VITAMIN D AND COGNITION IN ELDERLY1
The Effects of Vitamin D on Cognition in the Elderly
Alyssa Gormaly
California Polytechnic State University
November 25, 2014
Alzheimer’s Disease
VITAMIN D AND COGNITION IN ELDERLY2
Alzheimer’s disease is a neurodegenerative disease that plagues a portion of the elderly.
This paper will review clinical trials that have examined the effects of sufficient serum vitamin D
levels on the risk for Alzheimer’s disease.
Disease Background
Alzheimer’s disease is a progressive brain disease that affects the memory and thinking
skills of as many as 5.1 million Americans. It is irreversible and most symptoms appear after age
sixty. It was named after Dr. Alois Alzheimer, who studied the brain tissue of a woman with an
“unusual mental illness”. He discovered what are now known as amyloid plaques and neurofibril-
lary tangles as well as a depletion of neuron connections, which are the main features of the dis-
ease. Those plaques and tangles are formed by an excess deposit of protein in the brain, causing
neurons to function less efficiently [1]. Over time, this spreads throughout the brain. The true
cause of Alzheimer’s disease has not yet been pinpointed.
Stages of Alzheimer ’ s Disease
In the preclinical stage of Alzheimer’s disease, the brain begins to make changes without
showing symptoms. The earliest symptoms can include abnormal memory loss, difficulty with
movement, trouble with word-finding, vision and spatial issues, and impaired reasoning or
judgement.
The patient then progresses into mild Alzheimer’s disease, whose symptoms include
worsening memory and cognitive abilities; this is a common time for the disease to be noticed
and diagnosed.
In moderate Alzheimer’s, memory loss and cognitive abilities grow even worse. The pa-
tient’s activities of daily living become impaired and he or she may find it difficult to recognize
friends and loved ones.
VITAMIN D AND COGNITION IN ELDERLY3
In the final stage of Alzheimer’s, the patient is entirely dependent on others for care. The
plaques and tangles have spanned the shrunken brain tissue. The body often shuts down at this
stage [1].
Risk Factors
The main risk factors associated with Alzheimer’s disease are age, genetics, environment,
and lifestyle. The most outstanding risk factor of the four is age. The risk for developing
Alzheimer’s disease will double every five years after the age of 65.
Scientists have also found a genetic linkages to Alzheimer’s. This can enable a person to
get early-onset Alzheimer’s as early as 30 years old. It is related to a mutation in one of three
genes. Researchers have found a multitude of gene mutations that can induce late-onset
Alzheimer’s. Currently, genetic screening is being used to make predictions about the likelihood
of a person getting early-onset Alzheimer’s if he or she has a significant enough family history
[29].
Researchers speculate the role of environmental factors in cognitive decline, such as
other conditions like stroke, obesity, vascular disease, high blood pressure, and diabetes. Studies
have found a positive correlation between these conditions and cognitive decline related to
Alzheimer’s disease.
Two major lifestyle factors that affect Alzheimer’s disease are diet and exercise. Moder-
ate exercise has been shown to promote blood circulation, reducing risk for cognitive decline and
dementia. Some clinical studies have even shown a short-term improvement in skills like plan-
ning, organizing, and decision-making in the elderly. Socialization and brain stimulation have
also been shown to affect cognition. In a study, researchers found that those elderly people who
VITAMIN D AND COGNITION IN ELDERLY4
engaged in social or stimulating activities like games, puzzles, and reading showed a forty-seven
percent lower risk of developing Alzheimer’s disease. [2]
Diet has also been shown to make a difference in cognition of the elderly. Some research
suggests that eating a Mediterranean diet is associated with a reduced risk of Alzheimer’s. An-
other study also showed that a Mediterranean diet in those who already had Alzheimer’s pro-
longed survival [2]. The foods which seemed to be most beneficial were nutrient-dense, crucifer-
ous vegetables for increased antioxidants, and those foods with omega-3 fatty acids to reduce
plaques. Additionally, diets high in vitamin E and C were linked to lower risk of developing
Alzheimer’s [3,4,5].
Prevalence in American Elderly
In 2005, 24.2 million people in the world had dementia, with a growing annual rate of 4.6
million of new cases. Approximately 70% of those cases were caused by Alzheimer’s disease.
Pictured above is a graph displaying the past and current data relevant to Alzheimer’s disease as
Projections of Alzheimer’s Disease Prevalence in the United States. [6]
VITAMIN D AND COGNITION IN ELDERLY5
well as projected estimates of where Alzheimer’s is headed in terms of prevalence. Though the
affected population increases through the years, it is important to keep in mind that these esti-
mates were also adjusted for the growing overall population. These estimates also included state-
ments about the status of these individuals, namely, that the majority of them would continue to
be female and no longer have a spouse to care for them due to females’ statistically longer life-
spans [7].
