Impact of Vitamin B12,Folate and Homocysteine in Modulating Cognitive Functions and the Brain’s White Matter Hyperintensity in Alzheimer’s Disease

Abstract

Background

Deficiency of vitamin B12 and folate as surrogate factors attributed to cognitive deterioration among older adults with Alzheimer’s disease (AD). Increased homocysteine levels >15 µmol/L (hyperhomocysteinaemia) due to insufficiency of vitamin B12 contribute to damage to the small blood vessels in the brain and aggravate the white matter lesion.

Purpose

The study aimed to determine the impact of B12, folic acid and homocysteine in modulating cognitive functions and white matter hyperintensity in AD.

Methods

A case-control study of a total number of 82 patients (41 AD patients and 41 controls) was recruited. The cognitive functions were assessed by the Montreal Cognitive Assessment (MoCA), and white matter hyperintensity was marked by magnetic resonance imaging studies. The levels of vitamin B12, folic acid and homocysteine in serum were also assessed.

Results

The noticeable changes were observed in the cognitive scores and levels of B12, folic acid and homocysteine in AD and controls and found statistically significant (p < .001). Spearman’s rank correlations revealed that cognitive functions (MoCA score) showed a direct correlation with B12 (ρ = 0.513, p < .001). Conversely, MoCA was moderately negatively correlated with homocysteine (ρ = −0.422, p < .001). Participants with B12 deficiency showed a significantly higher frequency of white-matter hyperintensities (WMH) (χ² = 4.654, p = .031; Fisher’s exact p = .048).

Conclusion

Nutrient deficiencies, especially B12, have a disruptive impact on cognitive domains and WMH in AD, which could be considered as key indicators to identify the disease severity among older adults. Recommendations of vitamin B12 plus supplements might be connected to clinical and public health initiatives to halt the rate of progression of cognitive decline in AD.

Keywords

Alzheimer’s disease brain atrophy folic acid homocysteine

Introduction

Alzheimer’s disease (AD) is a progressive neurodegenerative disease of the brain. Deterioration of cognitive functions (including memory loss of recent events), behavioural changes, daily activities and brain atrophy changes are considered the leading manifestations of AD.¹ As per the World Health Organisation the global incidence of dementia in 2020 was 55 million elderly adults, which is also expected to surpass about 78 million in 2030 and 139 million in 2050.² Meanwhile, India, a country undergoing rapid globalisation with increasing life expectancies among Indians, witnessed 7.4% (approximately 8.8 million) of the population, especially older adults aged 60 years and above, living with dementia as per the national representative data between 2017 and 2020.³ The biochemical perspective of the disease is found to have a strong association with the amyloid pathology, apart from understanding the progression and severity of the disease. Raised homocysteine (Hcy) (hyperhomocysteinaemia) levels of >15 µmol/L, due to micronutrient deficiencies (vitamin B12 and folate), induce amyloid plaque and neurofibrillary tangle formation via an oxidative stress mechanism, ultimately causing cognitive impairment in AD.⁴ Furthermore, hyperhomocysteinaemia is also known to promote white-matter hyperintensities (WMH) or brain atrophy.⁵

Vitamin B12 (B12 or cobalamin) serves as one of the vital factors for cognitive function, neurotransmitter synthesis⁶ and regulating metabolic pathways, particularly the methylation cycle of methionine involving the generation of S-adenosyl methionine (SAM), which is a universal methyl donor in the methionine cycle or Hcy metabolism. The deprivation of B12 and folate (folic acid) disrupts one-carbon metabolism, including the Hcy metabolism. Increased methyltransferase activity in the methionine cycle accelerates the depletion of the SAM and readily converts SAM into S-adenosyl-homocysteine, eventually forming Hcy.⁷ The hyperhomocysteinaemia, which is also a sign of decreased B12 and folic acid, contributes to neurotoxic implications, including oxidative stress, vascular damage and excitotoxicity and consequently causes the structural alterations in the brain and memory impairment in AD.⁸

