Higher vitamin B12 from mid‐ to late life is related to slower rates of cognitive decline

Francesca R Marino; Gail Rogers; Joshua W Miller; Jacob Selhub; Jesse Mez; Paul K Crane; Shubhabrata Mukherjee; Andrew J Saykin; Timothy J Hohman; Emily H Trittschuh; Rhoda Au; Paul F Jacques; Phillip H Hwang

doi:10.1002/alz.70864

. 2025 Oct 28;21(10):e70864. doi: 10.1002/alz.70864

Higher vitamin B₁₂ from mid‐ to late life is related to slower rates of cognitive decline

Francesca R Marino ^1,^✉, Gail Rogers ², Joshua W Miller ³, Jacob Selhub ⁴, Jesse Mez ^2,^5,^6,⁷, Paul K Crane ⁸, Shubhabrata Mukherjee ⁸, Andrew J Saykin ^9,^10,¹¹, Timothy J Hohman ^12,¹³, Emily H Trittschuh ^14,¹⁵, Rhoda Au ^1,^2,^5,^16,^17,¹⁸, Paul F Jacques ⁴, Phillip H Hwang ^1,^2,¹⁶

^¹Department of Anatomy and Neurobiology, Boston University Chobanian and Avedisian School of Medicine, Boston, Massachusetts, USA

^²The Framingham Heart Study, Boston University Chobanian and Avedisian School of Medicine, Boston, Massachusetts, USA

^³Department of Nutritional Sciences, Rutgers University, New Brunswick, New Jersey, USA

^⁴USDA Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts, USA

^⁵Department of Neurology, Boston University Chobanian and Avedisian School of Medicine, Boston, Massachusetts, USA

^⁶Alzheimer's Disease Research Center, Boston University Chobanian and Avedisian School of Medicine, Boston, Massachusetts, USA

^⁷CTE Center, Boston University Chobanian and Avedisian School of Medicine, Boston, Massachusetts, USA

^⁸Division of General Internal Medicine, University of Washington School of Medicine, Seattle, Washington, USA

^⁹Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, Indiana, USA

^¹⁰Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA

^¹¹Indiana Alzheimer's Disease Research Center, Indiana University School of Medicine, Indianapolis, Indiana, USA

^¹²Vanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA

^¹³Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, Tennessee, USA

^¹⁴Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, Washington, USA

^¹⁵Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA

^¹⁶Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts, USA

^¹⁷Department of Medicine, Boston University Chobanian and Avedisian School of Medicine, Boston, Massachusetts, USA

^¹⁸Slone Epidemiology Center, Boston University Chobanian and Avedisian School of Medicine, Boston, Massachusetts, USA

Correspondence: Francesca R. Marino, Department of Anatomy and Neurobiology, Boston University Chobanian and Avedisian School of Medicine, 72 East Concord Street, Boston, MA 02118, USA. Email: fmarino1@bu.edu

^✉

Corresponding author.

PMCID: PMC12568389 PMID: 41152187

Abstract

INTRODUCTION

Evidence is needed to evaluate whether low vitamin B₁₂ from mid‐ to late life, either alone or in the presence of elevated folate, is associated with cognitive decline.

METHODS

Participants from the Framingham Heart Study without baseline dementia who had ≥ 2 measures of a three‐component vitamin B₁₂ indicator (3cB₁₂) and neuropsychological factor scores were included (n = 1994; mean age: 60 years). Adjusted linear mixed effects models estimated annual changes in each factor score between 3cB₁₂ quartiles. Interaction by folate status was also evaluated.

RESULTS

Participants in the highest 3cB₁₂ quartile had slower declines in memory, executive function, and language compared to the lowest quartile (memory: β = 0.0071, 95% confidence interval [CI] = 0.003–0.01; executive function: β = 0.0056, 95% CI = 0.0009–0.01; and language: β = 0.0090, 95% CI = 0.004–0.01). Findings were largely robust by folate status (elevated: ≥ 20 ng/mL; non‐elevated: 6–19 ng/mL).

DISCUSSION

Improving B₁₂ status in dementia‐free older adults may help mitigate cognitive decline into later life.

Highlights

Higher vitamin B₁₂ status is associated with slower annual cognitive decline.
Higher B₁₂ was linked with 0.05 to 0.09 standard deviation less cognitive decline over 10 years.
B₁₂ and memory findings are robust for elevated, not non‐elevated, folate status.

Keywords: cognitive decline, dementia, lifestyle, nutrition, prevention

1. BACKGROUND

As the population of older adults continues to grow, it is important to identify modifiable risk factors to delay or prevent cognitive decline and dementia. The 2024 Lancet Commission attributes up to 45% of dementia cases to 14 modifiable risk factors across the life course. This report also includes several risk factors, including diet, that may be important for dementia prevention but currently have insufficient evidence. ¹ Although not included in The Lancet Commission report, specific dietary components, such as vitamins, may also affect cognitive decline or dementia risk.