Vitamin D
Sources of Vitamin D
A study shows that adequate vitamin D levels are associated with the intake of whole
milk dairy products, red meat, and eggs [8]. The flesh of fatty fish, their oils, and vitamin-D-for-
tified foods also provide food bound sources. Supplementation can also increase levels of serum
vitamin D [9]. Another shows that increased sun exposure, lower BMI, and use of indoor tanning
all have a positive correlation with increased levels of vitamin D [10].
Vitamin D Inadequacy Risk in the Elderly
Elderly persons are more at risk for a vitamin D deficiency because, as they age, vitamin
D becomes harder to synthesize from sun exposure through the skin. This is only amplified by
the fact that many elderly people tend to spend much more time indoors than younger persons
due to lack of mobility with age. Their food intake of vitamin D is also likely to decrease be-
cause many older people tend to have trouble getting themselves to eat; their overall food intake
decreases, and therefore, their oral vitamin D intake tends to decrease [9].
Safety: Deficiency and UI Levels of Vitamin D
VITAMIN D AND COGNITION IN ELDERLY6
Safe intake levels are important in assessing the effects of vitamin D on the elderly so
that the individual is not prescribed too much to make up for deficiency or too little to promote
deficiency. Below is a table indicating the upper intake (UI) levels for vitamin D.
[28]
Vitamin D deficiency in the elderly is a common concern and is defined as a serum level
of <25-50 nmol/L [9]. The rates of deficiency in the elderly could be affected by a number of
things including the increased DRI for the elderly (200 additional IU by age 70), decreased ab-
VITAMIN D AND COGNITION IN ELDERLY7
sorption with age, inadequate dietary intake, or increased excretion. Vitamin D deficiencies are
especially common in those who omit the common sources of vitamin D listed previously from
their diets. With vitamin deficiency comes the risk for developing rickets and osteomalacia [11].
Vitamin D and Alzheimer’s Disease
Role of Vitamin D in Cognition
Upon being ingested, vitamin D remains essentially dormant until it is metabolized in the
liver, then the kidneys. It then takes the psychologically active form of vitamin D labeled
1,25(OH)2D3. This activated form promotes the regulation of gene transcription through vitamin
D receptors present in the brain [12,13]. 1,25(OH)2D3 produces biological effects 50+ different
tissues throughout the body [14]. Vitamin D receptors and the enzyme responsible for formation
of the active form of the vitamin in the brain [13] span neurons and glial cells in the parts of the
brain which are crucial for cognition [15, 16].
Amyloid beta is a known brain lesion seen in victims of Alzheimer’s disease. A study has
shown that the activated form of vitamin D will induce phagocytosis and clear the brain of amy-
loid beta [17]. In a study, introduction of the activated form to areas with amyloid beta protected
the neurons. It was seen to prevent cytotoxicity and cell death, while upregulating vitamin D re-
ceptors. 1,25(OH)2D3 treatment works against specific types of cell death in the hippocampal
cells, acting a neuroprotective mechanism [18].
Correlation Between Cognitive Dysfunction and Vitamin D Deficiency
Several studies across the globe have lent to the conclusion that vitamin D deficiency can
lead to cognitive decline. The results of a study done in the United States concluded that vitamin
D deficiency (serum level of <25 nmol/L) had a significant correlation with cognitive impair-
VITAMIN D AND COGNITION IN ELDERLY8
ment [19]. Another community sample in the United States found that those with vitamin D defi-
ciency were four times as likely to be cognitively impaired compared to those who had serum
levels of 75 nmol/L or greater [21].
A study done in France showed that women 75 or over participating in a trial who were
deficient in vitamin D were twice as likely to develop cognitive impairment in comparison to
those women who were not deficient [20]. A similar study done in England yielded the same re-
sults [22]. A six-year trial done in a population of 858 elderly Italians, deficient persons (<25
nmol/L) had an increased risk of cognitive decline in comparison to non-deficient persons [23].
A conducted trial assigning treatment of vitamin D to prevent cognitive decline resulted in the
finding that an improvement of cognitive function occurred in a small group of lean individuals
[24].
Clinical Trials of Alzheimer ’ s and Vitamin D Deficiency
A recent trial in the US was conducted using 1658 elderly persons. 102 of those partici-
pants developed Alzheimer’s disease. When tested, the serum levels of vitamin D of those who
developed Alzheimer’s was significantly lower. The study concluded that vitamin D deficiency is
associated with a substantial increase in risk for all-cause Alzheimer disease [25].
Another trial followed 498 women aged 75 or older for seven years. The results showed
that the women who developed Alzheimer’s were the ones with the lowest baseline vitamin D
levels. The study concluded that higher vitamin D intake is associated with a lower risk of devel-
oping Alzheimer’s disease among older women [30].