Previous research has examined different aspects of clinical studies investigating the role of micronutrients in preventing cognitive decline. However, there is still a lack of conclusive evidence, or absence of studies, regarding the effects of B12, B9 and Hcy levels on cognitive domains and white matter hyperintensity changes within the Indian population. Additionally, existing literature has reported inconsistent findings concerning the relationship between these micronutrients, Hcy levels and cognitive deficit.^{9, 10} Therefore, this study aims to determine the impact of B12, folic acid and hyperhomocysteinaemia in modulating cognitive functions and WMH in patients with AD.

Methods

A case-control study was conducted after approval from the Institutional Ethical Committee (JSSMC/IEC/050722/48NCT/2022-2023). Based on the sample size calculation, 82 older adults, including AD subjects (N = 41) and healthy control subjects (N = 41),¹¹ were recruited between 65 and 85 years of age, irrespective of gender. The participants were enrolled from the geriatric outpatient and inpatient departments, JSS Hospital, for the period of 1 year from July 2023 to June 2024, following the Declaration of Helsinki and good clinical practice (192). The study excluded patients who were taking vitamin B12 or folic acid supplements or cholinesterase inhibitors. Additionally, other types of dementia such as frontotemporal, vascular, Lewy body dementia, alcohol- or drug-induced dementia, diabetes mellitus and hypertension, Down syndrome, or comorbid conditions including cardiovascular, respiratory or renal insufficiency were excluded. The participants were interviewed by a geriatrician and clinical psychologist applying a structured questionnaire to obtain the information, including age (in years), sex, education, occupation, ethnicity, present and past medical history, memory, expression, daily functions, personality changes, thinking, sleeping, eating habits and other health issues.¹² Additionally, they also satisfied the International Classification of Diseases-11 criteria for selection of participants,¹³ further, the cognitive functions were evaluated by the Montreal Cognitive Assessment (MoCA)¹⁴ score of 10–24. This was followed by cranial MRI scanning of all AD participants with a 3-Tesla scanner for four high-resolution axial sequences, that is, a T2-weighted fluid-attenuated inversion recovery sequence. Brain atrophy with chronic small vessel disease, periventricular and deep WMH, prominence of the temporal horn of the lateral ventricles, and other findings were noted. Furthermore, 2 mL of a random blood sample was also collected intravenously in a serum separation tube and allowed to clot at room temperature for 30 min. The samples were continued with centrifugation at 4,000 rpm for 10 min to separate the serum samples for the analysis of markers. Samples were stored at −80 °C until they were processed. Serum samples were analysed for B12, B9 and Hcy using Roche Cobas, after validating with appropriate internal controls. Vitamin B12 was estimated using the ECLIA method (cat# Elecsys Vit B12 II) on Cobas e 402/801. Folic acid was estimated using the ECLIA method (cat# Elecsys Folate III) on the Cobas e pure 402 platform, and Hcy was estimated using an enzymatic method, spectrophotometric principle containing multiple enzymes such as Hcy methyltransferase, S-adenosyl-l-homocysteine hydrolase, adenosine deaminase and glutamate dehydrogenase. Parameter values were interpreted using the integrated laboratory information system Backbone.

Statistical Analysis

An open-source statistical programme, JASP (version 0.19.3; JASP team, Amsterdam, Netherlands), was used to conduct the statistical calculations. The descriptive values were plotted in terms of mean ± standard deviation. Mann–Whitney U test, Welch’s t-test, effect sizes (rank-biserial r for non-parametric data and Cohen’s d for parametric data), Spearman’s correlation and the chi-square test were employed. All tests were two-tailed, and the p value was statistically significant less than .05 or .001 (p < .05 or <.001).

