Zinc deficiency in alzheimer’s disease: a cross-sectional study with a control group

Abstract

Objective

To identify whether there is a difference in plasma and erythrocyte zinc concentration in older adults with and without Alzheimer's disease.

Methods

Crosssectional study with a comparative group, conducted with older adults with and without Alzheimer's disease, matched by sex, education, and age. Zinc concentration was measured by atomic absorption spectrophotometry in a graphite furnace.

Results

There were 102 people, 68 in the healthy group (NDA-g) and 34 in the group with disease (AD-g). The AD-g group had lower plasma zinc concentrations and higher frequency in the first quartile for intraerythrocyte zinc concentrations. Plasma and erythrocyte concentrations did not correlate with the time of diagnosis and age in both groups. In the logistic regression analysis, plasma concentration was associated with AD-g (OR=0.964; p=0.028).

Conclusion

Older people with Alzheimer's disease have lower plasma and erythrocyte zinc concentrations.

Keywords
Zinc; Alzheimer's disease; Cognitive Dysfunction

Resumo

Objetivo

Identificar se há diferença na concentração plasmática e eritrocitária de zinco na pessoa idosa com e sem a doença de Alzheimer.

Métodos

Estudo transversal com grupo comparação, realizado com pessoas idosas com e sem doença de Alzheimer, pareadas por sexo, escolaridade e idade. A concentração de zinco foi medida através de espectrofotometria de absorção atômica em forno grafite.

Resultados

Total de 102 pessoas, 68 no grupo saudável (NDA-g) e 34 o grupo com doença (DA-g). O grupo DA-g apresentou menores concentrações plasmáticas e maior frequência no primeiro quartil para concentrações intraeritrocitárias de zinco. As concentrações plasmáticas e eritrocitárias não apresentaram correlação com tempo de diagnóstico e a idade em ambos os grupos. Na análise de regressão logística, a concentração plasmática esteve associada à DA-g (OR=0,964; p=0,028).

Conclusão

Pessoas idosas com doença de Alzheimer apresentam menores concentrações plasmáticas e eritrocitárias de zinco.

Palavras-Chave:
Zinco; Doença de Alzheimer; Disfunção cognitiva

INTRODUCTION

Alzheimer's disease (AD) is a complex pathological process since environmental, metabolic, genetic, dietary, and vascular factors are associated with its development. There is a trend of increasing the prevalence of AD and a potential decrease in the quality of life of older adults because they are an important risk group for this disease¹.

Although age is the main associated factor, other factors pose an indirect risk for AD, such as hypertension, diabetes, and stroke. Physical activity, mentally demanding activities, and ingesting of certain foods establish a protective relationship against the disease². In Brazil, epidemiological studies on AD are still advancing slowly³.

Despite several recognized causes, the exact etiology of AD development and progression still needs to be established. Oxidative stress is an early process that favors its development and is sustained over the years, promoting the more rapid progression of AD⁴.

The homeostasis of some metals, such as zinc (Zn), can increase reactive oxygen and nitrogen species (RONS) and the accumulation of β-amyloid (Aβ) plaques. Aβ is an extracellular deposit of insoluble aggregates of a beta-amyloid protein capable of promoting neuronal dysfunction, oxidation, excitotoxicity, and neuroinflammation, responsible for apoptosis in central nervous system (CNS) cells, contributing to AD in a feedback loop⁴,⁵.

The Aβ peptide accumulation seems to induce oxidative stress in the CNS, causing neurodegeneration and contributing to AD⁴,⁵. In addition, low plasma concentrations of Zn were observed in older adults with cognitive impairment or dementia compared with healthy older adults. However, there is no consensus on Zn homeostasis and the development or progression of AD⁶,⁷.

Zn is essential for the maintaining of several metabolic pathways and functions as an enzyme cofactor for more than 300 enzymes, especially those related to energy metabolism and oxidative stress in the CNS. Thus, it is suggested that the deficiency in the concentrations of this nutrient may cause the onset of chronic diseases in older adults, promote oxidative stress, and contribute to AD progression⁸.

Zn accumulation has been observed in AD patients' brains and is linked to Aβ plaques, responsible for the synaptic dysfunction seen in these patients. This dyshomeostasis may play a critical role in AD progression¹.

If, on the one hand, the low metal concentration can favor oxidative stress, increase the production of RONS, and favor Aβ plaques formation, on the other hand, the accumulation of Aβ peptides can cause Zn retention in the CNS and contribute to the impairment of Zn homeostasis and promote AD⁴,⁹.