Another, less conclusive trial tested the serum vitamin D levels in 75 older persons in
Sweden. Some factors associated with Alzheimer’s disease, like amyloid-beta presence, were as-
VITAMIN D AND COGNITION IN ELDERLY9
sociated with the lowest serum vitamin D values. Other factors, like tau proteins (contributing to
tangles in the brain), were not significantly associated with the low vitamin D levels [32].
A longer longitudinal study followed 418 participants over thirty years. The study
grouped participants into 3 sections: those with severe deficiency (<25 nmol/L), moderate defi-
ciency (> 50 nmol/L), and sufficiency (> 75nmol/L). The study concluded that the more deficient
the individual was, the greater risk he or she had of developing Alzheimer’s disease [31].
Research Limitations
The variety of genetic makeup in trial participants plays a role in the standards of what is
considered “low” or “sufficient” serum vitamin D levels when using those numbers to suggest
risk for cognitive decline. Because one of the risk factors for Alzheimer’s is a specific genetic
mutation, one might not be deficient in vitamin D according to the standards, but that person’s
specific genetic sequence might put them at higher risk for Alzheimer’s. This type of occurrence
could have swayed the results of trials.
Assessments of the correlation between serum vitamin D levels and cognitive dysfunc-
tion have used different methods to measure serum vitamin D levels, such as competitive protein
binding assay, ELISA and liquid chromatography-tandem mass spectrometry. These different
methods have the potential to yield different results for the same set of data. Liquid chromatogra-
phy-tandem mass is currently seen as the most reliable method [26].
Another study speculates the idea of reverse causation, in which cognitive decline is the
cause of a vitamin D deficiency [27]. It is said that the severity of the disease could cause de-
creased mobility, lack of exposure to sunlight, and restricted intake of food and therefore vitamin
D.
Future Research
VITAMIN D AND COGNITION IN ELDERLY10
At this point, there is an ample amount of research, but more studies should be done over
long periods of time. Studies should also include a broad variety of people and a great amount of
people in order to draw conclusive data. Researchers should use the same, reliable standardized
methods to determine amounts of vitamin D. There is very little research on the affects of vita-
min D supplementation on the prevention of improvement of Alzheimer’s disease. More work
needs to be done to determine if supplementation has the same effects and ease of absorption as
food-bound sources and sunlight. Supplementation is a more convenient alternative for some el-
derly people and could make a positive difference if proven to be beneficial.
Conclusion
Much of recent research has determined a positive correlation between vitamin D defi-
ciency and increased risk for Alzheimer’s disease. There are still limitations in the research and
methods that could decrease the strength of the evidence shown, though the evidence is fairly
unanimous. Vitamin D deficiency is common in older adults and solidification in methods for
testing vitamin D sufficiency should be improved because recent research associates deficiency
with cognitive decline and Alzheimer’s disease.
References(1) National Institute of Health. Alzheimer's Disease Fact Sheet. National Institute on Aging. September, 2012. Available at http://www.nia.nih.gov/sites/default/files/alzheimers_disease_fact_sheet_0.pdf. Accessed November 18, 2014.
(2) National Institute of Health. Looking for the Causes of AD. National Institute on Aging. March 20, 2014. Available at http://www.nia.nih.gov/alzheimers/publication/part-3-ad-research-better-questions-new-answers/looking-causes-ad. Accessed November 18, 2014.
(3) Morris, M. C. et al. Dietary intake of antioxidant nutrients and the risk of incident Alzheimer disease in a biracial community study. JAMA 287, 3230-3237 (2002).
(4) Engelhart, M. J. et al. Dietary intake of antioxidants and risk of Alzheimer disease. JAMA 287, 3223-3229 (2002).
VITAMIN D AND COGNITION IN ELDERLY11
(5) Masaki, K. H. et al. Association of vitamin E and C supplement use with cognitive function and dementia in elderly men. Neurology 54, 1265-1272 (2000).
(6) Brookmeyer R, Gray S, Kawas C. Projections of Alzheimer’s disease in the United States and the public health impact of delaying disease onset. Am J Public Health. 1998;88:1337–1342.
(7) Reitz C, Mayeux R. Alzheimer disease: epidemiology, diagnostic criteria, risk factors and biomarkers. Biochem Pharmacol. 2014;88(4):640-51.
(8) Mcdonnell SL, French CB, Heaney RP. Quantifying the food sources of basal vitamin d in-put. J Steroid Biochem Mol Biol. 2014;144 Pt A:149-51.
(9) Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: National Academy Press, 2010.
(10) Mcdonnell SL, French CB, Heaney RP. Quantifying the non-food sources of basal vitamin D input. J Steroid Biochem Mol Biol. 2014;144 Pt A:146-8.
(11) Wharton B, Bishop N. Rickets. Lancet 2003;362:1389-400.
