A Daily Dose of Vitamin D May Preserve Cognition in Ageing

The prevalence of dementia is increasing in line with the ageing of the UK population, making research into potential preventative measures fundamental in preserving quality of life for the elderly. It is frequently suggested that vitamin D may reduce risk of neurodegenerative diseases [1], yet a recent study by Olsson et al. found no association between vitamin D and incident dementia or cognitive impairment [2]. From evaluating the wider literature, particularly considering the quality of the published research, it has been found that there is not sufficient evidence to make a definite conclusion. Nonetheless, it could be said to be beneficial for all older adults to take a daily vitamin D supplement to prevent deficiency, which would have adverse effects on skeletal health, resulting in functional decline. This action may allow for neuroprotective effects attributed to vitamin D to also be obtained.

Dementia is a term that describes a set of symptoms that result from damage to the brain. The most common cause is Alzheimer’s disease (AD), but other dementias include vascular dementia, dementia with Lewy bodies and frontotemporal dementia [3]. Symptoms vary between dementias, but can be categorised as cognitive impairment, affecting memory, language, attention, thinking, orientation, calculation and problem-solving; psychiatric or behavioural disturbances, with changes in personality, emotional control, social behaviours, depression, agitation, hallucinations and delusions; and difficulties with activities of daily living (ADL) including driving, shopping, eating and dressing. Progressive degeneration tends to occur, with an increase in symptom severity over time and a gradual loss of independence [4], resulting in a significant health and social care burden and a reduction in quality of life for sufferers.

Age is the most common risk factor for the development of neurodegenerative diseases [5] so an increase in life expectancy predisposes individuals to dementia. Consequently, prevalence in the UK is predicted to rise from 850,000 in 2015 to over 1 million by 2025 [6]. Current treatments available are limited; they only help with the management of symptoms but do not prevent the onset of the causative diseases [3]. This makes research into potential mechanisms to slow cognitive decline and reduce incident dementia is invaluable.

Consumption of oily fish is frequently associated with brain health due to its omega-3 fatty acid content. However, studies investigating dietary supplementation with omega-3 have yielded variable results. It has therefore been suggested that other components of oily fish may also contribute to preservation of cognitive function and be a modulating factor that explains the conflicting data [7]. One nutrient of particular interest is vitamin D.    

Vitamin D can be obtained from both endogenous synthesis in the skin, where 7-dehydrocholesterol isomerises to cholecalciferol upon exposure to UVB radiation [1], or from dietary sources such as oily fish and fortified dairy products [8]. Hydroxylation in the liver by 25-hydroxylase forms 25-hydroxyvitamin D (25(OH)D) [9], which is biologically inert until activation (5) by 1-α-hydroxylase to calcitriol (1,25(OH)₂D) [8]. 1,25(OH)₂D has a genomic effect by binding to nuclear vitamin D receptors (VDRs) which interact with retinol X receptors to form heterodimers that bind to vitamin D response elements on DNA initiating a cascade that modulates gene transcription, and also has a non-genomic effect by binding to non-nuclear VDRs [5].

The primary role of vitamin D is in calcium and phosphorous homeostasis, stimulating an increase in calcium absorption in the intestines by calbindin synthesis and promoting deposition in bones [9]. However, VDRs are ubiquitous throughout the body and a number of tissues have 1-α-hydroxylase enzymes, suggesting the potential for 1,25(OH)₂D to have a local paracrine role [9], with it modulating immunity, cell growth and inflammation, cell proliferation, cell differentiation and cell death [8]. To relate this to cognitive function, VDRs and 1-α-hydroxylase have been located in neurons and glial cells throughout the central nervous system [10], particularly being expressed in regions for cognition such as the hippocampus, hypothalamus, cortex and subcortex [11].