Given the above, it is important to note that regions where social inequalities are evident and many older people live in food insecurity, such as the north and northeast of Brazil, have relevant rates of micronutrient deficiencies that favor the onset of various diseases and cognitive impairment, such as zinc, iron, and selenium¹⁰. It should also be noted that these regions have shown an increasing frequency and greater annual percentage variation in mortality rates due to AD over the last 20 years³, factors which justify this research.

Thus, Zn deficiency and excess may be associated with impaired neuronal cellular activities. The results of this research may contribute to the understanding of factors that can trigger the development of AD or to its evolution, helping researchers and professionals in geriatrics and gerontology in the result of actions to prevent the onset of the disease and contributing to science to the elucidation of pathophysiological processes that favor AD.

The present study aims to determine possible differences in Zn concentrations in plasma and erythrocytes in older adults with and without AD and understand Zn homeostasis in older adults with and without AD.

METHODS

Cross-sectional study with a comparison group and hospital-based, with a sample composed of older adults aged >60 years, seen at the Gerontology Nutrition Outpatient Clinic of the Nutrition School of the Federal University of Alagoas - Brazil, from April 5, 2017, to July 30, 2018, using the STROBE tool as a guide (Strengthening the Reporting of Observational Studies in Epidemiology).

For the sample size calculation, it was observed the mean value ± standard deviation of plasma Zn concentrations observed in a pilot project, in addition to significant mean differences of serum Zn concentrations in original published studies with Alzheimer’s patients⁷. Thus, considering the significance level of 5% and power of 90%, the expected sample size for comparison of the two proportions of 34 patients for the Alzheimer’s disease group (AD-g) and 68 for the comparison group without the AD (NAD-g) was defined (two controls for each case - 1:2 ratio).

After evaluating and diagnosing the disease, The AD-g group met the study's inclusion criteria, referred by a geriatrician. The NAD-g was composed of healthy older adults, preferably referred by the patient or caregiver, or by older adults already seen by the same geriatrician, provided they did not present criteria for AD-g, were evaluated by the same professional, and met the pairing criteria (age ± five years). The study included older adult subjects of both genders, over 60 years, and residents of Maceió and the metropolitan region - Alagoas.

The inclusion criteria for the study were: no nutritional Zn supplementation; no metabolic diseases known to compromise the metabolism of this mineral; and a probable diagnosis of Alzheimer’s disease as defined by a medical specialist for the AD-g, and no cognitive impairment, also evaluated by a geriatrician, for the NAD-g.

All data was collected using a previously established questionnaire applied during the first consultation. All the information on older adults with AD was provided with the help of the caregiver or family member, while in the NAD-g, the individual answered the research questions.

The sociodemographic variables collected were age, education, income, housing conditions, marital status, and occupation. Age was categorized as 60 to 69 years, 70 to 79 years, and ≥80 years; education as <5 years and ≥5 years of study; and family income stratified by the Brazilian minimum wage (BMW) in effect in 2018, categorized as ≤1BMW and >1BMW. The occupation was classified as retired/with fixed monthly income or unemployed/without income.

The participant's body mass was determined using a digital scale (200 kg capacity and 50g precision)¹¹. Height was obtained using a portable stadiometer (Seca®), graduated in tenths of centimeters, and affixed on a flat surface¹².

The Body Mass Index (BMI), calculated by the ratio between body mass and the square of height, was used to classify the individual's nutritional status. The nutritional status classification followed criteria considering eutrophic the BMI values between 22 and 27kg/m²; lean, BMI < 22kg/m²; and overweight, BMI >27kg/m²¹³.

A geriatrician made the diagnosis of probable Alzheimer’s disease based on the criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association (NINCDS - ADRDA) and the National Institute on Aging-Alzheimer’s Association ¹⁴,¹⁵. The time of diagnosis of the disease was counted from the first day of recording the diagnosis in medical records.

The cognitive ability assessment in both groups was performed using the Mini Mental State Examination (MMSE)¹⁶ on the first day of admission to this research by a trained researcher.

For analysis of hemoglobin (Hb), plasma, and erythrocyte Zn concentrations, 6 mL of blood were collected in vacuum tubes (Vacutainer® BD) with EDTA after a minimum fasting period of 8 hours. The aliquots were centrifuged at 3,000 rpm for 15 minutes to obtain the erythrocyte mass and plasma. After plasma removal, the red cell mass was washed with 0.9% saline solution and centrifuged in triplicate at 10,000 rpm for 10 minutes. Plasma and erythrocyte concentrations were fractionated and stored at -22 °C until analysis.