(12) DeLuca HF. Overview of general physiologic features and functions of vitamin D. Am J Clin Nutr 2004 Dec; 80 (6 Suppl.): 1689S-96S.
(13) Eyles DW, Smith S, Kinobe R, et al. Distribution of the vitamin D receptor and 1 alpha-hy-droxylase in human brain. J Chem Neuroanat 2005 Jan; 29 (1): 21-30
(14) Stumpf WE. Drug localization and targeting with receptor microscopic autoradiography. J Pharmacol Toxicol Methods 2005 Jan-Feb; 51 (1): 25-40
(15) Sutherland MK, Somerville MJ, Yoong LK, et al. Reduc- tion of vitamin D hormone recep-tor mRNA levels in Alzheimer as compared to Huntington hippocampus: correlation with cal-bindin-28k mRNA levels. Brain Res Mol Brain Res 1992 Apr; 13 (3): 239-50
(16) Zehnder D, Bland R, Williams MC, et al. Extrarenal ex- pression of 25-hydroxyvitamin d(3)-1 alpha-hydroxylase. J Clin Endocrinol Metab 2001 Feb; 86 (2): 888-94
(17) Masoumi A, Goldenson B, Ghirmai S, et al. 1alpha,25-dihy- droxyvitamin D3 interacts with curcuminoids to stimulate amyloid-beta clearance by macrophages of Alzheimer’s dis- ease pa-tients. J Alzheimers Dis 2009; 17 (3): 703-17
(18) Obradovic D, Gronemeyer H, Lutz B, et al. Cross-talk of vitamin D and glucocorticoids in hippocampal cells. J Neurochem 2006 Jan; 96 (2): 500-9
(19) Buell JS, Scott TM, Dawson-Hughes B, et al. Vitamin D is associated with cognitive func-tion in elders receiving home health services. J Gerontol A Biol Sci Med Sci 2009; 64 (8): 888-95
VITAMIN D AND COGNITION IN ELDERLY12
(20) Annweiler C, Schott AM, Allali G, et al. Association of vitamin D deficiency with cognitive impairment in older women: cross-sectional study. Neurology 2010; 74 (1): 27-32
(21) Llewellyn DJ, Lang IA, Langa KM, et al. Vitamin D and cognitive impairment in the el-derly U.S. population. J Gerontol A Biol Sci Med Sci 2011 Jan; 66 (1): 59-65
(22) Llewellyn DJ, Langa KM, Lang IA. Serum 25-hydroxy- vitamin D concentration and cogni-tive impairment. J Geriatr Psychiatry Neurol 2009; 22 (3): 188-95
(23) Llewellyn DJ, Lang IA, Langa KM, et al. Vitamin D and risk of cognitive decline in elderly persons. Arch Intern Med 2010; 170 (13): 1135-41
(24) Manders M, De Groot LC, Hoefnagels WH, et al. The effect of a nutrient dense drink on mental and physical function in institutionalized elderly people. J Nutr Health Aging 2009; 13 (9): 760-7
(25) Littlejohns TJ, Henley WE, Lang IA, et al. Vitamin D and the risk of dementia and Alzheimer disease. Neurology. 2014;83(10):920-8.
(26) LaiJK,LucasRM,ClementsMS,etal.AssessingvitaminD status: pitfalls for the unwary. Mol Nutr Food Res 2010 Aug; 54 (8): 1062-71
(27) Suzuki T, Murase S. Influence of outdoor activity and in- door activity on cognition decline: use of an infrared sensor to measure activity. Telemed J E Health 2010; 16 (6): 686-90
(28) Ross AC, Taylor CL, Yaktine AL, et al., editors. Dietary Reference Intakes for Calcium and Vitamin D. Washington (DC): National Academies Press (US), 2011.
(29) National Institute of Health. Risk Factors for Alzheimer’s Disease. National Institute on Ag-ing. March 21, 2014. Available athttp://www.nia.nih.gov/alzheimers/publication/preventing-alzheimers-disease/risk-factors-alzheimers-disease. Accessed November 18, 2014.
(30) Annweiler C, Rolland Y, Schott AM, et al. Higher vitamin D dietary intake is associated with lower risk of alzheimer's disease: a 7-year follow-up. J Gerontol A Biol Sci Med Sci. 2012;67(11):1205-11.
(31) Afzal S, Bojesen SE, Nordestgaard BG. Reduced 25-hydroxyvitamin D and risk of Alzheimer's disease and vascular dementia. Alzheimers Dement. 2014;10(3):296-302.
(32) Hooshmand B, Lökk J, Solomon A, et al. Vitamin D in relation to cognitive impairment, cerebrospinal fluid biomarkers, and brain volumes. J Gerontol A Biol Sci Med Sci. 2014;69(9):1132-8.