Vitamin B12 and folate in relation to the development of Alzheimer’s disease
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Abstract
Objective: To explore the associations of low serum levels of vitamin B12 and folate with AD occurrence.
Methods: A population-based longitudinal study in Sweden, the Kungsholmen Project. A random sample of 370 nondemented persons, aged 75 years and older and not treated with B12 and folate, was followed for 3 years to detect incident AD cases. Two cut-off points were used to define low levels of vitamin B12 (≤150 and ≤250 pmol/L) and folate (≤10 and ≤12 nmol/L), and all analyses were performed using both definitions. AD and other types of dementia were diagnosed by specialists according to DSM-III-R criteria.
Results: When using B12 ≤150pmol/L and folate ≤10 nmol/L to define low levels, compared with people with normal levels of both vitamins, subjects with low levels of B12 or folate had twice higher risks of developing AD (relative risk [RR] = 2.1, 95% CI = 1.2 to 3.5). These associations were even stronger in subjects with good baseline cognition (RR = 3.1, 95% CI = 1.1 to 8.4). Similar relative risks of AD were found in subjects with low levels of B12 or folate and among those with both vitamins at low levels. A comparable pattern was detected when low vitamin levels were defined as B12 ≤250 pmol/L and folate ≤12 nmol/L.
Conclusions: This study suggests that vitamin B12 and folate may be involved in the development of AD. A clear association was detected only when both vitamins were taken into account, especially among the cognitively intact subjects. No interaction was found between the two vitamins. Monitoring serum B12 and folate concentration in the elderly may be relevant for prevention of AD.
Higher prevalences of both vitamin B12 deficiency1 and lower serum vitamin B12 levels2-4⇓⇓ have been found in subjects with AD, other dementias, and in people with cognitive deficits, as compared with controls. In contrast, other cross-sectional studies5,6⇓ and a prospective study using a volunteer cohort7 have failed to find an association. Furthermore, some intervention studies have shown the effectiveness of vitamin B12 supplementation in improving cognition in demented or cognitively impaired subjects,8,9⇓ but others have failed to confirm the beneficial effects.10 Most of the clinical trials were not random control studies. An intervention study found that supplementation treatment was more effective in subjects with a short history of cognitive dysfunction.8
Regarding folate levels, few studies have explored the relationship between this vitamin and AD or dementia, and most of them were cross-sectional studies. Low serum folate levels have been related not only to AD3,11⇓ and all types of dementia12 but also to vascular diseases.12 In addition, low folate levels have been found to be associated with specific domains of cognitive functioning, such as episodic recall and recognition.13,14⇓ There are also intervention studies showing a positive effect of folate treatment for memory deficits.15,16⇓
The aim of this study was to explore whether low serum levels of vitamin B12 and folate constitute risk factors for dementia, in particular for AD. As vitamin B12 and folate levels are highly interdependent,17,18⇓ the combined effects of the two vitamins were also studied. Some studies have examined concomitant effects of deficiency in both vitamins on cognitive function,13,14⇓ but to our knowledge no study has examined the combined effects on the occurrence of AD. Data for the study were gathered from the Kungsholmen Project, a community-based cohort of people aged 75 and older.
Methods.
Study population.
The Kungsholmen Project19 is a large, longitudinal population-based study on aging and dementia that included all inhabitants born in 1912 or earlier, who lived in one area of Stockholm (Kungsholmen) on October 1987. From the original population, all subjects with a Mini-Mental State Examination (MMSE) score of less than 24 (n = 314) and a random sample of subjects with an MMSE score >23 (n = 354) underwent an extensive medical and psychological examination.20 Of those 668 subjects, 443 were diagnosed as nondemented. Among the nondemented, 51 individuals who refused blood tests and 22 subjects who were taking B12 or folate replacement therapy were excluded from the study. Therefore, 370 subjects who were nondemented and without vitamin treatment were included in this study and followed, on average, for 3 years to detect incident dementia cases.