Zn concentrations were determined by atomic absorption spectrophotometry in a graphite furnace, with Zeeman background correction, in Spectra AA 240Z (Varian®), following the manufacturer's recommendations. Measurements were performed in three readings with an integration time of 3 seconds. The plasma Zn concentration was determined according to Rodriguez and collaborators¹⁷, and the erythrocyte count was performed after plasma separation according to Whitehouse and collaborators¹⁸. The Zn standard used was 1g/L of Titrisol ® (Merck). Values lower than 65 µg/dL were considered indicative of Zn deficiency¹⁹.

For the absence of a previously established cutoff point, intracellular Zn concentrations were stratified by quartile of the study population itself; the 1st quartile value, used for deficiency determination, was 32 μgZn/gHb. To express the results, in terms of the mass of Zn/hemoglobin, a 20 μL aliquot of red cell lysate was used to determine hemoglobin concentration using the cyanmethemoglobin method of the Labtest Diagnostica kit ²⁰.

The statistical analyses were performed considering the nature of the probability distribution of the variables studied, verified by applying the Kolmogorov-Smirnov Test with Lilliefors correction and their classification and experimental design. The level of rejection of the null hypothesis was set at 5%.

For discrete/count variables, absolute (n) and relative (%) frequencies were calculated, and proportions were compared using Pearson's Chi-square Test or Fisher's exact Test. For continuous variables, measures of central tendency (mean or median) and dispersion/position (standard deviation or interquartile ranges) were used; differences in means between the two groups were evaluated by Student's T-Test and the respective nonparametric Mann-Whitney Test. The magnitude of the association between exposure and outcome was assessed using the odds ratio (OR) or its respective confidence interval (CI 95%).

To model the association of Alzheimer’s disease as a function of body Zn stores (plasma and erythrocyte concentrations) and other possible confounding variables, the GLM (generalized linear models; binomial family) method adjusted for the variables gender, age, and education was adopted.

To choose the multiple linear regression model that suitably fits the relationship between zinc (plasma and erythrocyte) and cognitive impairment assessed by the MMSE, the method of ordinary least squares (MQO) in the backward option was adopted. Thus, a model composed of all explanatory variables for the outcome AD was adopted until a best-fit model was obtained, respecting the assumptions of normality of residuals, homoscedasticity, and absence of multicollinearity, in addition to the quality of adjustment by the adjusted determination coefficient (R_adj ²).

A logistic regression model was proposed to investigate probable associations between AD diagnosis and the independent variables. AD diagnosis was the dependent variable in these analyses, while plasma and erythrocyte Zn concentrations were the independent variables. A p-value <0.05 was considered significant in all tests.

The study was developed following the recommendations of Resolution 466/2012 of the National Health Council of Brazil and Resolution No. 510/2016. The Research Ethics Committee approved the opinion of the Federal University of Alagoas, Brazil with CAAE no. 19199013.3.0000.5013. Eligible patients and study participants signed the Informed Consent Form.

RESULTS

The sample was composed of 102 older adults, 34 AD-g, and 68 NAD-g. The mean age in the NAD-g was 71.46 +5.1 years, and in the AD-g was 74.41 +7.1 years, with a higher frequency between 70 and 79 years in both groups (p >0.05). The number of years of education (<5 years) was associated with the presence of AD, increasing by approximately 3.2 times the chance that older adults had the disease (table 1).

Table 1
Sociodemographic characterization and health conditions of older adults with and without Alzheimer's disease, Maceió– Alagoas, 2018.

	NAD-g		AD-g
	n (%)		n (%)		OR	p-value
Gender
Male	15 (22.1)		12 (35.3)		0.51	0.153*
Female	53 (77.9)		22 (64.7)
Age (Years)
60 – 69 years	30 (44.2)		12 (35.3)		-	0.585*
70 – 79 years	36 (52.9)		20 (58.8)
80 or more	2 (2.9)		2 (5.9)
Marital status
Married/ stable union	40 (58.8)		24 (70.6)		0.59	0.247*
Single/ divorced/ widowed	28 (41.2)		10 (29.4)
Labor situation
Retired or with income	64 (94.1)		32 (94.1)		1.00	1.00**
Unemployed / No income	4 (5.9)		2 (5.9)
Income
> 1 BMW	39 (57.3)		24 (70.6)		0.56	0.195*
< 1 BMW	29 (42.7)		10 (29.4)
Housing Conditions
Alone	1 (1.5)		1 (2.9)		2.03	0.614**
Family or caregiver	67 (98.5)		33 (97.1)
Education
> 5 years of study	39 (57.4)		10 (29.4)		3.23	0.008*
< 5 years of study	29 (42.6)		24 (70.6)
BMI
Underweight	4 (5.9)		3 (8.8)		1.10	0.625**
Eutrophic/ Overweight	64 (94.1)		31 (81.2)
Hypertension
Yes	42 (61.8)		20 (58.8)		0.85	0.706*
No	26 (38.2)		14 (41.2)
Diabetes
Yes	10 (14.7)		9 (26.5)		2.09	0.150*
No	58 (85.3)		25 (73.5)