Vitamin B₁₂ is an important dietary factor that has been linked with cognitive function. As is the case for diet, there is mixed epidemiologic evidence regarding relationships between vitamin B₁₂ and cognition. In observational studies, higher vitamin B₁₂ status is cross‐sectionally associated with lower odds of dementia ² and better performance on memory ³ or processing speed tests, ⁴ but evidence is mixed. ⁵ , ⁶ Observational studies often assess B₁₂ intake using self‐reported food frequency questionnaires, which may result in misclassification of B₁₂ status due to misreporting of diet. ⁷ , ⁸ Dietary intake of vitamin B₁₂ is also less strongly correlated with B₁₂ status among older adults because of malabsorption related to atrophic gastritis or use of gastric acid suppressing medications. ⁹ – ¹¹ To date, prospective studies evaluating blood‐based vitamin B₁₂ levels have not found associations with cognitive decline or dementia status. However, limitations of existing studies include short follow‐up duration (< 5 years on average) and lack of longitudinal, repeated measures of vitamin B₁₂ status, ¹² , ¹³ which may result in regression dilution bias. ¹⁴ Another important limitation is the use of total circulating B₁₂ (cobalamin) concentrations as the sole measure of vitamin B₁₂ status, as cobalamin concentrations may not be a sensitive marker of B₁₂ status. ¹⁵ Indeed, efforts have been made to generate a more sensitive measure of vitamin B₁₂ status by incorporating information from other B₁₂‐related biomarkers, including cobalamin, methylmalonic acid (MMA), and total homocysteine (Hcy). ¹⁵ As such, there is a need for evidence to evaluate whether a combined indicator of vitamin B₁₂ status assessed at multiple timepoints is associated with prospective cognitive decline across different domains over longer time periods.

Some randomized controlled trials have reported that vitamin B₁₂ supplementation is linked with slower cognitive decline in global cognition ¹⁶ or executive function, ¹⁷ but not in other domains. ¹⁷ Other trials either found associations among certain subgroups with global cognition ¹⁸ and memory ¹⁹ or no significant associations with any cognitive domain. ²⁰ , ²¹ However, these trials have not examined the prospective associations between vitamin B₁₂ status from mid‐ to late life with cognitive decline. Existing trials are also limited by enrolling only older adults ¹⁷ , ¹⁸ , ²⁰ or individuals with cognitive impairment, ¹⁶ , ¹⁷ , ¹⁸ short follow‐up (< 2 years), ¹⁶ , ¹⁷ , ¹⁸ , ²⁰ , ²¹ or randomizing only a dietary intervention. ¹⁹

In the present study, we evaluate whether low vitamin B₁₂ status—defined by a combined measure of B₁₂, starting in mid‐life and continuing through older age—is associated with a faster rate of memory, executive function, or language decline during that time period. Additionally, we examine whether elevated folate levels, which generally indicate excess folic acid intake, are associated with a higher rate of cognitive decline among those with low B₁₂, as prior studies suggest that low B₁₂ status may be associated with poorer cognitive function among those with elevated folate. ²² , ²³ , ²⁴ , ²⁵ We hypothesize that individuals with low vitamin B₁₂ status exhibit faster annual decline in all cognitive domains compared to those with high status. We also expect that there is a worsening impact of low B₁₂ status on cognitive function in the presence of high folate levels.

2. METHODS

2.1. Study population

The Framingham Heart Study (FHS) is a community‐based, prospective cohort study aimed at understanding risk factors for cardiovascular and cerebrovascular disease. Beginning in 1948, the Original Cohort enrolled 5209 adults living in Framingham, Massachusetts, and surviving participants have since been followed every 2 years. Full details of the study are described elsewhere. ²⁶ In 1971, the offspring and offspring spouses of the Original Cohort were recruited to join the Offspring Cohort (n = 5124). Participants in the Offspring Cohort complete examinations every 3 to 4 years. ²⁷

RESEARCH IN CONTEXT

Systematic review: The authors reviewed the literature using established sources. It is unknown whether a combined indicator of vitamin B₁₂ status measured at multiple timepoints is associated with prospective cognitive decline from mid‐ to later life, or if findings differ by folate status. Prior evidence is limited by use of self‐reported food frequency questionnaires, single measures of vitamin B₁₂, or short follow‐up.
Interpretation: This study included 1994 participants without baseline dementia and with ≥ 2 assessments of vitamin B₁₂ biomarkers and neuropsychological tests. Higher vitamin B₁₂ status from mid‐ to later life was associated with small but significant slowing of cognitive decline across multiple domains. Findings were robust among those with elevated or non‐elevated folate for executive function and language, but not memory.
Future directions: Future prospective studies should examine whether improving B₁₂ status over the life course can result in small mitigations in cognitive decline into older age.

The present analysis includes Offspring Cohort data from the seventh, eighth, and ninth core exams (1998–2001, 2005–2008, and 2011–2014, respectively) and neuropsychological (NP) factor scores measured at or after core exam 7 (1998–2018). The timing of measurements is shown in Figure S1 in supporting information. There were 1994 participants in the Offspring Cohort who were free of dementia at exam 7, had ≥ 2 measures of vitamin B₁₂ status, and ≥ 2 measures of NP factor scores (Figure 1). All procedures were approved by the Boston University Medical Center Institutional Review Board. Written informed consent was obtained from all participants.

2.2. Vitamin B₁₂ status

The primary exposure was cumulative average vitamin B₁₂ status. This was assessed using a three‐component indicator of vitamin B₁₂, 3cB₁₂, which combines cobalamin, MMA, and Hcy, and then corrects for low folate levels (< 10 nmol/L). The full details of this method have been described elsewhere. ¹⁵ The three vitamin B₁₂ biomarkers (cobalamin, MMA, and Hcy) and folate were measured at the seventh (1998–2001), eighth (2005–2008), and ninth (2011–2014) core exams from fasting blood samples. MMA was assessed at exams 7 and 9 using one liquid chromatography tandem mass spectrometry (LC‐MS/MS) method (Lasko) ²⁸ and at exam 8 using another LC‐MS/MS method (Adaikalakoteswari). ²⁹ Hcy concentrations were assessed at exam 7 and 9 using an high‐performance liquid chromatography method (Araki) ³⁰ and at exam 8 using an LC‐MS/MS method (Adaikalakoteswari). ²⁹ For exam 7, cobalamin was assessed using the Immulite 1000 assay (Siemens Healthcare Diagnostics) and folate concentrations were assessed by the Lactobacillus casei assay. Cobalamin and folate were assessed using the Immulite 2000 assay (Siemens Healthcare Diagnostics) for exam 8 and 9 samples. We calculated 3cB₁₂ at each exam and then took the cumulative average level across exams 7 through 9. If participants were missing data for an exam, the cumulative average level was calculated from the other two exams. All participants had measures of 3cB₁₂ at ≥ 2 exams, and 76% had measures at all three exams.

