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Journal of the American College of Nutrition, Vol. 25, No. 6, 502-508 (2006)
Published by the American College of Nutrition

Low Folate and the Risk of Cognitive and Functional Deficits in the Very Old: The Monzino 80-plus Study

Mauro Tettamanti, PhD, Maria Teresa Garrì, PhD, Alessandro Nobili, MD, Emma Riva, MD, PhD and Ugo Lucca, MSc

Laboratory of Geriatric Neuropsychiatry, Department of Neuroscience, Istituto di Ricerche Farmacologiche "Mario Negri", Milano, ITALY

Address reprint requests to: Ugo Lucca, Laboratory of Geriatric Neuropsychiatry, Istituto di Ricerche Farmacologiche "Mario Negri", Via Eritrea 62, 20157 Milano, ITALY. E-mail: lucca{at}marionegri.it


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Objective: To cross sectionally investigate the association of serum vitamin B12 and folate concentrations with cognitive and functional ability in the very old in the general population.

Methods: Serum vitamin B12 and folate concentrations were assessed in 471 consenting subjects participating in the Monzino 80-plus study (mean age: 87.4 years), a door-to-door population-based survey among very old subjects living in Northern Italy. Cognitive and functional evaluations included Mini-Mental State Examination (MMSE), Instrumental Activities of Daily Living (IADL) and Spontaneous Behavior Interview-basic Activities of Daily Living (SBI-bADL).

Results: MMSE, IADL and SBI-bADL scores were all significantly correlated with folate concentrations (respectively: r = 0.36, r = –0.39, r = –0.35; p < 0.0001), while no significant associations were found with vitamin B12 concentrations. When entered into multiple linear regression analyses with several covariates, folate showed a highly significant, curvilinear association with both cognitive and functional scores (p < 0.0001). Subjects in low and middle folate tertiles had significantly higher odds ratios for dementia (p < 0.0001; adjusted ORs = 5.40 and 6.56, lower 95% CIs 2.53 and 3.11, higher 95% CIs 12.73 and 15.29).

Conclusions: Findings of this population-based study suggest that subclinical folate deficiency may represent a risk factor for the cognitive decline associated with aging that could contribute to AD as well as other dementia development.

Key words: folate, vitamin B12, elderly, cognitive deficits, functional disability, dementia


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Cognitive functioning declines and prevalence and incidence of dementia rises with advancing age. Most dementia sufferers (about 65%) are eighty years or older [1,2], the fastest growing segment of elderly populations in western countries [1,3]. "Patients with dementia that are included in clinical research are systematically younger than patients in the general population" and this age gap may represent an important source of bias when generalizing study results [4].

B vitamin status is frequently inadequate in the elderly [5]. Since Strachan and Henderson’s papers in the sixties [6,7] and the more than century long antecedent literature on the cerebral manifestations of pernicious anemia, low vitamin B12 and folate have been persistently though controversially associated with reversible dementias. Most of these studies, however, were based on small selected samples of patients. The associations between nutritional status and cognitive performance were examined in several healthy elderly samples as well [8–10].