Vitamin D enters the cerebrospinal fluid (CSF) by crossing the blood-CSF barrier in the plexus choroideus, and it enters the brain by passive diffusion across the blood brain barrier and by carriers in cerebral capillaries [11]. It has been stipulated to act as a neurosteroid hormone [12], offering neuroprotection via a number of mechanisms. In parallel to other tissues, 1,25(OH)₂D has a role in maintenance of calcium homeostasis [13], which prevents an increase in intracellular free calcium and the consequential impairment of brain function and memory formation, cell death [10], and stimulation of glutamate release [14]. It also prevents hyperparathyroidism, which has further neuropsychiatric and cognitive effects [13]. In addition, 1,25(OH)₂D is thought to regulate of synthesis of neurotransmitters such as dopamine, serotonin and γ-aminobutyric acid [11], increase acetylcholine availability by altering choline acytransferase activity [13], and enhance innate antioxidant pathways including upregulation of glutathione production [5], reducing reactive oxygen and nitrogen species and free radical damage to DNA and membrane lipids [13]. It has been shown to promote neurogenesis by controlling levels of neurotrophic agents including nerve growth factor, neurotrophin-3, which protects nerve transmission, and glial cell line derived neurotrophic factor, which affects the survival and differentiation of dopaminergic cells [5], as well as inhibiting synthesis of nitric oxide to reduce its associated neuronal cell alterations [10].

Further to this, 1,25(OH)₂D has been implicated to confer disease specific effects related to dementia. Low vitamin D is thought to be a cardiovascular risk factor [15] so may offer protection against vascular lesions [12] and vascular dementia. Whereas, in AD, stimulation of the innate immune system may increase clearance of amyloid-β 42 peptide by macrophage phagocytosis [12], reducing its accumulation and the formation of amyloid plaques. These plauqes cause inflammation, death of affected neurons and increased phosphorylation of Tau proteins, which subsequently disassemble from microtubules and aggregate to neurofibrillary tangles [13], causing neuronal degeneration, glutamatergic excitotoxicity, excessive calcium entry into post-synaptic neurons, neuronal necrosis and apoptosis [10], and cerebral atrophy. The brain to blood amyloid efflux may also be enhanced to further this effect [11]. 

The vast number of proposed neuroprotective effects of 1,25(OH)₂D suggests that vitamin D deficiency may be associated with risk of cognitive impairment and dementia. However, there are inconsistencies within the literature. A recent study by Olsson et al. investigated the association between baseline vitamin D status, measured by plasma 25(OH)D and intake from diet and supplements, with risk of dementia or cognitive impairment over an 18-year period [2]. This review will discuss their conclusions within the wider research to evaluate whether there is sufficient scientific evidence to consider vitamin D deficiency as a risk factor for cognitive decline and neurodegenerative diseases, and, consequently, whether there is rationale to encourage increasing intake from dietary sources, sun exposure and the use of supplements for this purpose.

Method

Study population

Data from the third investigation in the Uppsala Longitudinal Study of Adult Men was used, with age of subjects at this examination being 69-74 years. Baseline anthropometric and lifestyle measurements were taken.  

Vitamin D exposure

25(OH)D concentration was determined from fasting plasma samples, with season of collection recorded. A 7-day food record was completed with daily energy and nutrient intakes calculated with subjects with extreme reported intakes being excluded. Vitamin D supplement use was recorded and its contribution combined with dietary intake.

A genetic risk score (GRS) was calculated, reflecting the number of alleles associated with higher 25(OH)D concentrations in two single nucleotide polymorphisms.

Dementia and cognitive impairment assessment

A mini mental state examination (MMSE) was completed at baseline and at follow-up with low scoring subjects being referred to a memory clinic for dementia diagnosis. Medical records were reviewed to identify incident cases of AD, vascular dementia and all-cause dementia.

Cognitive impairment was defined as a decline of ≥3 points or a score at follow up of <25 points in the MMSE.

Statistical analysis

Plasma 25(OH)D was analysed as continuous variables and in predefined categories, and dietary vitamin D as continuous variables and in tertiles. The GRS was assessed as a continuous variable.

The associations between exposures and AD, vascular dementia and all-cause dementia were analysed using Cox proportional hazards regression, calculating time at risk from baseline examination until dementia diagnosis, death or end of follow-up. Potential non-linear trends between exposures and outcomes were investigated using restricted cubic splines.  

Results

Subject characteristics

Total follow-up time was 18 years. 116 cases of AD, 64 cases of vascular dementia and 250 cases of all-cause dementia were identified, and 16.4% of those completing the MMSE at follow-up were classified as cognitively impaired. Only 408 of the 863 men to complete the MMSE at baseline did so at follow-up.

Plasma 25(OH)D concentrations varied between season of sampling.

Results of statistical analysis

No association between plasma 25(OH)D and incident AD, vascular dementia, all-cause dementia or cognitive impairment was identified for either the continuous or categorised data, and no non-linear associations were observed. Total vitamin D intake was not associated with any of the outcomes.