2.3. NP factor scores

The primary outcomes were changes in memory, executive function, or language factor scores. Participants completed a NP test battery administered by trained examiners every 2 to 3 years between FHS core study exams. The NP battery included tests of verbal memory, visual memory, learning, attention and concentration, abstract reasoning, language, visuoperceptual organization, psychomotor speed, and premorbid intelligence. ³¹ In a previous analysis focused on cross‐study harmonization, cognitive domain factor scores were derived across multiple FHS exams. ³² First, experts assigned each individual NP test to a single cognitive domain. Then, factor scores for each domain were estimated using separate bi‐factor confirmatory factor analysis models for each domain. Models contained fixed item parameters for NP tests previously calibrated from other studies as part of the cross‐study harmonization, as well as freely estimated item parameters from NP tests only administered in FHS. Factor analysis methods have several advantages including: using all available NP test data, accounting for study design, minimizing ceiling effects, and addressing measurement precision. ³² Full methods for generating the FHS calibrated cognitive domain factor scores are published elsewhere. ³³

2.4. Covariates

The following potential confounders were treated as time fixed at core exam 7: age, sex (male or female), educational attainment (did not graduate high school, high school graduate, some college, or college graduate), multivitamin use, and apolipoprotein E (APOE) ε4 allele carriage (0 or ≥ 1 ε4 alleles). We took the cumulative average of the following covariates across all available exams: body mass index, measured as body mass (kg) divided by height squared (m²); depressive symptoms (defined as non‐elevated [score < 16] or elevated [score ≥ 16] on the Center for Epidemiologic Studies Depression scale); ³⁴ and physical activity, measured in metabolic equivalents based on the Physical Activity Index. ³⁵ The following covariates were treated as time fixed at the last core exam: smoking status, self‐reported as non‐smoker, former smoker, or current smoker; and alcohol consumption, self‐reported and then categorized as never, former, or current. ³⁶ The remaining covariates were treated as time varying, with the most recent status carried forward: hypertension (defined as systolic blood pressure ≥ 130 mmHg, diastolic blood pressure ≥ 90 mmHg, or treatment for hypertension), dyslipidemia (defined as total cholesterol > 200 mg/dL or treatment for lipids), diabetes, coronary heart disease, stroke, and atrial fibrillation. Diabetes, coronary heart disease, stroke, or atrial fibrillation, and dementia status were determined by a panel of physicians after reviewing the participant's medical records. A missing category was generated for covariates with incomplete information (multivitamins [n = 195, 10%], APOE ε4 [n = 40, 2%], alcohol consumption [n = 21, 1%], depressive symptoms [n = 8, 0.4%], and diabetes [n = 3, 0.02%]).

2.5. Statistical analysis

Sample characteristics at FHS exam 7 were summarized as means ± standard deviation (SD) for continuous variables or as counts and proportions for categorical variables. Differences in sample characteristics were evaluated by quartiles of 3cB₁₂.

Linear mixed‐effects models estimated the average annual change in memory, executive function, or language factor scores for participants in each 3cB₁₂ quartile compared to those in the lowest quartile (reference group). Separate models were fitted for each NP factor score. Random intercepts and slopes were included to estimate participant‐specific changes in NP factor scores. The time origin was defined as the date of the exam with the first NP factor score measure. The time scale was years since this exam for each participant. We evaluated models with time as a linear term, quadratic term, or linear splines. The model with linear and quadratic terms for time had the lowest Akaike and Bayesian information criteria and was determined to be the best fit to the data for all cognitive domains. Models were adjusted for age, sex, education, body mass index, smoking status, alcohol consumption, multivitamin use, hypertension, diabetes, dyslipidemia, coronary heart disease, stroke, atrial fibrillation, physical activity, depressive symptoms, and APOE ε4 allele carriage. We also included terms for time² and the difference in time between measurement of 3cB₁₂ and NP factor scores. An interaction between time and 3cB₁₂ status was included to determine whether 3cB₁₂ status was associated with changes in cognitive factor scores. Positive coefficients represented slower cognitive decline for participants in higher 3cB₁₂ quartiles compared to the lowest quartile, while negative coefficients represented faster cognitive decline.

We also conducted several secondary analyses. First, we stratified by elevated (≥ 20 ng/mL) versus non‐elevated (6–19 ng/mL) folate ³⁷ to determine whether there was a potential worsening impact of low B₁₂ status on cognitive function in the presence of high folate levels. ²⁴ , ²⁵ Second, we examined 3cB₁₂ as a continuous variable. Third, we changed the primary exposure in each model to quartiles of cumulative average cobalamin, MMA, or Hcy to evaluate how 3cB₁₂ compares to each individual B₁₂ biomarker.