Results

The baseline sample consisted of 82 participants (41 AD, 41 controls). Controls were slightly younger (mean ≈ 72 years) than AD patients (mean ≈ 75 years). Group comparisons revealed large and meaningful differences between AD patients and controls. MoCA scores were substantially lower in AD (mean ≈ 15.8) compared to controls (mean ≈ 26.2) and showed an exceptionally strong separation between groups (rank-biserial correlation = 0.951 and p < .001), confirming the expected cognitive impairment in the AD cohort. There was a significant spike in the Hcy levels in AD (Cohen’s d = −1.20, p < .001), indicating a very large effect size and suggesting a robust association between hyperhomocysteinaemia and AD status. The cobalamin and folic acid insufficiency were significantly higher in AD patients, with moderate-to-large effects (rank-biserial correlations = 0.576 and 0.459, and p < .001, respectively), supporting their role as potential modifiable risk factors. Age showed only a small difference between groups (r = −0.264), indicating limited confounding by age.

Cognitive performance, assessed using the MoCA, differed significantly according to vitamin B12, folate and Hcy status. B12 deficiency was markedly associated with lower MoCA scores compared with those with normal B12 levels (Mann–Whitney U = 386.5, p < .001) (Table 2). The rank-biserial correlation was −0.479 (95% CI −0.658 to −0.249), which represented a strong effect. Similarly, reduced folate levels were also associated with cognitive domains (U = 348.5, p = .011) with a rank-biserial correlation of −0.395 (95% CI −0.618 to −0.113), corresponding to a moderate negative effect size. Hyperhomocysteinaemia was related to poorer cognitive function (U = 558.5, p = .013); however, the magnitude of association was smaller (rank-biserial correlation −0.321, 95% CI −0.528 to −0.078). The effect sizes for all three variables consistently pointed towards worse cognitive performance in the presence of micronutrient abnormalities. Vitamin B12 status exerts the strongest effect (Figure 1 and Table 1).

Table 1.

Baseline Characteristics and Group Comparisons (Alzheimer’s Disease vs Control).

Variables	Control (n = 41)(Mean ± SD)	AD (n = 41)(Mean ± SD)	Test Statistic (U)	p Value	Effect Size
Age (years)	72.15 ± 4.93	75.12 ± 6.26	U = 618.5	.039	r_rb= −0.26
Montreal Cognitive Assessment	26.20 ± 1.35	15.81 ± 8.64	U = 1,640.0	<.001	r_rb = 0.95
Vitamin B12 (pg/mL)	398.90 ± 198.95	232.41 ± 120.16	U = 1,324.5	<.001	r_rb = 0.58
Folate (ng/mL)	9.41 ± 4.21	6.72 ± 5.48	U = 1,226.5	<.001	r_rb = 0.46
Homocysteine (µmol/L)	14.47 ± 3.90	24.15 ± 10.72	t = −5.44	<.001	d = −1.20

Notes: Indicates significant at p < .05** and indicates significant at <.001***. Mann–Whitney test (U) for non-normal*; Welch’s t-test for Hcy (normal)*. Effect sizes: rank biserial r (non-parametric) and Cohen’s d (Hcy). pg/mL: picogram per millilitre; µmol/L: micromole per litre; ng/mL: nanogram per millilitre.

Table 2.

Association of Vitamin B12, Folate and Homocysteine Status with Montreal Cognitive Assessment.

Micronutrient Deficient	U	p Value	Rank-biserial Correlation	95% CI
Vitamin B12	386.5	<.001	−0.479	−0.658 to −0.249
Folate	348.5	.011	−0.395	−0.618 to −0.113
Homocysteine	558.5	.013	−0.321	−0.528 to −0.078

Notes: Indicates significant at p < .05** indicates significant at <.001***. Mann–Whitney test (U), rank-biserial correlation.