• NAD-g - No Alzheimer's disease group (comparison); AD-g - Alzheimer's disease group (case); OR - Odds ratio; BMW - Brazilian minimum wage. * Pearson Chi-square; **Fisher exact Test. Fonte: authors, 2018.

The mean time diagnosis of AD was approximately 11.4 months. None of the older adults were classified as having a severe level of disease, 15 (44.1%) were classified as having mild AD, and 19 (63.9%) as having moderate cases.

As for plasma Zn, the AD-g had the lowest concentrations compared to the NAD-g (88.49 ± 15.95 µg/dL vs. 101.79 ± 16.53 µg/dL; p < 0.001). When stratifying each group by gender, this result was also observed among women but not among men. Similarly, the frequency of older adults classified with deficiency of this mineral was higher in the AD-g (14.7% vs. 1.47%; p = 0.015) (table 2).

Table 2
Association between plasma and erythrocyte Zn levels with and without Alzheimer's disease. Maceió, Alagoas, 2018.

	NAD-g			AD-g
	n	mean (SD)		n	mean (SD)	IC 95%	p-value
Zn Plasma
Total	68	101.76 (16.53)		34	88.49 (15.95)	6.46 – 20.08	< 0.001***
Male	15	102.13 (15.49)		12	91.19 (12.53)	-0.44 – 22.32	0.059***
Female	53	101.65 (16.96)		22	87.02 (17.63)	5.68 – 23.59	0.002***
Zn Erythrocyte
Total	68	36.79 (6.96)		34	36.32 (6.07)	-2.31 – 3.26	0.737***
Male	15	37.53 (5.17)		12	38.29 (7.75)	-5.89 – 4.37	0.764***
Female	53	36.59 (7.42)		22	35.25 (4.79)	-2.08 – 4.76	0.439***

• NAD – No Alzheimer's disease group (comparison); AD-g - Alzheimer's disease group (case); SD - standard deviation. *** T-Test. Fonte: authors, 2018.

The frequency of older adults classified in the 1st quartile for intraerythrocytic Zn concentrations was higher in the AD-g (32.35% vs. 14.71%; p=0.038). When stratified by gender, a higher frequency of older adult women with low intraerythrocytic Zn concentrations was also observed in the AD-g. No difference was observed between men (table 3).

Table 3
Association between plasma and erythrocyte zinc levels with and without Alzheimer's disease. Maceió, Alagoas, 2018.

	NAD-g		AD-g
	N	(%)	n	(%)	IC 95%	p-value
Zn Plasma
Total
Normal	67	98.53	29	85.29	1.29 – 103.30	0.015**
Deficient	1	1.47	5	14.71
Male
Normal	15	100.00	11	91.67	-	0.444**
eficient	0	0.00	1	8.33
Female
Normal	52	98.11	18	81.82	1.21 – 110.28	0.024**
Deficient	1	1.89	4	18.18
Zn Erythrocyte
Total
> 1st, quartile	58	85.29	23	67.65	1.04 – 7.41	0.038*
≤ 1st, quartile	10	14.71	11	32.35
Male
> 1st, quartile	13	86.67	9	75.00	0.30 – 15.70	0.28**
≤ 1st, quartile	2	3.17	3	25.00
Female
> 1st, quartile	45	84.91	14	63.64	1.02 – 10.15	0.041*
≤ 1st, quartile	8	15.09	8	36.36

• NAD-g - No Alzheimer's disease group (comparison); AD-g - Alzheimer's disease group (case); * Pearson Chi-square; **Fisher exact Test. Fonte: authors, 2018.

Plasma and erythrocyte Zn concentrations did not correlate with age (in both groups), nor with the time of diagnosis and disease intensity in the AD-g.