Finally, we conducted sensitivity analyses to evaluate the robustness of our findings. First, we excluded participants with possible low vitamin B₁₂ status (3cB₁₂ values < –0.5; n = 30) ¹⁵ to determine whether participants with low 3cB₁₂ status were driving the results. Second, we excluded participants with 3cB₁₂ measures at only two of the three exams (n = 484). Third, we compared the sample characteristics of participants who were included versus excluded from the analytic sample to evaluate possible selection bias. We also performed a complete case analysis after excluding participants with missing covariate information (n = 247).

Statistical significance was defined as α < 0.05. All analyses were performed using Stata version 18.0 (StataCorp LLC), and figures were generated using R version 4.2.2 (http://CRAN.R‐project.org).

3. RESULTS

3.1. Sample characteristics

On average, participants in the sample were 60 years old at baseline. In this sample, 54% were female and 99% were non‐Hispanic White. On average, compared to participants in the lowest quartile of 3cB₁₂, those in the highest quartile were younger; had higher education attainment; were more likely to be female or take a multivitamin; had lower body mass index; and had lower prevalence of hypertension, diabetes, coronary heart disease, stroke, and atrial fibrillation. As expected, these participants also had the highest levels of cumulative average cobalamin but lowest Hcy or MMA (Table 1).

TABLE 1.

Sample characteristics overall and by quartiles of cumulative average three‐component vitamin B₁₂ indicator (3cB₁₂)_.

	Overall (n = 1994)	Quartile 1 (Low) (n = 499)	Quartile 2 (Low/Med) (n = 498)	Quartile 3 (Med/High) (n = 499)	Quartile 4 (High) (n = 498)	P value
Age (years), mean (SD)	59.8 (9.0)	63.4 (9.3)	60.0 (8.3)	58.6 (8.6)	57.2 (8.4)	< 0.001
Female, N (%)	1079 (54%)	229 (46%)	234 (47%)	276 (55%)	340 (68%)	< 0.001
Non‐Hispanic White, N (%)	1968 (99%)	494 (99%)	494 (99%)	491 (98%)	489 (98%)	0.59
College graduate, N (%)	824 (41%)	182 (36%)	202 (41%)	232 (46%)	208 (42%)	0.02
APOE ε4 allele, N (%)	446 (22%)	103 (21%)	117 (24%)	110 (22%)	116 (23%)	0.86
BMI (kg/m²), mean (SD) ^a	28.2 (5.1)	28.7 (5.0)	28.5 (5.2)	28.2 (5.0)	27.5 (5.1)	0.001
Current smoker, N (%) ^b	124 (6%)	25 (5%)	27 (5%)	34 (7%)	38 (8%)	0.37
Current alcohol drinker, N (%) ^b	1206 (61%)	290 (58%)	319 (64%)	298 (60%)	199 (60%)	0.63
Multivitamin use, N (%)	957 (48%)	182 (37%)	229 (46%)	254 (51%)	292 (59%)	< 0.001
Hypertension, N (%) ^c	1625 (82%)	441 (88%)	411 (83%)	391 (78%)	382 (77%)	< 0.001
Diabetes, N (%) ^c	352 (18%)	126 (25%)	81 (16%)	82 (16%)	63 (13%)	< 0.001
Dyslipidemia, N (%) ^c	1655 (83%)	421 (84%)	399 (80%)	427 (86%)	408 (82%)	0.10
Coronary heart disease N (%) ^c	243 (12%)	91 (18%)	57 (11%)	55 (11%)	40 (8%)	< 0.001
Stroke, N (%) ^c	79 (4%)	30 (6%)	26 (5%)	12 (2%)	11 (2%)	0.002
Atrial fibrillation, N (%) ^c	230 (12%)	80 (16%)	57 (11%)	54 (11%)	39 (8%)	< 0.001
Depressive symptoms, N (%) ^a	130 (7%)	39 (8%)	25 (5%)	24 (5%)	42 (8%)	0.07
Physical activity index, mean (SD) ^a	36.0 (4.6)	35.7 (4.4)	35.8 (4.2)	36.3 (5.0)	36.1 (4.7)	0.11
3cB₁₂, mean (SD) ^a , ^d	0.52 (0.42)	—0.036 (0.27)	0.41 (0.08)	0.68 (0.08)	1.02 (0.18)	< 0.001
Vitamin B₁₂ (pmol/L), mean (SD) ^a	462.2 (185.9)	324.3 (103.8)	407.1 (118.4)	493.2 (134.8)	624.3 (214.7)	< 0.001
Homocysteine (µmol/L), mean (SD) ^a	9.0 (2.5)	11.2 (3.0)	9.2 (2.1)	8.3 (1.5)	7.3 (1.3)	< 0.001
Methylmalonic acid (µmol/L), mean (SD) ^a	0.20 (0.12)	0.30 (0.19)	0.20 (0.05)	0.17 (0.04)	0.14 (0.03)	< 0.001
Elevated folate, N (%) ^a , ^e	828 (42%)	183 (37%)	193 (39%)	219 (44%)	233 (47%)	0.004
Years since baseline, mean (SD) ^f	14.2 (3.7)	13.5 (3.9)	14.3 (3.6)	14.3 (3.6)	14.6 (3.5)	<0.001

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Abbreviations: APOE, apolipoprotein E; BMI, body mass index; SD, standard deviation.

^{^a}

Cumulative average across all available visits.

^{^b}

Time‐fixed at last core exam.

^{^c}

Last status carried forward.

^{^d}

Three‐component indicator of vitamin B₁₂ (cobalamin, methylmalonic acid, and total homocysteine, and then corrected for low folate levels [< 10 nmol/L]).

^{^e}

Elevated folate based on a cut‐point of 20 ng/mL.

^{^f}

Years since baseline (Core Exam 7).