Heatmap Spearman’s ρ coefficients for pairwise associations between MoCA, age, serum B12, B9 and Hcy status in the entire cohort (N = 82). Positive correlations are shown in blue, negative correlations in red, with colour intensity reflecting the strength of association. Spearman’s rank correlations revealed that cognitive performance (MoCA score) showed a strong positive correlation with vitamin B12 (ρ = 0.513, p < .001) and a slight positive correlation with B9 (ρ = 0.332, p = .002). Conversely, MoCA scores were substantially inversely related to Hcy (ρ = −0.422, p < .001), indicating that elevated Hcy is linked to worse cognitive performance. Meanwhile, B12 and B9 were inversely related to Hcy concentrations (ρ = −0.414, p < .001), (ρ = −0.425, p < .001), respectively, which suggests that deprivation of B12 and B9 leads to hyperhomocysteinaemia (Figure 2).

Participants with B12 deficiency showed a significantly higher frequency of WMH (χ² = 4.654, p = .031; Fisher’s exact p = .048), as illustrated in Table 3. While no significant difference was found in WMH frequency with folate deficiency and Hcy concentration (χ² = 0.344, p = .558) and (χ² = 0.008, p = .931), respectively.

Table 3.

Association of Micronutrient Status with White-matter Hyperintensities Presence (Contingency Analyses).

Micronutrient Status	WMH Present (%)	WMH Absent (%)	χ² (df = 1)	p Value (χ²)	Fisher’s Exact p	Log Odds Ratio (95% CI)
Vitamin B12 (deficient vs normal)	100 versus 80	0 versus 20	4.654	.031	0.048	−2.46 (−5.45 to 0.53)
Folate (deficient vs normal)	86.7 versus 92.3	13.3 versus 7.7	0.344	.558	0.615	0.60 (−2.13 to 3.33)
Homocysteine (high vs normal)	90.0 versus 90.9	10.0 versus 9.1	0.008	.931	1.000	0.10 (−2.55 to 4.16)

Notes: Indicates significant at p < .05** and indicates significant at p < .001***. χ² (df = 1) – Chi-square (degree of freedom = 1). WMH: White-matter hyperintensities.

Labelled ‘A’ denotes brain atrophy, ‘B’—presence of white matter hyperintensity and ‘C’—enlarged temporal horn of the lateral ventricle (Figure 3).

Chronic small vessel disease and presence of WMH in the frontoparietal, temporal and occipital lobes. Labelled ‘A’ denotes the presence of white matter hyperintensity and ‘B’ an enlarged temporal horn of the lateral ventricle (Figure 4).

Discussion

The substantial rise in Hcy levels and decreased B12 and B9 debilitate the neurocognitive functions in AD.^{15, 16} Additionally, hyperhomocysteinaemia also promotes an immunoinflammatory response by increasing the production of pro-inflammatory cytokines, such as tumour necrosis factor alpha and interleukin 6, which have a direct effect on cognitive domains in AD.¹⁷ Additionally, high Hcy also triggers the generation of reactive oxygen species, such as superoxide anions and hydrogen peroxide, which further promotes neurodegeneration. The damage to the microvasculature of the brain causes brain atrophy and white matter lesions (WMLs) via inflammation, oxidative damage and injury to endothelial cells.^{18, 19}

