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A recent Cochrane review reported that although vitamin B-12 deficiency is known to be associated with cognitive impairment in old age, benefits of supplementation on mental ability are unclear.1 The situation is similar to that for blood pressure, in which hypertension is associated with neuropsychological deficits in adulthood but cognitive outcomes of lowering blood pressure in randomised controlled trials are equivocal. We found that for blood pressure, the limited effect of intervention is partly explained by the relation between childhood IQ and adult blood pressure—children with higher IQs had lower mid-life blood pressures.2 As approximately 50% of the variance in adult IQ is explained by childhood IQ, studies failing to account for “pre-morbid” mental ability are likely to overestimate the association between adult IQ and blood pressure. Previously we reported significant relations between various tests of mental ability in old age and vitamin B-12 and folic acid concentrations in the blood.3 We now describe the association between vitamin B-12 and serum folate and lifetime change in mental ability using the same cognitive test at age 11 and age 79.
As reported more fully elsewhere,4 the 1932 Scottish Mental Survey (SMS1932) measured the mental ability of almost all (n = 87 498) children born in 1921 and attending Scottish schools on 1 June 1932 with a validated test of IQ, the Moray House test (MHT). With local ethics approval, 550 survivors of the SMS1932 were recruited in Lothian, Scotland by a variety of means. They underwent a health assessment, including blood sampling for vitamin B-12 and folate, and the MHT was re-administered.4 In all, 483 participants were matched to age 11 MHT scores from the SMS1932, and an age-in-days-adjusted IQ score was calculated. As previously, we included only participants with mini-mental state examination scores greater than 23 and no history of dementia, to exclude pathological cognitive decline as far as possible.4 None of the participants had a history of head trauma or ongoing CNS affecting disease. The resultant sample comprised 470 participants (194 men, 276 women).
Mean (SD) serum vitamin B-12 was 390 (161) ng/l (n = 422) and mean serum folate was 337 (155) μg/l (n = 391). Pearson correlation coefficients with age 11 IQ were: r = 0.04 (p = 0.42) for B-12 and r = 0.13 (p = 0.010) for folate; and with age 79 IQ, r = 0.12 (p = 0.018) for B-12 and r = 0.12 (p = 0.016) for folate. Linear regression of age 79 IQ controlling for age 11 IQ confirmed a significant effect on age 79 IQ for B-12 (β = 0.092, p = 0.016, R2 improvement = 0.008) but not for folate (β = 0.038, p = 0.33). Only two participants had folate levels below the normal range (<5 μg/l) and omitting these did not affect correlation coefficients with age 11 and age 79 IQ scores. Twenty five participants had vitamin B-12 levels below the normal range (<200 ng/l) and there was a stronger correlation with age 79 IQ in this group (r = 0.57, p<0.001) than in those well within the normal range ⩾250 ng/l (r = 0.10, p = 0.031). The difference between these two correlation coefficients was significant (p = 0.016). After adjusting for all variables known to be associated with lifetime change in IQ (sex, APOE ε4 status, cigarette smoking, statin use, and number of drugs prescribed),4 vitamin B-12 remained a significant contributor (β = 0.095, p = 0.011). Together, these variables explained 4.5% of total variance in age 79 IQ scores after adjusting for IQ at age 11. The number of units of alcohol consumed per week was also positively correlated with age 79 IQ score (Spearman ρ = 0.10, p = 0.026), but was no longer significantly associated (β = −0.01, p = 0.73) once age 11 IQ and vitamin B-12 were adjusted for.
Both vitamin B-12 and folate correlate with IQ in old age in a non-demented population. Lower serum B-12 at age 79 is associated with cognitive decline between age 11 and age 79. By contrast, serum folate at age 79 correlates with age 11 IQ, and controlling for this reduces the correlation with IQ in old age to almost zero. Hence, in this sample the relation between serum folate and old age mental ability can be fully explained by its correlation with IQ scores on the same test given 68 years previously. This is a similar situation to that with blood pressure.2 This further emphasises the importance of interpreting associations between cognition and other variables in older people in the context of “pre-morbid” mental ability. The effect size of vitamin B-12 is smaller than those found with more domain specific cognitive tests,3 contributing less than 1% of total variance in age 79 IQ. It is unlikely to be clinically apparent. However, the effect was more significant in the small subsample with laboratory defined deficiency.
Inspection of the relation between vitamin B-12 and the standardised residual score of age 79 IQ regressed on age 11 IQ (fig 1) suggests that the overall correlation is accounted for by a subgroup that is cognitively vulnerable to vitamin B-12 deficiency. Moreover, this vulnerability occurs at levels within the normal laboratory range. An IQ decline of >1 SD occurred in seven of 18 participants (39%) with a serum vitamin B-12 of <200 ng/l, 19 of 84 (23%) with levels of 200–299 ng/l, 21 of 103 (20%) with levels of 300–399 ng/l, and 21 of 149 (14%) with levels of >399 ng/l. Further work is required to confirm this and ascertain what makes these individuals vulnerable. One explanation is that this is a group having “metabolically significant” vitamin B-12 deficiency within the normal range with raised homocysteine or methylmalonic acid levels.5 This may help target B-12 therapy, but at present identifying this group remains challenging. Our data suggest that in a non-demented, relatively healthy population, serum folate concentrations were not related to IQ in old age after controlling for childhood mental ability. However, only two participants in our sample had folate values below the normal range, so other studies are needed to assess the cognitive effects of folate deficiency and treatment with folic acid.
The research was supported by the UK Biotechnology and Biological Sciences Research Council. JMS is the recipient of a “Leading Practice Through Research” award from the Health Foundation. IJD is the recipient of a Royal Society–Wolfson Research Merit Award. LJW holds a Wellcome Trust Career Development Award.
Competing interests: none declared
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