In a large ambulatory population of consecutive elderly subjects (60-plus years old, mean age 77.5 years), we have recently found that relative folate deficiency, besides being associated with Alzheimer disease (AD) and vascular dementia, may also precede dementia onset [11,12]. This finding goes along with the association of low serum folate with all types of dementia reported in the Canadian Study of Health and Aging [13], and the strong negative correlation between folate and cortical atrophy on autopsy found in the Nun Study [14], a correlation previously suggested also by a neuropsychological and neuroimaging study in 16 patients with neurological and psychiatric disorders [15]. Moreover, in a case-control study, Clarke et al. found that low folate and vitamin B12 and elevated homocysteine were associated with histologically confirmed AD [16]. These results prompted us to further investigate the association of serum vitamin B12 and folate concentrations with cognitive and functional abilities in a population-based study in the very old.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Study Population
The research was performed within the ongoing Monzino 80-plus Study, a prospective door-to-door population-based survey among all eighty years or older residents in the lower Olona Valley, Northern Italy. At first visit, trained psychologists collected information about participants’ lifestyle, habits, medical history and health status from both the subject and a collateral source (usually a family member) who was also asked to rate subject’s everyday cognitive and functional ability as well as behavior. During the same visit participants were administered a set of neuropsychological tests (including CERAD battery [17] as well as other tests) assessing several aspects of cognition. Cognitive, behavioral, and functional evaluations included, among others, Mini-Mental State Examination (MMSE) [18], Instrumental Activities of Daily Living (IADL) [19], Spontaneous Behavior Interview-basic Activities of Daily Living (SBI-bADL) [20], and Geriatric Depression Scale (GDS, 10-item version) [21]. All participants were asked to have a blood examination including routine investigations as well as laboratory tests targeted at identifying potentially reversible dementias and aggravating factors. During the first visit, subjects who screened positive for possible cognitive impairment (i.e. scoring 23 or below on the MMSE or above 23 but with a neuropsychological profile or a clinical history suggestive of possible cognitive impairment) were then requested to undergo physical and neurological examinations in their place of residence by an experienced neurologist and, when needed, a brain imaging study. The diagnosis of dementia was made according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, fourth edition [22].

Among the present 1302 participants, baseline serum folate and vitamin B12 concentrations were assessed in 471 consenting subjects. To avoid the possible confounding due to present or earlier B vitamin supplementation, participants with serum concentrations of vitamin B12 above 1000 pg/mL or folate above 15 ng/mL were excluded from the analyses (n = 31) together with three subjects for whom these tests were either not available (n = 2) or unreliable (n = 1).

MMSE could not be reliably administered to 87 individuals because of serious sensory deficits, advanced cognitive deterioration, or acute medical condition. Excluding these individuals from the analyses, far from improving the accuracy of the results, would introduce a selection bias instead and truncate the MMSE score variability. Thus, for these subjects a MMSE score was calculated following a methodology previously described [23,24]: the score of 29 subjects on Blessed Information Memory Concentration test (BIMC) [25] and that of 58 subjects on SBI-Social Interaction (SBI-SI) were converted to MMSE scores applying a formula provided by regression analyses. MMSE showed a very high degree of correlation with both SBI-SI (r = 0.85, p < 0.0001) and BIMC (r = 0.90, p < 0.0001). BIMC is a brief mental status test similar to the MMSE but also administrable to the short sighted, manually impaired or illiterate, and with excellent test-retest reliability (r = 0.90, n = 765) as assessed in a previous study. SBI-SI is the section of a structured interview with an informant assessing the subject’s everyday cognitive ability which has shown excellent test-retest and inter-rater reliability (r = 0.92 and 0.94 respectively, n = 305) in a previous study [20].

The study protocol was submitted to and approved by the Local Research Ethics Committee (Azienda Sanitaria Locale of Varese Province). Separate written informed consents for data and blood sample collections were obtained from all participants.

Laboratory Measures
Fasting serum vitamin B12 and folate concentrations were determined by Microparticle Enzyme Immuno-Assay (Abbott IMx system). Within-run coefficients of variation of these assays were between 4.3% and 4.5% for vitamin B12 and between 2.6% and 7.3% for folate. Samples that fell above and below the reference range were reassayed.

Statistical Analysis
Demographic and clinical characteristics of subjects with and without blood tests were compared using t test for numeric variables and chi-square test for categorical variables. Because of the slightly skewed distribution of vitamin B12, folate and creatinine concentrations, these variables were log-transformed before all analyses. Linear correlations were assessed using Pearson r correlation coefficient. Multiple linear regression analyses were used to study the association of serum vitamin B12 and folate concentrations with cognitive and functional scores.