Our study reported a substantial positive relationship between B12 and cognitive deficits, suggesting that sufficient cobalamin levels might improve neurocognitive functions, which was parallel with the previous findings by Jatoi et al.,²⁰ Ueno et al.²¹ and Lachner et al.,²² who advocated that hypovitaminosis induces disruption in myelin formation and disturbs the nerve signal, modulating the DNA synthesis of myelin-producing oligodendrocytes. Moreover, B12 affects the cellular growth of myelin, cellular energetic processes and neurotransmitter synthesis. Moreover, recent literature has depicted that myelin impairment might be the key trigger for cognitive deterioration and could even precede β-amyloid plaques and tau pathologies.²³ Another study by Rabensteiner et al. reported that there was no association of reduced B12 levels and memory impairment in dementia patients.²⁴ A nationwide multicentre study by Soh et al.²⁵ witnessed no apparent relationship between cognitive impairment and B12 deficiency. They advocated that B12 levels might be a contributing factor to dementia and brain functions. Similarly, serum levels of folate were slightly linked to cognitive domains. O’Connor et al. reported that insufficiency of folic acid promotes cognitive deficit, especially memory, attention and visuospatial functions and risk of dementia among elderly adults, owing to the debilitating effects of folic acid on hippocampal neurogenesis.²⁶ As the episodic memory formation is governed by the hippocampus and associated subregions, the brain’s dynamic and continuous process of memory formation is explained by the hippocampus-dependent memory signals, whereas the CA3 of hippocampal formation transfers recent memory traces into the neocortex to consolidate the memory and is deeply implicated in the pathogenesis of AD.²⁷ Meanwhile, in our findings, hyperhomocysteinaemia was inversely related to the cognitive functions. Zuin et al.²⁸ and Lauriola et al.,²⁹ while Kim and Lee³⁰ identified a weak relationship between hyperhomocysteinaemia and cognitive impairment. Hyperhomocysteinaemia acts through a mechanism called neurotoxicity, which is also brought about by the binding action of homocysteic acid (byproduct of Hcy) on the N-methyl-d-aspartate receptor.³¹ Furthermore, excitotoxicity and neuronal death are caused by perpetual activation of neurons with NMDA receptors and disturbed calcium homeostasis. Consequently, it alters the neurons, involving oxidised lipids and neural network degeneration, and propagates the memory deficit and progression of AD.³²

Participants with B12 deficiency showed a significantly higher frequency of WMHs and brain atrophy changes in the current findings. B12 has an impact on the brain’s microvasculature (small vessel disease), which exaggerates the WMLs and lacunar infarcts.³³ Eventually, small vessel disease affects the integrity of the blood–brain barrier,³⁴ which implies that a significant reduction in vitamin B12 aggravates neurodegeneration and cognitive decline. Tangney et al.³⁵ advocated that poor vitamin B12 status worsens cognitive performance through increased white matter hyperintensity. The WMLs are described as hyperintensity of cerebral white matter under MRI studies³⁶ where WMLs are portrayed as confluent, punctuate and periventricular. Confluent lesions are associated with small vessel disease, which causes the vessel wall to thicken and massive shrinkage of the lumen, further leading to axonal destruction, gliosis and total myelination. While punctate lesions relate to the widening of the perivascular space. Conversely, periventricular influences ependymal lining dysfunction or fluid absorption, which spreads fluid penetration along axons and results in enlarged ventricles, affecting the axons. Consequently, WMLs result in significant brain damage and promote the severity of cognitive impairment in AD.³⁷

Conclusion

Based on these findings, it can be summarised that there is a potential biological pathway linking vitamin B12 and cognitive decline, as well as WMH or brain atrophy changes. Henceforth, early identification and management of modifiable risk factors, such as deficiency of vitamin B12 and folate or recommendation of these micronutrient supplements, could be beneficial as part of clinical and public health strategies in reducing the severity of cognitive deterioration and neuronal loss in older adults. Nevertheless, further longitudinal studies are needed to establish causality and to assess the effects of nutritional deficiencies, especially vitamin B12 deficiency, on cognitive outcomes in AD.

Limitations

The sample size was smaller due to the low number of attending AD patients in both inpatient and outpatient wards. Additionally, the sample was collected only at a tertiary care hospital attached to the medical college.

Footnotes

Acknowledgement

The authors thank all the participants for their cooperation during the study and the radiologists for the interpretation of MRI findings.

Author’s Contribution

Conceptualisation, writing—original draft, investigation, RPS; conceptualisation, funding acquisition, project administration, CSV; methodology, writing—review & editing, SJ; data curation, writing—review & editing, AKY; investigation, supervision, PP; editing and proofreading, JD.

Data Availability

Available upon request to the corresponding author.