The GRS was positively associated with plasma 25(OH)D concentration but not with incident dementia or cognitive impairment. 

Discussion

The study by Olsson et al. concluded that there was no association between plasma 25(OH)D and incident AD, vascular dementia or all-cause dementia [2]. There is much diversity within the wider literature, although a general skew against the findings of Olsson et al.. Littlejohns et al. observed a monotonic association between plasma 25(OH)D concentration and both risk of AD and all-cause dementia over 5.6 years of follow-up, as well as a link with cerebrovascular pathology, risk of stroke, and neurodegeneration due to vascular mechanisms [16]. Moreover, Annweiler et al. observed an association between vitamin D at baseline and the onset of non-AD dementia within 7 years, although no association with AD was found [17]. Similarly, MMSE score has been shown to correlate with 25(OH)D levels, where individuals classified as suffering from mild dementia had lower concentrations [18]. In contrast, although a smaller hippocampal volume was found in those with vitamin D deficiency in the Framingham Heart Study, no association with incident dementia or clinical AD was observed [19], and Littlejohns et al. reported no difference in the risk of development of cerebrovascular and neurodegenerative pathologies associated with dementia such as worsening white matter grade, or risk of ventricular or incident infarcts with serum 25(OH)D concentration [20]. A meta-analysis of five observational studies reporting risk of dementia to be higher in those with serious vitamin D deficiency compared to those with sufficiency, state that the strength of the evidence was low due to the lack of consideration of all important confounders [21]. Differences in adjustment in models may therefore provide some explanation as to the variation in the literature.  In addition, there is a high potential for reverse causality as, in more advanced cases, dementia can affect the ability to undertake ADLs such as cooking and eating, and may result in reduced sun exposure due to functional limitations [22]. This could imply that any positive associations between 25(OH)D concentrations and dementia may in fact be a reflection of poor health resulting from the causative diseases rather than vitamin D deficiency forming part of their aetiology.

In addition, Olsson et al. did not observe an association between dementia and total vitamin D intake from dietary and supplementary sources combined [2]. Annweiler et al. reported dietary intake and sun exposure at midday to be inversely associated with AD, with a 4 times decreased incidence for those with highest vitamin D consumption [7], whereas Rossom et al. reported no difference in incident dementia between placebo and treatment groups, where a combined calcium carbonate and vitamin D3 supplement was provided containing 400IU of vitamin D3 [23]. It could be that dietary but not supplemented vitamin D may confer neuroprotective effects, potentially due to the effects of additional nutrients in vitamin D rich foods such as omega 3 fatty acids in oily fish, but also that cognitively impaired individuals may provide unreliable data in food frequency questionnaires, causing inaccurate results. Moreover, the supplemented dose of vitamin D may not have been sufficient to affect cognitive functioning, and its combination with calcium may have attenuated any effect that may result from supplementation of vitamin D alone. The small number of studies considering intake of vitamin D as opposed to plasma 25(OH)D concentration limits the ability to make any evaluation of its potential direct role. Nonetheless, it is thought that 25(OH)D is a good indicator of vitamin D stores due to its 2-3 week half-life, and reflects both diet and sun exposure [8], meaning that taking supplements or increasing dietary intake to optimise serum 25(OH)D may be of benefit, yet supraphysiological doses may not.

The study by Olsson et al. also considered cognitive impairment as a secondary outcome, although no association was observed with vitamin D intake or serum 25(OH)D concentration [2]. The reasonably consistent conclusions within the literature regarding this association, contrasting that made by Olsson et al., indicates that the study method may have biased the data. Cognitive decline was measured as a change in MMSE, but only in those healthy enough to attend examinations at baseline and follow-up, potentially resulting in the ‘healthy cohort effect’, where subjects included in this analysis were not representative of the true population.

The wider literature generally reports lower levels of 25(OH)D to be associated with greater cognitive decline within an elderly population in cross-sectional analyses [12][22][24][25][26][27][28], with a systematic review by van der Schaft et al. found 18 of 25 cross-sectional studies to report worse performance in one or more cognitive tests by those with low vitamin D [29]. However, the nature of these studies means results may be explained by reverse causation, although the effect may be less significant for those with mild cognitive impairment than individuals with dementia [12]. In addition, many of these studies were conducted at a memory assessment clinic or within those with subjective memory complaints, suggesting the likelihood of diagnosis of mild cognitive impairment to be higher than within the general elderly population. Despite this, the same systematic review reported 4 of 6 prospective studies concluding that there was a greater risk of cognitive decline at follow up for those with low 25(OH)D at baseline [29]. The follow-up time for these was only between 4 and 7 years, yet the study by Olsson et al. spanned 18 years. In this instance, it may be that taking only one measurement of 25(OH)D at baseline resulted in misclassification of individuals as serum concentration could vary considerably throughout an 18 year period.