Univariate and multivariate logistic regression analyses were applied to estimate the crude and adjusted odds ratios (ORs) of being in the dementia group in the three tertile concentrations of vitamin B12 and folate: these tertiles were obtained using the distribution of concentrations of these biochemical variables in dementia-free participants with a MMSE score > 23. We also compared the group of subjects in the reference (top) tertile against the group of those with vitamin B12 < 180 pg/mL or folate < 2.5 ng/mL, that is with vitamin concentrations highly specific for vitamin B12 or folate deficiencies. To correct for the slight imbalances found between subjects who agreed and those who did not agree to donate the blood, all analyses were redone weighting the contribution of each subject, utilizing as weights the proportion of subjects of the total population belonging to the same sex and tertiles of age and IADL.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
ACKNOWLEDGMENTS
 REFERENCES
 
Demographic, clinical, cognitive and functional characteristics of the study population are summarized in Table 1. Characteristics of subjects who agreed to donate the blood (n = 471) did not differ substantially from those who did or could not consent (n = 831). Individuals with biochemical data available were in fact only slightly older (+1 year) and, consequently, more often institutionalized (+3%) with a moderately higher proportion of women (+6%) and degree of dependence on IADL measure (+7%) than individuals with missing biochemical data. Prevalence of dementia and functional disabilities (SBI basic ADL) did not differ significantly between groups. Once corrected for age, sex, and education, differences in cognitive and functional characteristics between groups were no longer significant (MMSE: p = 0.62; IADL: p = 0.091; basic ADL: p = 0.58), thus revealing how all the differences (sex, living in institution, and prevalence of dementia as well) were the results of the clinically negligible slight age difference (1 year) between groups.


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  		Table 1. Demographic and Clinical Characteristics of Subjects with and without Blood Tests

 
One hundred and two participants had serum B vitamin concentrations lower than the laboratory reference values: 63 (14%) vitamin B12 (< 180 pg/mL), 35 (8%) folate (< 2.5 ng/mL), and 4 (0.9%) both. On the whole, anemia (i.e. a hemoglobin value < 13 g/dL in men and < 12 g/dL in women) and macrocytosis (i.e. an MCV > 99 fL) were found in 8 subjects, 7 of whom had vitamin B12 concentrations < 246 pg/mL and 5 < 180 pg/mL.

Linear correlations between folate concentrations and scores on MMSE (r = 0.37), IADL (r = –0.39) and SBI-bADL (r = –0.35) were all significant (p < 0.0001), while no significant association was found between vitamin B12 concentrations and the aforementioned measures (respectively: r = –0.03, r = 0.01, r = 0.04; p > 0.35). Vitamin B12 and folate were not significantly correlated (r = –0.002, p = 0.96). Age was significantly and inversely correlated with folate (r = –0.28; p < 0.0001), but not with vitamin B12 concentrations (r = 0.02; p = 0.62).

In a multiple linear regression analysis entering vitamin B12 and folate concentrations together with other known or putative risk factors for cognitive decline (age, sex, education, present or previous smoking habit, history of hypertension or diabetes, history of myocardial infarction or stroke, and creatinine concentration) folate continued to show a highly significant association with MMSE score (p < 0.0001) while no relation between MMSE and vitamin B12 was found (p = 0.77). If folate is removed from the regression, the adjusted R2 drops from 0.29 to 0.23.

Should the analyses be limited only to the subjects living in the community (i.e. not institutionalized, p < 0.0001) or to those who actually did the MMSE (p = 0.0002), the association with folate remains about the same. Results did not change (p < 0.0001) even when including Geriatric Depression Scale score in multiple regression analyses.

To better assess the way in which folate is related to cognitive performance, we added a quadratic term for this vitamin to the model, finding that squared folate concentration was also significantly associated with the MMSE score (p = 0.02) further increasing the adjusted R2 to 0.30. Thus, the total proportion of cognitive performance variability explained by folate concentration was about 7%. Fig. 1 shows the quadratic function that best describes the relation between folate concentration and cognitive performance on the MMSE.