Declaration of Conflict of Interests

The authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship and/or publication of this article: JSSMC/R&D/3618/2022-2023 dated 11 August 2022.

Statement of Ethics

The study was approved by the Institutional Ethics Committee (Reference no JSSMC/IEC/050722/48NCT/2022–2023).

Patient Consent

Informed consent was obtained from all the subjects.

ORCID iD

Ram Prakash Sah

References

Scheltens

, Blennow

, Breteler

MMB

, . Alzheimer’s disease. Lancet 2016; 388(10043): 505–517.

Shin

JH.

Dementia epidemiology fact sheet 2022. Ann Rehabil Med 2022; 46(2): 53–59.

Lee

, Meijer

, Langa

, . Prevalence of dementia in India: National and state estimates from a nationwide study. Alzheimer’s Dement 2023; 19(7): 2898–2912.

, Chu

, Barrero

, . Homocysteine exacerbates β-amyloid pathology, tau pathology, and cognitive deficit in a mouse model of Alzheimer disease with plaques and tangles. Ann Neurol 2014; 75(6): 851–863.

Feng

, Isaac

, Sim

, . Associations between elevated homocysteine, cognitive impairment, and reduced white matter volume in healthy old adults. Am J Geriatr Psychiatry 2013; 21(2): 164–172.

El-Mezayen

, Abd el Moneim

RehabA

, and El-Rewini

SH.

Vitamin B12 as a cholinergic system modulator and blood brain barrier integrity restorer in Alzheimer’s disease. Eur J Pharm Sci 2022; 174: 106201.

Pusceddu

, Herrmann

, Kirsch

, . One-carbon metabolites and telomere length in a prospective and randomized study of B- and/or D-vitamin supplementation. Eur J Nutr 2017; 56(5): 1887–1898.

Jeon

, Kwon

, Lee

, . Vitamin B12 reduces TDP-43 toxicity by alleviating oxidative stress and mitochondrial dysfunction. Antioxidants 2021; 11(1): 82.

Kwok

, Lee

, Law

, . A randomized placebo controlled trial of homocysteine lowering to reduce cognitive decline in older demented people. Clin Nutr 2011; 30(3): 297–302.

10.

Aisen

, Schneider

, Sano

, . High-dose B vitamin supplementation and cognitive decline in Alzheimer disease: a randomized controlled trial. JAMA 2008; 300(15): 1774–1783.

11.

Uslu

, Akarkarasu

, Ozbabalik

, . Levels of amyloid beta-42, interleukin-6 and tumor necrosis factor-alpha in Alzheimer’s disease and vascular dementia. Neurochem Res 2012; 37(7): 1554–1559.

12.

Weiner

and Lipton

AM.

The American Psychiatric Publishing textbook of Alzheimer disease and other dementias. 1st ed. Washington (DC): American Psychiatric Publishing; 2009.

13.

World Health Organization. Clinical descriptions and diagnostic requirements for ICD-11 mental, behavioural and neurodevelopmental disorders. 1st ed. Geneva: World Health Organization; 2024. p. 617–623.

14.

Nasreddine

, Phillips

, Bédirian

, . The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc 2005; 53(4): 695–699.

15.

, Barrero

, Gupta

, . Homocysteine modulates 5-lipoxygenase expression level via DNA methylation. Aging Cell 2017; 16(2): 273–280.

16.

Sah

, Vidya

, Pereira

, . Elevated homocysteine level and brain atrophy changes as markers to screen the Alzheimer disease: case series. Ann Geriatr Med Res 2024; 28(1): 116–120.

17.

Yin

, Wang

, . Maresin 1 improves cognitive decline and ameliorates inflammation in a mouse model of Alzheimer’s disease. Front Cell Neurosci 2019; 13: 466.

18.

Sharma

, Tiwari

, and Tiwari

RK.