NP factor scores, on average, declined 0.012, 0.024, and 0.013 SD per year over a mean of 14.2 years for memory, executive function, and language, respectively. Cognitive function declined across all quartiles of 3cB₁₂ (Figures S2–S4 in supporting information).

3.2. 3cB₁₂ and cognitive decline

After full covariate adjustment, higher cumulative average 3cB₁₂ status from mid‐ to later life was associated with slower cognitive decline. Indeed, cognitive function declined across all 3cB₁₂ quartiles, but those in the highest quartile exhibited the slowest decline (Figures S2–S4). Compared to participants in the lowest quartile of 3cB₁₂, those in the highest quartile had 0.0090 SD/year slower language decline, 0.0071 SD/year slower memory decline, and 0.0056 SD/year slower executive function decline (language: β: 0.0090, 95% confidence interval [CI]: 0.0040–0.0139; memory: β: 0.0071, 95% CI: 0.0026–0.0117; and executive function: β: 0.0056, 95% CI: 0.0009–0.0103; Table 2). The P for trend was statistically significant for all cognitive domains (language: 0.003, memory: 0.004, and executive function: 0.03), suggesting a linear trend between 3cB₁₂ and cognitive decline (Table 2). Findings were consistent when examining 3cB₁₂ as a continuous variable for memory and language. However, associations with 3cB₁₂ and executive function decline were attenuated (Table S1 in supporting information).

TABLE 2.

Associations between cumulative average three‐component vitamin B₁₂ indicator (3cB₁₂) quartiles and mean annual cognitive decline (n = 1994).

Quartile ^a	Change in memory		Change in executive function		Change in language
Quartile ^a	β (95% CI)	P value	β (95% CI)	P value	β (95% CI)	P value
Model 1
Low	REF	REF	REF	REF	REF	REF
Low/Med	0.0027 (–0.002, 0.008)	0.26	0.0019 (–0.003, 0.007)	0.43	0.0074 (0.002, 0.01)	0.005
Med/High	0.0047 (–0.00007, 0.01)	0.05	0.00053 (–0.004, 0.005)	0.83	0.0050 (–0.0003, 0.01)	0.06
High	0.0073 (0.003, 0.01)	0.002	0.0056 (0.0009, 0.01)	0.02	0.0087 (0.004, 0.01)	0.001
Model 2
Low	REF	REF	REF	REF	REF	REF
Low/Med	0.0027 (–0.002, 0.007)	0.27	0.0017 (–0.003, 0.006)	0.48	0.0075 (0.002, 0.01)	0.004
Med/High	0.0046 (–0.0002, 0.009)	0.06	0.00033 (–0.004, 0.005)	0.89	0.0048 (–0.0004, 0.01)	0.07
High	0.0071 (0.003, 0.01)	0.002	0.0056 (0.0009, 0.01)	0.02	0.0090 (0.004, 0.01)	< 0.001
P‐for‐trend	0.004		0.03		0.003

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Abbreviations: APOE, apolipoprotein E; CI, confidence interval.

^{^a}

Range of 3cB₁₂ values for each quartile were: –1.32 to 0.26 for quartile 1 (low); 0.26 to 0.54 for quartile 2 (low/med); 0.54 to 0.81 for quartile 3 (med/high); and 0.81 to 1.78 for quartile 4 (high). Model 1: Unadjusted. Model 2: Adjusted for baseline age, sex, education, body mass index, smoking status, alcohol status, baseline multivitamin use, hypertension, diabetes, coronary heart disease, stroke, atrial fibrillation, depressive symptoms, physical activity index, APOE ε4 allele carriage, and difference in time between cognitive and vitamin B₁₂ measurements.

3.3. Differences in associations by folate status

Among those with elevated folate (cumulative average ≥ 20 ng/mL, n = 828), participants in the highest quartile of 3cB₁₂ had slower memory, executive function, and language decline than those in the lowest quartile (memory: β: 0.0106, 95% CI: 0.0038–0.0184; executive function: β: 0.0069, 95% CI: –0.0013–0.0151; and language: β: 0.0086, 95% CI: 0.0003–0.0169; Figure 2). Likewise, among those with non‐elevated folate (cumulative average 6–19 ng/mL, n = 1148), participants in the highest quartile of 3cB₁₂ had slower memory, executive function, and language decline than those in the lowest quartile (memory: β: 0.0049, 95% CI: –0.0007–0.0105; executive function: β: 0.0064, 95% CI: 0.0007–0.0121; language: β: 0.0101, 95% CI: 0.0040–0.0163), although the estimate for memory was not statistically significant (Figure 2).

Associations between cumulative average three‐component vitamin B₁₂ indicator (3cB₁₂) quartiles and mean annual cognitive decline stratified by elevated versus non‐elevated folate (cut‐point 20 ng/mL; n = 1994). Range of 3cB₁₂ values for each quartile were: –1.32 to 0.26 for quartile 1 (low), 0.26 to 0.54 for quartile 2 (low/med), 0.54 to 0.81 for quartile 3 (med/high), and 0.81 to 1.78 for quartile 4 (high). Model adjusted for baseline age, sex, education, body mass index, smoking status, alcohol status, baseline multivitamin use, hypertension, diabetes, coronary heart disease, stroke, atrial fibrillation, depressive symptoms, physical activity index, *APOE* ε4 allele carriage, and difference in time between cognitive and vitamin B₁₂ measurements. *APOE*, apolipoprotein E; CI, confidence interval.