Figure 1
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  		Fig. 1. Relation between Mini-Mental State Examination score and serum folate concentration. Regression line and 95% confidence intervals drawn from estimates taken from univariate fitting of logarithm and squared logarithm of folate.

 
In multiple regression analyses with the above covariates, folate also showed a highly significant association with both instrumental and basic activities of daily living (p < 0.0001), at variance with vitamin B12 (p > 0.65).

In univariate and multivariate logistic regression analyses (see Table 2), a higher prevalence of dementia was significantly (p < 0.0001) associated with both middle (adjusted OR = 5.40, 95% CI 2.53 to 12.73) and bottom (adjusted OR = 6.56, 95% CI 3.11 to 15.29) folate tertiles, while no significant association was found with vitamin B12 concentrations (p = 0.85). When using a cut-off level with a suggested higher specificity for vitamin B12 and folate deficiencies, the adjusted OR for dementia remained almost the same for vitamin B12 concentrations < 180 pg/mL (p = 0.96; adjusted OR = 1.02, 95% CI 0.51 to 1.99), whereas the association with folate concentrations < 2.5 ng/mL was greatly magnified (p < 0.0001; adjusted OR = 20.98, 95% CI 6.72 to 78.79). When the analyses were done utilizing the weights used to even out the differences between the sample and the total population, results were almost alike or identical to those reported above for the non-weighted sample, in particular, levels of significance of the tests remained the same.


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  		Table 2. Unadjusted and Adjusted Odds Ratios (95% Confidence Intervals) for Dementia According to Tertiles of Serum Vitamin B12 and Serum Folate Concentrations1

 

   DISCUSSION
 
The present findings suggest that relatively low serum folate concentration has a sizeable, independent, curvilinear relation with cognitive and functional performance in the very old. This subclinical deficiency very likely contributes to AD as well as other dementia development, as indicated by the approximately 5 times greater risk for dementia in the lowest folate tertiles, a risk steeply increasing to about 20 times in subjects with folate concentrations lower than the reference value. The results are consistent with those of our previous study in younger elderly ambulatory patients (60-plus years old, mean age 77.5 years) [11,12]. To our knowledge, this is the first population-based study on the association of vitamin B12 and folate in the very old, an age group systematically and grossly under-represented in dementia and AD clinical research [4] notwithstanding some 65% of the prevalent cases in the general population belongs to this age segment.

Whether B vitamin deficiencies in the elderly are partially responsible or the consequence of cognitive decline and dementia is still unclear. The findings that in this elderly population folate concentration correlated inversely with age while the association of folate with cognitive and functional performance was not modified when adjusted for age, may suggest that subclinical folate deficiency can arise from age-related changes and that folate inadequacy could contribute to the brain aging process. In this direction, low folate appeared to be a risk factor for cognitive decline in a prospective study of high-functioning adults in their seventies [26]. Following along, a decline of folate in cerebrospinal fluid has been associated both with age (with the greatest drop, 54%, between 80 and 99) and AD [27,28]. However, the cross-sectional nature of our data limited the possibility of ascertaining a causal relation. To further investigate the temporal relationship between relative B vitamins deficiency and cognitive decline, these cross-sectional results will be verified in the follow-up part of the study, though it is important to take into consideration that in advanced ages the effect of attrition, a source of potential selective bias inherent in longitudinal research, tends to be considerably increased.

In line with the Bronx Longitudinal Aging Study and the Kungsholmen population-based Study results in younger subjects [29–31], in the current study low vitamin B12 alone was not significantly associated with dementia. Folate was also shown to be more critical than vitamin B12 to memory and cognitive functioning in old age [26,32,33].