To specify its effects on neuronal function further, many studies have considered the association between serum 25(OH)D and domain-specific cognitive performance. Most frequently, low 25(OH)D is related to poorer executive function [30][31][32], as well as processing speed [15][33] and visual perceptual skills [19]. However, the only associations observed with memory tend to be for working memory [30][34][35], and the broad findings are that there is no association with memory performance [32][33][36]. This suggests that any potential link with dementias such as AD would be driven by non-amnestic cognitive decline [36].

In contrast to the previously discussed correlations observed between serum 25(OH)D and cognitive performance, where lowest concentrations indicate worse outcomes, two studies found have reported subjects in the middle categories of serum 25(OH)D to have lower odds of cognitive impairment than both the highest and lowest [37][38]. Granic et al. observed that those in the highest category of serum 25(OH)D concentration were more likely to be taking prescribed vitamin D and have osteoporosis [38], which may imply that those subjects are potentially less healthy and at greater risk of cognitive decline than those with moderate serum concentrations. Studies observing no association between vitamin D status and cognition may have been similarly affected, with both healthy and unhealthy individuals being categorised in the highest group. With inadequate adjustment for covariates there would be the potential for this to attenuate any positive association that may exist. 

Finally, Olsson et al. observed no association between two genetic variants involved in vitamin D synthesis and incidence of dementia or cognitive impairment [2]. The two alleles considered were in the 7-dehydrocholesterol reductase gene and the vitamin D 25-hydroxylase gene. Conversely, Pettersen et al. found there to be no significant difference in vitamin D intake from food or supplements, nor difference in sun exposure within subjects, yet serum 25(OH)D concentrations varied. It was therefore suggested that other mediators of vitamin D level such as VDR genotype may have a role in cognition [30]. Gezen-Ak et al. reported an association between the ApaI gene polymorphism in the VDR ligand binding site and late onset AD [39], suggesting interindividual differences in the response to 1,25(OH)₂D may influence its effects. Moreover, Kueider et al. observed an association between cognitive decline and single nucleotide polymorphisms in the GC gene, which encodes for the 25(OH)D carrier protein, [32], suggesting that individuals with greater susceptibility to low bioavailability of vitamin D metabolites to target cells may affect the association between serum 25(OH)D and cognitive outcome. It may therefore be that a lack of adjustment for such polymorphisms results in inconclusive or incorrect conclusions being obtained in both cross-sectional and prospective studies.

Impacts

Discussion of the null findings in the study by Olsson et al. [2] has found that there are great inconsistencies within the literature regarding the role of vitamin D in dementia risk, and opposing but potentially inaccurate observations with regards to association with cognitive impairment. This, as well as the significant heterogeneity between studies as a result of variation in diagnostic criteria, methods of assessing cognition, vitamin D thresholds and choice of subjects [40], makes it challenging to reach a well evidenced conclusion. The potential for reverse causality cannot be disregarded as a significant factor in cross-sectional studies, which comprise the majority of those published. Nonetheless, combining the observations in human studies with findings from animal or in vitro investigations into the neuroprotective mechanisms of vitamin D, it could be suggested that there may be some benefit from ensuring all individuals at least reach sufficiency [13].

It has been estimated that 1 in 2 older adults suffer from vitamin D deficiency [11]. The cause is multifactorial, with lack of sun exposure, low dietary intake, accelerated losses by medication induced catabolism, impaired hepatic and renal metabolism, reduced bioavailability by malabsorption and sequestration in fat being major mechanisms [41]. However, most significantly for the elderly, the 25% reduction in epidermal 7-dehydrocholesterol compared to younger adults greatly decreases the capacity for endogenous synthesis, as does reduced sun exposure from functional decline [42]. Owing to there being few dietary sources of vitamin D, mainly being obtained from oily fish such as salmon, mackerel and tuna, and from vitamin D fortified dairy products, if a strong association were to exist between serum 25(OH)D and cognitive function, regular supplementation would be the most appropriate public health approach.

