcholine was significantly depleted, which was reversed with supplemental methionine. In contrast, neither elevated plasma homocysteine nor brain S-adenosylmethionine and S-adenosylhomocysteine concentrations predicted cognitive impairment and its prevention by methionine. The correspondence of cognitive outcomes to changes in brain membrane phosphatidylcholine content suggests that altered phosphatidylcholine and possibly choline metabolism might contribute to the manifestation of folate deficiency-related cognitive dysfunction.

Depression associated with low plasma Amyloid-β peptide 42 (Aβ42) leading to a high ratio of Aβ40/Aβ42, a biomarker of Alzheimer's disease (AD), may represent a unique depression subtype. The relationship between low plasma Aβ42 in depression and the major risk factor of AD, Apolipoprotein E4 (ApoE4), is unknown. With the goal of clarifying this relationship, we analyzed 1060 homebound elders with ApoE characterization and depression status in a crosssectional study. Plasma Aβ40 and Aβ42 were measured, and cognition were evaluated. In the absence of the ApoE4 allele, depressed subjects had lower plasma Aβ42 [median (Q1, Q3): 17.1 (11.6, 27.8) vs. 20.2 (12.9, 32.9) pg/ml, P = 0.006], a higher Aβ40/Aβ42 ratio [median (Q1, Q3): 7.1 (4.6, 11.3) vs. 6.9 (3.4, 9.7), P = 0.03], and lower cognitive function (mean ± SD of MiniMental State Examination: 24.5 ± 3.1 vs. 25.5 ± 3.3, P < 0.0001) than those without depression. In contrast, these relationships were not observed in the presence of ApoE4. Instead, regardless the depression status ApoE4 carriers had lower plasma Aβ42 and a higher Aβ40/Aβ42 ratio than nonApoE4 carriers. Using multivariate logistic regression, it was found that depression was not associated with ApoE4 allele, but with the interaction between plasma Aβ42 and ApoE4 (OR = 3.94, 95% CI = 1.50, 10.33, P = 0.005), denoting low plasma Aβ42 in the absence of ApoE4. Both ApoE4 carriers and non-ApoE4 carriers with depression had lower Aβ42 and a higher Aβ40/Aβ42 ratio in plasma compared to non-ApoE4 carriers without depression in the homebound elderly. Since a combination of low plasma Aβ42 and high plasma Aβ40 has been shown to increase the risk of AD in two large cohort studies, amyloid-associated depression shown in this study may suggest a risk factor of AD in the absence of ApoE4.

Phylloquinone, the primary dietary form of vitamin K, is converted to menaquinone-4 (MK-4) in certain tissues. MK-4 may have tissue-specific roles independent of those traditionally identified with vitamin K. Fischer 344 male rats of different ages (2, 12, and 24 mo, n = 20 per age group) were used to compare the conversion of phylloquinone to MK-4 with an equivalent dose of another dietary form of vitamin K, 2',3'-dihydrophylloquinone. Rats were age- and diet-group pair-fed phylloquinone (198 +/- 9.0 microg/kg diet) or dihydrophylloquinone (172 +/- 13.0 microg/kg diet) for 28 d. MK-4 was the primary form of vitamin K in serum, spleen, kidney, testes, bone marrow, and brain myelin fractions, regardless of age group. MK-4 concentrations were significantly lower in kidney, heart, testes, cortex (myelin), and striatum (myelin) in the dihydrophylloquinone diet group compared with the phylloquinone diet group (P < 0.05). The MK-4 concentrations in 2-mo-old rats were lower in liver, spleen, kidney, heart, and cortex (myelin) but higher in testes compared with 24-mo-old rats (P < 0.05). However, there were no age-specific differences in MK-4 concentrations among the rats fed the 2 diets. These data suggest that dihydrophylloquinone, which differs from phylloquinone in its side phytyl chain, is absorbed but its intake results in less MK-4 in certain tissues. Dihydrophylloquinone may be used in models for the study of tissue-specific vitamin K deficiency.