In the current door-to-door survey we could not determine serum methylmalonic acid (MMA) and plasma total homocysteine (tHcy) concentrations. Although some investigators have suggested that the levels of these metabolites are more sensitive indicators of tissue vitamin B12 deficiency than vitamin B12 concentrations [34,35], there is no general agreement [36,37]. Elevated MMA and tHcy levels can often be explained by conditions other than vitamin B12 deficiency (poor specificity) [38]. In ambulatory patients evaluated for possible vitamin B12 deficiency, Solomon found that neither vitamin B12 nor metabolites were reliable assays to detect vitamin B12 deficiency [39]. A low percentage of elderly with vitamin B12 levels > 350 pg/mL (>258 pmol/L) shows signs of metabolic vitamin B12 deficiency (i.e. elevated concentrations of MMA, or tHcy, or both), and, accordingly, most of the metabolic deficient cases have serum vitamin B12 levels < 350 pg/mL, whereas most of the elderly with vitamin B12 concentrations below common laboratory reference values of 190–200 pg/mL (140–148 pmol/L) have metabolic vitamin B12 deficiency [40–44]. In the present study, neither the most sensitive (≤ 350 pg/mL) nor the most specific (< 180 pg/mL) vitamin B12 concentrations for deficiency states were associated with a greater risk for dementia.

The measurement of vitamin B12 bound to transcobalamin (holotranscobalamin), the biologically active fraction of vitamin B12, has been proposed to improve the reliability of the diagnosis of functional vitamin B12 deficiency [45]. In light of the very high correlation between holotranscobalamin and vitamin B12 [46–47], their similar ability to predict subjects likely to have metabolic vitamin B12 deficiency [46,48], as well as the conflicting results about the presence of decreased levels of holotranscobalamin in AD patients vs elderly controls [49–51], "what low holotranscobalamin concentrations really tell us remains elusive" [52].

Folate is an important factor for the normal development and functioning of the central nervous system at all ages [53,54]. Iskandar and colleagues showed that the effect of folic acid supplementation is not restricted to the embryonic period but can also enhance growth, repair and recovery in the injured central nervous system of adult rats [55]. By limiting the synthesis of methionine, folate deficiency can lead to both an accumulation of homocysteine and a decreased production of S-adenosylmethionine (SAM), a major methyl donor in a variety of methylation reactions important to the central nervous system. SAM concentration has been found to be severely decreased in the brain of AD patients [56–58]. Folic acid deficiency and high homocysteine have been reported to promote cortical neurodegeneration [59]. High-dose folic acid has been found to improve endothelial function independent of its homocysteine-lowering effect [60].

In an age when overt malnutrition leading to dramatic and long lasting vitamin deficiencies is of very rare clinical observation in western countries, dementias without other neurologic abnormalities caused simply by B vitamin deficiency is likely a self-perpetuating conception devoid of firm evidence. Considering their low sensitivity and specificity, serum vitamin B12 and folate concentrations can not even be proposed as useful diagnostic markers for dementia. That subclinical folate deficiency in old age can represent a sizeable and modifiable risk factor implicated both in cognitive aging and the multifactorial process leading to AD or other dementias, is a much more realistic possibility deserving further investigation. Current dementia treatments confer modest benefit of controversial clinical relevance. Improving cognitive and functional efficiency in old age and postponing dementia onset call for a multifaceted intervention strategy able to challenge the complex and heterogenous pathophysiological processes underlying ageing-related cognitive decline and dementia. Preventing relative folate deficiency through dietary modification or folic acid supplementation could contribute to the success of this combined therapeutic approach. In this respect, large controlled clinical trials on the effect of folate supplementation on dementia onset and course are needed.


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 ACKNOWLEDGMENTS
REFERENCES
 
This study is being supported by a research grant from the Fondazione Italo Monzino, Milano, Italy.

We are very grateful to all the participants who made this investigation possible. We thank the members of the Monzino Study Group for their help.

Received September 2, 2005. Accepted March 1, 2006.


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