Dementia and AD.
The same clinical assessment, diagnostic procedure, and criteria were used both at cohort inception (baseline examination) and at detection of incident cases (follow-up examination). At both times, all subjects were clinically examined following a standardized protocol, including collection of family and personal history by nurses, clinical examination by physicians, and administration of psychological tests by trained personnel.20,21⇓ When the subject was not able to answer the anamnestic questions, an informant, usually the next of kin, was interviewed.
Dementia and type of dementia were diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, third edition, revised.22 More specifically, for an AD diagnosis gradual onset and progressive deterioration of dementia were required and all other specific causes of dementia had to be excluded. The diagnosis of vascular dementia (VaD) was based on clinical feature of dementia with abrupt onset, stepwise deterioration, history of stoke, and/or focal deficits. Hachinski’s scale23 was also used as support for the differential diagnosis between AD and VaD. The clinical diagnosis was based on a double diagnostic procedure. Two preliminary diagnoses were made by physicians working independently. Concordant diagnoses were accepted as final diagnosis, whereas a third opinion was obtained in case of disagreement.24
The follow-up examination was conducted after an average of 3 years from baseline. The incident cases of AD and other dementias were all subjects who had developed the disease during this period. If the subject had moved, she or he was traced and asked to participate in the follow-up examination. For those subjects who had died after the first examination (n = 86), information regarding their health status was obtained from the Computerised Inpatient Register System, which is a registry of admission and discharge diagnoses from all hospitals in Stockholm since 1969. The individual hospital records, discharge diagnoses, and death certificates were examined. Among the 86 dead subjects, 8 dementia cases were detected. The dead subjects had lower mean MMSE scores and folate levels than those alive (mean MMSE score: 23 versus 26.3; serum folate: 18.2 versus 21.4 nmol/L) and more frequently lived in an institution (7.4% dead versus 6.3% alive). A higher proportion of women died than men. The distributions were similar in dead and alive subjects with regard to education and serum B12 levels.
Baseline data collection.
Baseline serum vitamin B12 and folate levels were assessed according to the recommended procedure for a commercial radioligand kit (Dual Count Solid Phase No Boil, Diagnostic Products Corporation, Los Angeles, CA). For both vitamin B12 and folate two cut-off points were used to define low levels in serum. For vitamin B12, cut-off points of 151 and 251 pmol/L were used. The lower cut-off point was chosen because approximately 90% of older patients with serum B12 ≤150 pmol/L show tissue deficiency.25,26⇓ The higher cut-off point was chosen following the indications of other authors who suggest a lower limit of serum B12 value of 220 pmol/L or 258 pmol/L to define B12 deficiency in the elderly.27-29⇓⇓ Similarly, two cut-off points were used to define low serum folate levels. A lower and a higher (folate ≤10 and ≤12 nmol/L) cut-off point was chosen according to the suggestion of previous studies.13,29⇓ All the analyses were done using the two cut-off points for each of the vitamins.
As some medication may interact with folate metabolism, we examined the most commonly used drugs, trimethoprim and phenytoin. In our sample, only one person was using trimethoprim and another was using phenytoin.
Information on age and sex was obtained from the municipality. The following information was obtained in interviews of subjects or informants (in the case of demented persons) conducted by trained nurses. Education was assessed as the highest degree achieved at school. Smoking history was assessed as whether the subjects had ever smoked or not (current and former smokers versus nonsmokers). Alcohol consumption was categorized as whether the subjects were drinking alcohol or not (drinking alcohol versus nondrinking at all). No heavy drinkers were found in the sample. Living place was categorized as living at home or in an institution. Dietary habits were assessed as number of meals per day and number of hot meals per day. Baseline cognitive functioning was assessed by the MMSE.30 Hemoglobin and albumin levels were obtained through laboratory tests.