The rarity of vitamin D toxicity due to the physiological regulation of its formation and metabolism [8], the proven role of vitamin D in skeletal health and prevalence of deficiency within the demographic most at risk of cognitive decline and dementia, means it could be said that all older adults should consider taking a daily vitamin D supplement, as per current UK guidelines. This would aim to prevent the adverse effects of deficiency such as osteomalacia, osteoporosis and hyperparathyroidism [42], yet may also potentially minimise rate of cognitive decline, onset of dementia and the resulting loss of independence.  

---

[1] Linus Pauling Institute. (2014) Vitamin D. URL: http://lpi.oregonstate.edu/mic/vitamins/vitamin-D.

[2] Olsson, E., Byberg, L., Karlström, B., Cederholm, T., Melhus, H., Sjögren, P. & Kilander, L. (2017). Vitamin D is not associated with incident dementia or cognitive impairment: an 18-y follow-up study in community-living old men.

[3] Alzheimer's Research UK. (2017). 10 things you need to know about dementia. URL: http://www.alzheimersresearchuk.org/about-dementia/facts-stats/10-things-you-need-to-know-about-dementia/.

[4] Alzheimer's Society. (2016a). What is dementia? URL: https://www.alzheimers.org.uk/info/20007/types_of_dementia/1/what_is_dementia.

[5] Buell, J. S. & Dawson-Hughes, B. (2008). Vitamin D and neurocognitive dysfunction: Preventing "D"ecline? Molecular Aspects of Medicine, 29 (6), 415-422.

[6] Alzheimer's Society. (2016a). Dementia UK. URL: https://www.alzheimers.org.uk/info/20025/policy_and_influencing/251/dementia_uk.

[7] Annweiler, C., Rolland, Y., Schott, A. M., Blain, H., Vellas, B., Herrmann, F. R. & Beauchet, O. (2012). Higher Vitamin D Dietary Intake Is Associated With Lower Risk of Alzheimer's Disease: A 7-Year Follow-up. Journals of Gerontology Series a-Biological Sciences and Medical Sciences, 67 (11), 1205-1211.

[8] Haines, S. T. & Park, S. K. (2012). Vitamin D Supplementation: What's Known, What to Do, and What's Needed. Pharmacotherapy, 32 (4), 354-382.

[9] Barnard, K. & Colon-Emeric, C. (2010). Extraskeletal Effects of Vitamin D in Older Adults: Cardiovascular Disease, Mortality, Mood, and Cognition. American Journal of Geriatric Pharmacotherapy, 8 (1), 4-33.

[10] Downey, C. L., Young, A., Burton, E. F., Graham, S. M., Macfarlane, R. J., Tsapakis, E. M. & Tsiridis, E. (2017). Dementia and osteoporosis in a geriatric population: Is there a common link? World Journal of Orthopedics, 8 (5), 412-423.

[11] Annweiler, C., Allali, G., Allain, P., Bridenbaugh, S., Schott, A. M., Kressig, R. W. & Beauchet, O. (2009). Vitamin D and cognitive performance in adults: a systematic review. European Journal of Neurology, 16 (10), 1083-1089.

[12] Annweiler, C., Schott, A. M., Allali, G., Bridenbaugh, S. A., Kressig, R. W., Allain, P., Herrmann, F. R. & Beauchet, O. (2010). Association of vitamin D deficiency with cognitive impairment in older women Cross-sectional study. Neurology, 74 (1), 27-32.

[13] Annweiler, C. & Beauchet, O. (2011). Vitamin D-Mentia: Randomized Clinical Trials Should Be the Next Step. Neuroepidemiology, 37 (3-4), 249-258.

[14] Annweiler, C., Rolland, Y., Schott, A. M., Blain, H., Vellas, B., Herrmann, F. R. & Beauchet, O. (2012). Higher Vitamin D Dietary Intake Is Associated With Lower Risk of Alzheimer's Disease: A 7-Year Follow-up. Journals of Gerontology Series a-Biological Sciences and Medical Sciences, 67 (11), 1205-1211.

[15] Annweiler, C., Maby, E., Meyerber, M. & Beauchet, O. (2014). Hypovitaminosis D and Executive Dysfunction in Older Adults with Memory Complaint: A Memory Clinic-Based Study. Dementia and Geriatric Cognitive Disorders, 37 (5-6), 286-293.