Slower declines in language were also observed among participants with elevated folate and 3cB₁₂ in the second quartile (β: 0.0100, 95% CI: 0.0015–0.0186) or with non‐elevated folate and 3cB₁₂ in the third quartile (β: 0.0068, 95% CI: 0.0006–0.0131) compared to those in the respective first quartiles. Those with non‐elevated folate and 3cB₁₂ in the third quartile also had slower annual memory decline than those in the first quartile (β: 0.0100, 95% CI: 0.0043–0.0157; Figure 2). The interaction P value between continuous 3cB₁₂ and folate status were not statistically significant for any cognitive domain (memory P interaction: 0.76, executive function P interaction: 0.64, and language P interaction: 0.84).

3.4. Associations with cobalamin, MMA, or Hcy

We then evaluated associations between each component of the 3cB₁₂ composite indicator (cobalamin, MMA, and Hcy) with cognitive decline. Compared to the first quartile, cumulative average MMA in the third and fourth quartiles was associated with faster memory and executive function decline, and values in the fourth quartile were also associated with faster language decline (Table S2 in supporting information). Similarly, Hcy in the third and fourth quartiles was associated with faster executive function and language decline, while values in the fourth quartile were also associated with faster memory decline compared to the first quartile (Table S3 in supporting information). Higher cobalamin was only associated with executive function decline (Table S4 in supporting information).

3.5. Exclusion of participants with low vitamin B₁₂

Results were robust after excluding participants from our sample with possible low vitamin B₁₂, as defined by 3cB₁₂ values below –0.5 (n = 30; Table S5 in supporting information). ¹⁵

3.6. Exclusion of participants with two of three vitamin B₁₂ measures

Results were robust after excluding participants from our sample with only two of three visits with 3cB₁₂ measurements (n = 484). However, findings with executive function decline were attenuated (Table S6 in supporting information).

3.7. Evaluation of possible selection bias

Results were robust after performing a complete case analysis among the n = 1747 participants with complete covariate data (Table S7 in supporting information). Comparing sample characteristics of participants included versus excluded from the analytic sample, those who were excluded for having insufficient 3cB₁₂ and/or cognitive measures were older; had lower education attainment; higher physical activity; lower prevalence of currently drinking, taking a multivitamin, hypertension, or dyslipidemia; higher prevalence of currently smoking, diabetes, coronary heart disease, or depressive symptoms; lower mean 3cB₁₂, vitamin B₁₂, and folate, as well as shorter follow‐up time (Table S8 in supporting information).

4. DISCUSSION

In this study of middle aged and older adults in the FHS Offspring cohort, we found that having higher cumulative average vitamin B₁₂ status (as indicated by 3cB₁₂) from mid‐ to later life was associated with slightly slower declines in memory, executive function, and language over a mean of 14.2 years. Compared to participants with the lowest 3cB₁₂, those in the highest quartile had 0.05 to 0.09 SD less cognitive decline over 10 years. This represents a small but statistically significant change in the rate of cognitive decline. There were no interactions between vitamin B₁₂ and folate status with cognitive decline, although significant associations between B₁₂ status and memory decline were found among those with elevated, but not non‐elevated, folate status. Thus, further attention to the role of B₁₂ status over the life course with cognitive decline is warranted.

This study adds to the body of evidence relating higher vitamin B₁₂ status to better cognitive function. Our findings were robust even when excluding individuals with low vitamin B₁₂ status, missing 3cB₁₂ measurements, or missing covariate information. Prior work has found that higher vitamin B₁₂ is related to higher memory levels ³ and slower declines in global cognition ¹⁶ or executive function. ¹⁷ , ³⁸ Higher B₁₂ is also cross‐sectionally linked to faster processing speed, smaller volumes of white matter hyperintensities, and less tau burden among older adults in the non‐deficient range of vitamin B₁₂. ⁴ However, null findings have been reported between vitamin B₁₂ and global cognition, ¹⁷ , ²⁰ , ³⁹ memory, ¹⁷ , ¹⁸ , ²⁰ , ³⁹ executive function, ¹⁸ , ²⁰ and language. ⁴⁰ , ⁴¹ , ⁴² To date, prospective studies have not found relationships between a single measure of plasma vitamin B₁₂ and global cognition ² , ¹³ or memory. ¹³ Indeed, in this study, we did not find that cumulative average cobalamin was associated with slower rates of cognitive decline when we evaluated individual biomarkers. This supports previous research findings that cobalamin can be a poor measure of B₁₂ status, particularly in older individuals. ¹⁵ This suggests that the differences between our study and previous null associations may be attributable to the use of repeated measures of vitamin B₁₂ that incorporate information from three B₁₂‐related biomarkers, as this is a more sensitive measure of vitamin B₁₂ status. ¹⁵ Other potential explanations include our study having longer follow‐up or using NP factor scores. ⁴³ Future work is needed to replicate these findings in larger, more diverse samples.