Information on subjects’ medical history was obtained from the Computerized Inpatient Register System. From these data, a new variable was created and labeled “cardiovascular disease.” This was defined as the presence of any of the following diseases:31 coronary heart disease (ICD-8 codes 410 to 414), cardiac dysrhythmia (ICD-8 code 427), heart failure (code 428), or stroke (ICD-8 codes 430 to 438).
Data analysis.
The Cox proportional hazard model was used to estimate the relative risk (RR) and corresponding 95% CI for developing AD or all types of dementia in relation to baseline low serum vitamin B12 and folate levels. Age, sex, and educational attainment were entered in all the models. To identify other potential confounders, correlation analyses were performed. From a set of relevant factors, such as baseline MMSE score, hemoglobin levels, albumin levels, drug use, alcohol consumption, smoking, cardiovascular disease, and depression symptoms, only baseline cognitive functioning (MMSE) and hemoglobin levels were related to both vitamins. Alcohol consumption was related to vitamin B12 levels only, and cardiovascular diseases were related to folate levels. As these variables were also related to the occurrence of AD or dementia, they were considered as potential confounders and included in the multiple regression models. Age, baseline MMSE scores, and hemoglobin levels were entered as continuous variables (one year/point increment, separately); sex, education, alcohol consumption, and cardiovascular disease were entered as dichotomous variables (women versus men; ≤7 years education versus >7 years; alcohol drinking versus no drinking; and presence of cardiovascular disease versus absence).
To evaluate the combined effect of the two vitamins, we first studied the relation of incident AD to a variable consisting of the following four categories: 1) both vitamin B12 and folate in normal levels; 2) low vitamin B12 and normal folate levels; 3) normal vitamin B12 and low folate levels; and 4) both vitamins in low levels. Second, a dichotomized variable, at least one of the vitamins at low levels versus both vitamins at normal levels, was examined.
Results.
Table 1 reports the number of subjects examined at baseline and prevalence (%) of low levels (defined with two cut-offs) of serum vitamin B12 (≤150 and ≤250 pmol/L) and folate (≤10 and ≤12 nmol/L) by demographic characteristics and other relevant variables. After a 3-year follow-up, 78 (21.1%) subjects were diagnosed as dementia cases and 60 (16.2%) as dementia of Alzheimer’s type.
Study population and prevalence of low levels of vitamin B12 and folate at baseline
Table 2 shows the number of incident cases and relative risks of AD and dementia in relation to baseline vitamin levels. When the low levels were defined as vitamin B12 ≤150 pmol/L, high crude and age-, sex-, and education-adjusted RR of AD were observed in relation to low levels of vitamin B12. As adjustment of hemoglobin levels and alcohol consumption did not alter the above results, only age, sex, and educational attainment were included as covariates in the multiple Cox regression model. In contrast to AD, no relation was observed between dementia and low levels of vitamin B12. When using vitamin B12 ≤250 pmol/L to define low levels, 42 dementia and 37 AD cases had low B12 levels, and 36 dementia and 23 AD cases had normal B12 levels. The crude RR for AD in relation to low B12 levels was 2.0 (95% CI = 1.2 to 3.3), and the adjusted RR was 1.8 (95% CI = 1.0 to 3.0). The crude RR for dementia was 1.5 (95% CI = 0.9 to 2.3), and the adjusted RR was 1.3 (95% CI = 0.8 to 2.1).
Number of incident cases (n) and relative risks (RR) of Alzheimer’s disease and dementia in relation to baseline vitamin levels
When the low levels were defined as folate ≤10 nmol/L, high crude and age-, sex-, and education-adjusted RR of both AD and dementia were detected in subjects with low serum folate levels (table 2). No significant changes in the results were found when hemoglobin levels and cardiovascular diseases were entered as covariates into the multiple Cox regression models, whether separate or together. Therefore, in the final model, only age, sex, and educational attainment were kept as covariates. When using folate ≤12 nmol/L to define low levels, 28 dementia and 22 AD cases had low folate levels, and 49 dementia and 37 AD cases had normal folate levels. Similar relative risks were found using the two definitions for the low levels. The crude RR for AD in relation to low folate levels was 1.7 (95% CI = 1.0 to 2.8), and the adjusted RR was 1.6 (95% CI = 0.9 to 2.7). The crude RR for dementia was 1.6 (95% CI = 1.0 to 2.5), and the adjusted RR was 1.5 (95% CI = 0.9 to 2.4).