[16] Littlejohns, T. J., Henley, W. E., Lang, I. A., Annweiler, C., Beauchet, O., Chaves, P. H. M., Fried, L., Kestenbaum, B. R., Kuller, L. H., Langa, K. M., Lopez, O. L., Kos, K., Soni, M. & Llewellyn, D. J. (2014). Vitamin D and the risk of dementia and Alzheimer disease. Neurology, 83 (10), 920-928.

[17] Annweiler, C., Rolland, Y., Schott, A. M., Blain, H., Vellas, B. & Beauchet, O. (2011). Serum Vitamin D Deficiency as a Predictor of Incident Non-Alzheimer Dementias: A 7-Year Longitudinal Study. Dementia and Geriatric Cognitive Disorders, 32 (4), 273-278

[18] Peterson, A., Mattek, N., Clemons, A., Bowman, G. L., Buracchio, T., Kaye, J. & Quinn, J. (2012). Serum vitamin d concentrations are associated with falling and cognitive function in older adults. Journal of Nutrition Health & Aging, 16 (10), 898-901.

[19] Karakis, I., Pase, M. P., Beiser, A., Booth, S. L., Jacques, P. F., Rogers, G., DeCarli, C., Vasan, R. S., Wang, T. J., Himali, J. J., Annweiler, C. & Seshadri, S. (2016). Association of Serum Vitamin D with the Risk of Incident Dementia and Subclinical Indices of Brain Aging: The Framingham Heart Study. Journal of Alzheimers Disease, 51 (2), 451-461.

[20] Littlejohns, T. J., Kos, K., Henley, W. E., Lang, I. A., Annweiler, C., Beauchet, O., Chaves, P. H. M., Kestenbaum, B. R., Kuller, L. H., Langa, K. M., Lopez, O. L. & Llewellyn, D. J. (2016). Vitamin D and Risk of Neuroimaging Abnormalities. Plos One, 11 (5).

[21] Sommer, I., Griebler, U., Kien, C., Auer, S., Klerings, I., Hammer, R., Holzer, P. & Gartlehner, G. (2017). Vitamin D deficiency as a risk factor for dementia: a systematic review and meta-analysis. BMC Geriatr, 17.

[22] Perna, L., Mons, U., Kliegel, M. & Brenner, H. (2014). Serum 25-Hydroxyvitamin D and Cognitive Decline: A Longitudinal Study among Non-Demented Older Adults. Dementia and Geriatric Cognitive Disorders, 38 (3-4), 254-263.

[23] Rossom, R. C., Espeland, M. A., Manson, J. E., Dysken, M. W., Johnson, K. C., Lane, D. S., LeBlanc, E. S., Lederle, F. A., Masaki, K. H. & Margolis, K. L. (2012). Calcium and Vitamin D Supplementation and Cognitive Impairment in the Women's Health Initiative. Journal of the American Geriatrics Society, 60 (12), 2197-2205.

[24] Matchar, D. B., Chei, C. L., Yin, Z. X., Koh, V., Chakraborty, B., Shi, X. M. & Zeng, Y. (2016). Vitamin D Levels and the Risk of Cognitive Decline in Chinese Elderly People: the Chinese Longitudinal Healthy Longevity Survey. Journals of Gerontology Series a-Biological Sciences and Medical Sciences, 71 (10), 1363-1368.

[25] Chei, C. L., Raman, P., Yin, Z. X., Shi, X. M., Zeng, Y. & Matchar, D. B. (2014). Vitamin D Levels and Cognition in Elderly Adults in China. Journal of the American Geriatrics Society, 62 (11), 2125-2129.

[26] Moon, J. H., Lim, S., Han, J. W., Kim, K. M., Choi, S. H., Kim, K. W. & Jang, H. C. (2015). Serum 25-hydroxyvitamin D level and the risk of mild cognitive impairment and dementia: the Korean Longitudinal Study on Health and Aging (KLoSHA). Clinical Endocrinology, 83 (1), 36-42.

[27] Przybelski, R. J. & Binkley, N. C. (2007). Is vitamin D important for preserving cognition? A positive correlation of serum 25-hydroxyvitamin D concentration with cognitive function. Archives of Biochemistry and Biophysics, 460 (2), 202-205.