Vitamin B₁₂ may exert protective effects on cognitive function through several mechanisms, such as increasing brain neurotrophic factors, which maintain the structural integrity of glial cells, myelin, and other components of the nervous system. ¹⁸ Vitamin B₁₂ also lowers concentrations of Hcy, which is linked to cognitive impairment, cerebrovascular disease, and brain atrophy. ¹⁸ , ³⁸ MMA, a common biomarker of vitamin B₁₂ deficiency, also increases with age and has been related to cognitive impairment and dementia. ⁴⁴ Indeed, Hcy may impact cognitive function through mechanisms including increased oxidative stress, damage to DNA, amyloid deposition, and neurotoxicity. ¹⁸ MMA is considered a neurotoxin in methylmalonic acidurias, and recent evidence suggests that moderate elevations of MMA may also have neurotoxic effects, as higher MMA levels have been linked to faster rates of cognitive decline independent of vitamin B₁₂ status. ⁴⁵ , ⁴⁶ These mechanisms align with our findings that higher cumulative average vitamin B₁₂ status is associated with slower cognitive decline, whereas higher cumulative average Hcy or MMA are linked to faster rates of decline. Indeed, 3cB₁₂, Hcy, and MMA were all associated with similar magnitudes in the rate of cognitive decline in this study. Future work is needed to determine whether 3cB₁₂ is a better predictor of future dementia status than Hcy or MMA. Studies may also consider evaluating differences in associations between B₁₂ and cognitive decline by demographic factors, as the prevalence of vitamin B₁₂ deficiency increases with age ⁴⁷ and may be more common among men. ⁴⁸ The prevalence of multivitamin use also tends to be higher among women than men at all ages, with the highest prevalence observed in older age. ⁴⁹

Vitamin B₁₂ may also influence specific cognitive domains. In animal studies, mice treated with vitamin B₁₂ and folic acid exhibit better learning and memory, likely through higher levels of hippocampal neurotrophic factors, restored myelination in the hippocampus, lower hippocampal atrophy, and improved mitochondrial structure and dynamics. ⁵⁰ Less is known about mechanisms linking vitamin B₁₂ with executive function or language. Higher B₁₂ intake is associated with activation of the dorsolateral prefrontal cortex, an important brain region for executive function. ⁵¹ Additionally, children of mothers with lower vitamin B₁₂ intake have lower vocabulary, word combinations, and speech intelligibility 2 to 6 years later. ⁵² Older adults with cognitive impairment also exhibit higher verbal fluency scores after vitamin B₁₂ treatment, possibly due to improved frontal lobe function. ⁵³ Future studies are needed to determine the mechanisms through which vitamin B₁₂ is related to specific cognitive domains.

In this study, higher cumulative average vitamin B₁₂ status was associated with similar slowing of cognitive decline among individuals with elevated (≥ 20 ng/mL) and non‐elevated (6–19 ng/mL) folate levels for memory, executive function, and language. Folate deficiency is associated with higher levels of Hcy and amyloid beta, both of which are adversely related to cognitive function. ⁵⁴ However, elevated folate is also associated with cognitive impairment, possibly due to disruptions in the pathway through which B₁₂ lowers Hcy concentrations. ²² , ⁵⁵ Folate or folic acid supplementation have also been linked to higher risk of dementia and smaller brain volumes. ⁵⁶ Indeed, this study found that the magnitude of the association between vitamin B₁₂ and memory decline was 2‐fold larger among those with elevated compared to non‐elevated folate status for the highest versus lowest B₁₂ quartiles, although this interaction was not statistically significant. There is some evidence of a worsening impact of low B₁₂ status on cognitive function in the presence of high folate levels. ²² , ²³ Yet, other studies have not found differences in associations between vitamin B₁₂ and cognition by folate status. ⁵⁴ , ⁵⁷ This aligns with our findings that higher cumulative average B₁₂ is related to slower executive function and language decline, regardless of folate level. It may be that the cut‐off for folate status used in this analysis was too low to be considered “elevated.” Additionally, no participants in this analysis were classified as having possible or probable vitamin B₁₂ deficiency (3cB₁₂ values –2.5 to 1.5 or < –2.5, respectively). ¹⁵ Future work is needed to determine whether there is an upper limit after which folate status is adversely associated with cognitive function.

Our findings are relevant to the growing interest in identifying modifiable risk factors to delay or prevent cognitive decline and dementia. Dementia progression can be an insidious process, during which the progression from asymptomatic to symptomatic can take decades before the thresholds for diagnosis are met. ⁵⁸ This study suggests that higher cumulative average vitamin B₁₂ status from mid‐ to later life could help to mitigate cognitive decline in the later years. These small but significant changes align with the clinical course of dementia, as defined by persistent, subtle changes that accumulate over time. ⁵⁸ Our results were observed among those with replete vitamin B₁₂ status and either elevated or non‐elevated folate levels, but vitamin B₁₂ and folate deficiencies are also known causes of cognitive impairment. ⁵⁴ , ⁵⁹ Further, this study suggests that incorporating information from multiple B₁₂ markers (cobalamin, MMA, and Hcy) may be important for evaluating cognitive risk. ¹⁵ Future studies are needed to determine whether higher cumulative average vitamin B₁₂ status also translates to lower risk of dementia.

4.1. Limitations and strengths

These findings should be interpreted in the context of the study's limitations. First, FHS participants are primarily European American, which may limit generalizability to more racially and ethnically diverse populations. Second, only participants with repeated measures of 3cB₁₂ and NP factor scores were included in this analysis. Indeed, excluded participants were older and had lower vitamin B₁₂ or folate levels. Third, NP tests were not measured at the same time as 3cB₁₂. We accounted for this time lag by including a covariate for the difference in time between B₁₂ and NP measurements. Fourth, different assays were used for the vitamin B₁₂ biomarkers across FHS exams. We expect that any potential error introduced from the different assays would be non‐differential. Additionally, we did not have access to genetic information to examine genetic polymorphisms affecting Hcy or other B₁₂ biomarkers. This should be evaluated in future studies. Finally, there was some overlap in timing of 3cB₁₂ and NP measures. Although cognitive function could impact vitamin B₁₂ status, the use of cumulative average 3cB₁₂ quartiles lessens this concern because we expect that participants in the highest and lowest 3cB₁₂ quartiles are stable over time. Further, we do not expect that cognitive function would impact malabsorption of vitamin B₁₂, which is the leading reason for B₁₂ deficiency among older adults. ⁴⁷

This study also has several strengths. First, the FHS Offspring cohort is well characterized and has prospective data on cognitive decline and its risk factors. Second, we leveraged repeated assessments of vitamin B₁₂ status, minimizing the threat of regression dilution bias. ¹⁴ We also used a three‐component indicator of vitamin B₁₂ status (3cB₁₂), which combines information from multiple blood‐based biomarkers. ¹⁵ Third, we used repeated measures of NP factors scores over a mean of 14.2 years. Factor scores also have methodological advantages. ⁴³ Finally, we included many potential confounders including demographic, lifestyle, and medical factors. However, bias due to residual or unmeasured confounding is still possible.