Eleven subjects had low levels of both vitamins, and only one of them developed AD during the 3-year follow-up. Due to the small numbers, we grouped the subjects with low levels of either vitamin B12 or folate together. High crude and adjusted RR for both AD and dementia were found in subjects with low levels of at least one of the vitamins (table 2). When low levels were defined as B12 ≤250 pmol/L and folate ≤12 nmol/L, 15 dementia and 13 AD cases had low levels of both vitamins; 55 dementia and 46 AD cases had low levels of vitamin B12 or folate; and 23 dementia and 14 AD cases had normal levels of both vitamins. Compared with subjects with normal levels of both vitamins, adjusted RR for AD in relation to low levels of at least one of the vitamins was 2.3, 95% CI = 1.2 to 4.2; adjusted RR for dementia was 1.7, 95% CI = 1.0 to 2.8.
The combined effects of the two vitamins on incidence of AD are reported in table 3. Using vitamin B12 ≤150 pmol/L and folate ≤10 nmol/L to define low levels after adjusting for age, sex, and education, a clear increased risk of AD was found in subjects with low levels of both vitamins (model 1, third column). Compared with subjects who had normal levels of both vitamins, significantly high RR for AD were found for subjects who had low levels of at least one of the vitamins (model 2, third column). However, all the associations were no longer significant when cognitive functioning was taken into account (models 1 and 2, fourth column). A similar pattern was found when low levels were defined as B12 ≤250 pmol/L and folate ≤12 nmol/L. The increased risk, associated with low levels of at least one of the vitamins, was modified by the MMSE (adjusted RR = 1.8, 95% CI = 1.0 to 3.4).
Number of subjects and incident cases (n), relative risks (RR), and corresponding 95% confidence intervals of Alzheimer’s disease associated with low levels of vitamin B12 (≤150 pmol/L) or folate (≤10 nmol/L)
Due to the modifying effects of baseline cognitive functioning on the associations between low levels of the vitamins and development of AD, stratified analyses were performed by grouping subjects according to MMSE score. An MMSE score >26 was chosen to define individuals with good cognition. In comparison with subjects with normal levels of both vitamins, a clearly increased AD risk, associated with the presence of low levels in at least one of the vitamins, was found in individuals with good baseline cognitive functioning, independent of age, sex, and educational attainment. No such effect was found in subjects with weaker cognitive performance (MMSE score ≤26) ( table 4). When low levels were defined as B12 ≤250 pmol/L and folate ≤12 nmol/L, the adjusted RR for AD was 7.0 (95% CI = 1.6 to 31.6) in subjects with MMSE score >26 and was 1.4 (95% CI = 0.7 to 2.7) in subjects with MMSE score ≤26. Comparable mean and median values were found across all groups in tables 3 and 4⇓.
Number of subjects and incident cases (n), relative risks (RR), and corresponding 95% confidence intervals of Alzheimer’s disease associated with the presence of low levels in at least B12 (≤150 pmol/L) or folate (≤10 nmol/L) versus normal levels of both vitamins stratified by cognitive functioning
To understand why the risk effect of low levels of vitamin B12 or folate was present only in subjects with good cognition, we compared the living arrangements of subjects with good cognition and those with lower cognitive performance. Subjects with good cognition were more likely to live at home rather than in an institution (97% vs 3%), and subjects living at home, especially when living alone, may have a decreased intake of vitamins because of improper eating habits. Therefore, it was thought that living place might correlate with vitamin levels. We repeated the analysis by excluding those subjects who were living in an institution and found a similar risk effect of low levels of vitamin B12 or folate in individuals with MMSE score >26 (RR = 2.7 [1.0 to 7.7] and 6.5 [1.4 to 29.5] for the lower and higher cut-off levels). In addition, subjects living at home had similar living arrangements (living alone or not) independent of their cognitive status. Finally, we compared individuals with MMSE scores ≤26 and >26 with respect to number of meals per day and number of cooked meals per day that they consumed. The results did not reveal any significant difference between the two groups (p > 0.85).