[28] Vedak, T. K., Ganwir, V., Shah, A. B., Pinto, C., Lele, V. R., Subramanyam, A., Shah, H. & Deo, S. S. (2015). Vitamin D as a marker of cognitive decline in elderly Indian population. Annals of Indian Academy of Neurology, 18 (3), 314-319.

[29] van der Schaft, J., Koek, H. L., Dijkstra, E., Verhaar, H. J. J., van der Schouw, Y. T. & Emmelot-Vonk, M. H. (2013). The association between vitamin D and cognition: A systematic review. Ageing Research Reviews, 12 (4), 1013-1023.

[30] Pettersen, J. A., Fontes, S. & Duke, C. L. (2014). The Effects of Vitamin D Insufficiency and Seasonal Decrease on Cognition. Canadian Journal of Neurological Sciences, 41 (4), 459-465

[31] Pettersen, J. A. (2016). Vitamin D and executive functioning: Are higher levels better? Journal of Clinical and Experimental Neuropsychology, 38 (4), 467-477.

[32] Kueider, A. M., Tanaka, T., An, Y., Kitner-Triolo, M. H., Palchamy, E., Ferrucci, L. & Thambisetty, M. (2016). State- and trait-dependent associations of vitamin-D with brain function during aging. Neurobiology of Aging, 39, 38-45.

[33] Buell, J. S., Scott, T. M., Dawson-Hughes, B., Dallal, G. E., Rosenberg, I. H., Folstein, M. F. & Tucker, K. L. (2009). Vitamin D Is Associated With Cognitive Function in Elders Receiving Home Health Services. Journals of Gerontology Series a-Biological Sciences and Medical Sciences, 64 (8), 888-895.

[34] Maddock, J., Geoffroy, M. C., Power, C. & Hypponen, E. (2014). 25-Hydroxyvitamin D and cognitive performance in mid-life. British Journal of Nutrition, 111 (5), 904-914.

[35] Assmann, K. E., Touvier, M., Andreeva, V. A., Deschasaux, M., Constans, T., Hercberg, S., Galan, P. & Kesse-Guyot, E. (2015). Midlife plasma vitamin D concentrations and performance in different cognitive domains assessed 13 years later. British Journal of Nutrition, 113 (10), 1628-1637.

[36] Kuzma, E., Soni, M., Littlejohns, T. J., Ranson, J. M., van Schoor, N. M., Deeg, D. J. H., Comijs, H., Chaves, P. H. M., Kestenbaum, B. R., Kuller, L. H., Lopez, O. L., Becker, J. T., Langa, K. M., Henley, W. E., Lang, I. A., Ukoumunne, O. C. & Llewellyn, D. J. (2016). Vitamin D and Memory Decline: Two Population-Based Prospective Studies. Journal of Alzheimers Disease, 50 (4), 1099-1108.

[37] Llewellyn, D. J., Langa, K. M. & Lang, I. A. (2009). Serum 25-Hydroxyvitamin D Concentration and Cognitive Impairment. Journal of Geriatric Psychiatry and Neurology, 22 (3), 188-195

[38] Granic, A., Hill, T. R., Kirkwood, T. B. L., Davies, K., Collerton, J., Martin-Ruiz, C., von Zglinicki, T., Saxby, B. K., Wesnes, K. A., Collerton, D., Mathers, J. C. & Jagger, C. (2015). Serum 25-hydroxyvitamin D and cognitive decline in the very old: the Newcastle 85+Study. European Journal of Neurology, 22 (1), 106-+.

[39] Gezen-Ak, D., Dursun, E., Ertan, T., Hanagasi, H., Guervit, H., Emre, M., Eker, E., Oztuerk, M., Engin, F. & Yilmazer, S. (2007). Association between vitamin D receptor gene polymorphism and Alzheimer's disease. Tohoku Journal of Experimental Medicine, 212 (3), 275-282.

[40] Etgen, T., Sander, D., Bickel, H., Sander, K. & Forstl, H. (2012). Vitamin D Deficiency, COgnitive Impairment and Dementia: A Systematic Review and Meta-Analysis. Dementia and Geriatric Cognitive Disorders, 33 (5), 297-305. 

[41] Podd, D. (2015). Hypovitaminosis D: A common deficiency with pervasive consequences. Jaapa-Journal of the American Academy of Physician Assistants, 28 (2), 20-26.

[42] Annweiler, C. & Beauchet, O. (2014). Vitamin D in older adults: the need to specify standard values with respect to cognition. Frontiers in Aging Neuroscience, 6.