Hyperhomocysteinemia: impact on neurodegenerative diseases. Basic Clin Pharmacol Toxicol 2015; 117(5): 287–296.

19.

Zhou

, Zhong

, Chen

, . Elevated homocysteine levels, white matter abnormalities and cognitive impairment in patients with late-life depression. Front Aging Neurosci 2022; 14: 931560.

20.

Jatoi

, Hafeez

, Riaz

, . Low vitamin B12 levels: an underestimated cause of minimal cognitive impairment and dementia. Cureus 2020; 12(2): e6976.

21.

Ueno

, Hamano

, Enomoto

, . Influences of vitamin B12 supplementation on cognition and homocysteine in patients with vitamin B12 deficiency and cognitive impairment. Nutrients 2022; 14(7): 1494.

22.

Lachner

, Steinle

, and Regenold

WT.

The neuropsychiatry of vitamin B12 deficiency in elderly patients. J Neuropsychiatry Clin Neurosci 2012; 24(1): 5–15.

23.

Papuć

and Rejdak

The role of myelin damage in Alzheimer’s disease pathology. Arch Med Sci 2018; 16(2): 345–351.

24.

Rabensteiner

, Hofer

, Fauler

, . The impact of folate and vitamin B12 status on cognitive function and brain atrophy in healthy elderly and demented Austrians, a retrospective cohort study. Aging 2020; 12(15): 15478–15491.

25.

Soh

, Lee

, and Won

CW.

Association between vitamin B12 levels and cognitive function in the elderly Korean population. Medicine 2020; 99(30): e21371.

26.

O’Connor

DMA

, Scarlett

, De Looze

, . Low folate predicts accelerated cognitive decline: 8-year follow-up of 3140 older adults in Ireland. Eur J Clin Nutr 2022; 76(7): 950–957.

27.

Karimi Abadchi

, Nazari-Ahangarkolaee

, Gattas

, . Spatiotemporal patterns of neocortical activity around hippocampal sharp-wave ripples. Elife 2020; 9: e51972.

28.

Zuin

, Cervellati

, Brombo

, . Elevated blood homocysteine and risk of Alzheimer’s dementia: an updated systematic review and meta-analysis based on prospective studies. J Prev Alzheimers Dis 2021; 8(3): 329–334.

29.

Lauriola

, D’Onofrio

, Ciccone

, . Relationship of homocysteine plasma levels with mild cognitive impairment, Alzheimer’s disease, vascular dementia, psychobehavioral, and functional complications. J Alzheimers Dis 2021; 82(1): 235–248.

30.

Kim

and Lee

KJ.

Serum homocysteine levels are correlated with behavioral and psychological symptoms of Alzheimer’s disease. Neuropsychiatr Dis Treat 2014; 10: 1887–1896.

31.

Obeid

and Herrmann

Mechanisms of homocysteine neurotoxicity in neurodegenerative diseases with special reference to dementia. FEBS Lett 2006; 580(13): 2994–3005.

32.

Luzzi

, Cherubini

, Falsetti

, . Homocysteine, cognitive functions, and degenerative dementias: state of the art. Biomedicines 2022; 10(11): 2741.

33.

Wardlaw

JM.

Blood–brain barrier and cerebral small vessel disease. J Neurol Sci 2010; 299(1–2): 66–71.

34.

Scalabrino

The multi-faceted basis of vitamin B12 (cobalamin) neurotrophism in adult central nervous system: lessons learned from its deficiency. Prog Neurobiol 2009; 88(3): 203–220.

35.

Tangney

, Aggarwal

, Li

, . Vitamin B12, cognition, and brain MRI measures. Neurology 2011; 77(13): 1276–1282.

36.

McKhann

, Knopman

, Chertkow

, . The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 2011; 7(3): 263–269.

37.

Brickman

, Meier

, Korgaonkar

, . Testing the white matter retrogenesis hypothesis of cognitive aging. Neurobiol Aging 2012; 33(8): 1699–1715.