Discussion.
We examined low serum levels of vitamin B12 and folate in relation to the incidence of AD and dementia in a community-based population of people aged 75 years and older who were nondemented and not treated with vitamin B12 and folate. In both analyses where two different cut-off points for vitamin B12 and folate were used to define low vitamin levels, neither low levels of vitamin B12 nor folate alone significantly affected the risk of AD. However, as compared with subjects with normal levels of both vitamins, subjects with low levels of vitamin B12 or folate had double the risk of developing AD, whichever cut-off level was chosen. This risk was even stronger in subjects with good cognition at baseline (MMSE score >26).
In the current study, we prospectively examined both vitamin B12 and folate levels in relation to the incidence of AD in a community. The relationship between B12 deficiency and dementia in elderly people aged 75 and older has been investigated previously in a longitudinal study.7 A cohort of 410 nondemented volunteers were followed for 5 years, and similar dementia incidences in subjects with low serum vitamin B12 levels <150 pg/mL (corresponding to 110 pmol/L) (13.6%) and subjects with normal B12 levels (14.7%) were reported. However, because of the small number of AD cases, this study could only examine dementia cases in general and not specifically AD.7
Formerly, low levels of serum folate were reported in subjects with AD,3 dementia,3 impaired cognition,13,14,32⇓⇓ and vascular diseases.12 We could not study the effects of low folate levels on vascular dementia because of the few cases of this dementia type. A risk effect of low folate levels on AD and dementia was detected as compared with normal levels. This finding is in line with Snowdon et al.’s finding that low serum folate was strongly associated with atrophy of the cerebral cortex.33
Two previous studies from the Kungsholmen Project found that people who had low levels of both vitamin B12 and folate showed memory deficits,14 and no joint effect of vitamin B12 and folate was found in any of the memory tasks.13 These results are in line with the findings from the current study.
Three main limitations of our study must be addressed. First, serum B12 level is generally not regarded as a sensitive indicator of metabolic B12 deficiency in the elderly.27,34⇓ When using vitamin B12 radioimmunoassays, falsely high serum vitamin B12 values may occur and mask a true deficiency,35,36⇓ and low levels may not correspond to B12 deficiency at tissue level. Serum methylmalonic acid (MMA) and homocysteine levels have been suggested as more specific markers for vitamin B12 and folate deficiencies.37-39⇓⇓ It has been reported that 76 or 80% of elderly individuals with elevated MMA and/or homocysteine levels indicating metabolic B12 deficiency have serum B12 level ≤258 pmol/L.29 The degree of elevation of metabolite concentrations was similar in subjects with serum B12 ≤147 and 148 to 258 pmol/L. A more recent article suggested that 78% of subjects with serum cobalamin concentrations <140 pmol/L had deficiency at tissue level, whereas the majority of subjects with B12 level equal to 140 to 258 pmol/L had no deficiency.40 Because of the disconcordant reports concerning the most appropriate cut-off for serum B12 and folate deficiencies, we used two different cut-off levels. The lower cut-off level of 151 pmol/L is likely to include only true deficiency cases, and the higher cut-off level of 251 pmol/L might include all subjects with probable deficiencies. The associations were similar across the different cut-off points chosen. Similarly, low serum levels of folate are not considered to be perfect indicators of folate deficiency, and no specific limit for low serum folate levels in old age has been proposed so far. Therefore, we chose two cut-off points to define low levels of folate.13,29⇓ Because the imprecision in measuring vitamin deficiencies is likely to dilute the strength of the association, we do not regard this limitation as a major threat to our results.