5. CONCLUSIONS

Higher cumulative average vitamin B₁₂ status from mid‐ to later life was associated with small but significant attenuation in the rate of cognitive decline across multiple domains. This B₁₂ effect size corresponds to being ≈ 0.5 years younger in age. Given that even small delays in the onset of symptoms can reduce the prevalence of cognitive impairment, ⁶⁰ , ⁶¹ efforts to manage vitamin B₁₂ status and improve nutrition throughout the life course may help mitigate cognitive decline into older age.

CONSENT STATEMENT

All procedures were approved by the Boston University Medical Center Institutional Review Board. Written informed consent was obtained from all participants.

CONFLICT OF INTEREST STATEMENT

Joshua W. Miller is a member of the Alzheimer's Prevention Expert Group of the Food for the Brain Foundation. Andrew J. Saykin serves on the dementia advisory board for Siemens Medical Solutions, serves on the scientific advisory boards for Eisai and Novo Nordisk, and serves as the editor‐in‐chief of Brain Imaging and Behavior. Timothy J. Hohman served on the scientific advisory board for Vivid Genomics, serves on the scientific advisory board for Circular Genomics, serves as deputy editor for Alzheimer's and Dementia: Translational Research and Clinical Interventions and as senior associate editor for Alzheimer's and Dementia. Rhoda Au is a scientific advisor to Signant Health, GSK, and NovoNordisk. Paul F. Jacques is a member of the Danone North America Essential Dairy and Plant‐Based Advisory Board. No other authors have disclosures to report. Author disclosures are available in the supporting information.

Supporting information

ALZ-21-e70864-s002.pdf^{(669.2KB, pdf)}

Supporting information

ALZ-21-e70864-s001.docx^{(1.8MB, docx)}

ACKNOWLEDGMENTS

The authors would like to acknowledge the Framingham Heart Study participants, staff, and study personnel. This study was supported by the Framingham Heart Study of the National Heart, Lung, and Blood Institute of the National Institutes of Health and Boston University School of Medicine. This project has been funded with federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, under contract number 75N92025D00012 and contracts N01‐HC‐25195 and HHSN269201500001I. The ADSP Phenotype Harmonization Consortium (ADSP‐PHC) is funded by the National Institute on Aging, National Institutes of Health (grant numbers U24AG074855, U01AG068057, and R01AG059716). The authors were supported by the National Institute on Aging, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, National Institute of Environmental Health Sciences, and National Library of Medicine of the National Institutes of Health, American Heart Association, Alzheimer's Association, Rutgers Brain Health Institute, Busch Biomedical Grant Program, US Department of Agriculture Agricultural Research Service, and US Department of Defense.

Marino FR, Rogers G, Miller JW, et al. Higher vitamin B₁₂ from mid‐ to late life is related to slower rates of cognitive decline. Alzheimer's Dement. 2025;21:e70864. 10.1002/alz.70864

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supporting information

ALZ-21-e70864-s002.pdf^{(669.2KB, pdf)}

Supporting information

ALZ-21-e70864-s001.docx^{(1.8MB, docx)}

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PERMALINK

Higher vitamin B12 from mid‐ to late life is related to slower rates of cognitive decline

Francesca R Marino

Gail Rogers

Joshua W Miller

Jacob Selhub

Jesse Mez

Paul K Crane

Shubhabrata Mukherjee

Andrew J Saykin

Timothy J Hohman

Emily H Trittschuh

Rhoda Au

Paul F Jacques

Phillip H Hwang

Abstract

INTRODUCTION

METHODS

RESULTS

DISCUSSION

Highlights

1. BACKGROUND

2. METHODS

2.1. Study population

RESEARCH IN CONTEXT

FIGURE 1.

2.2. Vitamin B12 status

2.3. NP factor scores

2.4. Covariates

2.5. Statistical analysis

3. RESULTS

3.1. Sample characteristics

TABLE 1.

3.2. 3cB12 and cognitive decline

TABLE 2.

3.3. Differences in associations by folate status

FIGURE 2.

3.4. Associations with cobalamin, MMA, or Hcy

3.5. Exclusion of participants with low vitamin B12

3.6. Exclusion of participants with two of three vitamin B12 measures

3.7. Evaluation of possible selection bias

4. DISCUSSION

4.1. Limitations and strengths

5. CONCLUSIONS

CONSENT STATEMENT

CONFLICT OF INTEREST STATEMENT

Supporting information

ACKNOWLEDGMENTS

REFERENCES

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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Cited by other articles

Links to NCBI Databases

Higher vitamin B₁₂ from mid‐ to late life is related to slower rates of cognitive decline

2.2. Vitamin B₁₂ status

3.2. 3cB₁₂ and cognitive decline

3.5. Exclusion of participants with low vitamin B₁₂

3.6. Exclusion of participants with two of three vitamin B₁₂ measures