Second, only one measurement of vitamin B12 and folate levels was available. Therefore it was impossible to estimate the duration of vitamin deficiency, which may be related to development of dementia. Third, the detection of dementia among those subjects who died during the follow-up period was based on the examination of death certificates and hospital clinical records. This can lead to an underestimation of cases. It is likely that these limitations decrease the power of our study rather than bias the results. Despite this, we have found a clear association between low levels of at least one of the vitamins and AD incidence.
Biologic mechanisms related to our findings have already been proposed.17,34,41,42⇓⇓⇓ Vitamin B12 or folate deficiency may increase the risk of AD because vitamin B12 is necessary for the conversion of homocysteine to methionine, and vitamin B12 or folate deficiency can increase homocysteine level due to slowed methylation reaction.17,42⇓ Homocysteine has a neurotoxic effect that could lead to cell death or neurologic and psychiatric disturbances such as AD.1,17,34⇓⇓ However, there is no evidence currently that vitamin B12 or folate deficiency is associated with the neuropathologic hallmarks of AD. The lack of interaction between the two vitamins in relation to dementia occurrence may be explained by the common metabolic mechanisms of these two vitamins.42 The fact that we could detect a positive association only when the combined effect of the two vitamins were examined may be due to the power of the current study not being sufficient to detect a small effect. The multiple regression analyses further reduced the power of our study. For example, using normal levels of both vitamins as the unexposed group, to detect a relative risk of 2.1 for the effect of low levels of B12, with α = 0.05 and 80% power, 525 subjects are required.
The fact that low levels of vitamin B12 or folate increase the risk of AD, especially in subjects with good cognition, was an unexpected result. Why would subjects with high MMSE score be more prone to developing dementia if they have vitamin B12 or folate deficiency? Eating habits such as number of meals per day and number of hot meals per day could not explain the observed associations. We can speculate that the effect of vitamin deficiency may be present only in the earliest prodromal phase of AD. This hypothesis could explain the inconsistent results from intervention studies in which these vitamins were supplemented.8-11,15⇓⇓⇓⇓ These studies involved a mixture of subjects with different levels of cognitive functioning. Further research concerning mechanisms underlying the observed relations are needed.
Acknowledgments
Supported by the Karolinska Institutet, the Alzheimerfonden, the Swedish Council for Social Research, the Swedish Council for Research in the Humanities and Social Sciences, the Swedish Municipal Pension Institute, the Torsten and Ragnar Söderbergs Foundation, the Gamla Tjänarinnor Foundation, the Groschinsky Foundation, the Gun and Bertil Stohne Foundation, and The Stiftelsen Hjälp till Medicinsk Forskning.
Acknowledgment
The authors thank all the members of the Kungsholmen Project Study Group for data collection and management.
- Received September 25, 2000.
- Accepted in final form January 26, 2001.
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Disputes & Debates: Rapid online correspondence
- Reply to Wang and Rieder
- Sander Fridman, psychiatry, Forensic Psychiatric Program of the Federal University of Rio de Janeiro - Rio de Janeiro - Brazilsander_fridman@hotmail.com
Submitted July 08, 2001 - Vitamin B12 and folate in relation to the development of Alzheimer’s disease
- Carlos R M Rieder, Neurology Service Hospital de Cliniicas de Porto Alegre Porto Alegre, Brazilsandi_moriarity@urmc.rochester.edu
- Daniele Fricke
Submitted June 26, 2001 - Reply to Carlos R M Rieder
- Hui-Xin Wang, Stockholm Gerontology Research Center Stockholm, SwedenHuixin.wang@phs.ki.se
Submitted June 26, 2001
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