A linear regression analysis, adjusted by gender, age, and education, was performed to explain the effect of plasma and erythrocyte Zn concentrations on reduced cognitive ability as assessed by the MMSE. In this analysis, the plasma concentration of Zn in the AD-g was associated with older adults' cognitive ability (table 4).

Table 4
Linear regression coefficients for cognitive ability assessed by the Mini Mental State Examination (MMSE) screening instrument in older adults with and without Alzheimer's disease. Maceió, Alagoas, 2018.

	Model 1		Model 2
	β a,	p-value b	β a	p-value b
NAD-g (n = 68)
Zn plasma	-0.025	0.849	-0.027	0.837
Zn erythrocyte	-0.142	0.268	-0.144	0.259
R²	0.051		0.048
R² adjusted	-0.025		-0.012
AD-g (n = 34)
Zn plasma	0.358	0.016	0.411	0.008
Zn erythrocyte	0.203	0.167	0.283	0.061
R²	0.498		0.423
R² adjusted	0.404		0.343

• NAD-g - No Alzheimer's disease (comparison); AD-g - Alzheimer's disease group (case) ^a, Estimated regression coefficients (Beta). ^b,T-Test; p<0,05. Model 1: adjusted for education, age, and gender. Model 2: adjusted for education and age. Fonte: authors, 2018.

Logistic regression analysis adjusted by gender, age, and education showed a significant association between plasma Zn concentration and AD (OR=0.964; p=0.028). With a 95% confidence, it was observed that for each 1μg/L increase of plasma Zn, there was a reduction of approximately 3.6% in the chance of older adults having AD.

DISCUSSION

This research aimed to establish the relationship between Zn homeostasis and AD development, determining the concentrations of Zn in two distinct organic compartments of older adults with and without AD who had similar socio-economic and demographic characteristics and were assisted in a geriatric service of a public hospital in Maceió, living in the same metropolitan region. In this context, it was observed that the group with AD showed lower mean plasma Zn concentration and a higher frequency of people with low concentrations of this mineral in the two compartments evaluated, plasma and erythrocytes. It is essential to highlight that no correlation between age and Zn concentrations was observed in this research.

Additionally, among the variables studied, an association was observed between less time spent studying and higher risk for the disease. This result corroborates other studies that have shown that brain-stimulating activities, such as more time spent reading and studying, play an essential role in reducing the risk of developing dementia syndromes²¹,²².

The role of circulating Zn in serum or plasma on the development of AD and cognitive decline in older adults is still poorly known and needs to be clarified since the results of studies are controversial²³. Like the present research, Gonzalez-Domíngues and collaborators²⁴ found significant changes in serum Zn concentrations in older adults with mild cognitive impairment and those with AD compared to the control group.

The reduction in Zn concentrations found in studies conducted with older adults with AD is the result of the effect of age and not the disease¹ since, in the analysis of this large cohort, the authors observed that after correcting serum Zn concentrations for age decline, no significant difference was observed between cases and controls. However, in the present study, the individuals with AD were matched by age with the group of older adults without the disease, and even so, lower Zn concentrations were observed among those in the case group without any correlation of this mineral with age.

It is known that older adults have several factors that can contribute to a lower concentration of Zn, such as lower absorption capacity, use of medications, especially diuretics that increase the urinary excretion of the mineral, and use of calcium or iron supplements that compromise the bioavailability of Zn²⁵. An important fraction of the older adult population presents nutritional Zn deficiency, contributing to the development of chronic diseases, cognitive deficit, and reduced immune response capacity²⁶,²⁷.

Evidence suggests that some metal ions, such as Zn, are responsible for regulating neuronal activity at synapses and in various biological functions so that both excess and deficiency of this metal are involved in metabolic processes that can result in neurodegeneration and cell death²⁸,²⁹.

Although not associated with disease severity in this study, Zn concentrations in both compartments assessed correlated with lower cognitive ability. Other studies have also found similar results associated with low Zn concentrations and poor cognitive ability scores³⁰.

Although not yet elucidated, possibly this association is related to the failure of endogenous regulatory mechanisms, which compromises metabolic functionality in some cellular compartments and the central nervous system since Zn is a regulator of neurotransmission and assumes complex and essential neurotrophic regulatory functions through the activation of brain-derived neurotrophic factor (BDNF)¹. Defects in neurotrophic signaling have already been associated with neurodegenerative disorders, including AD³¹,³².

In addition, low plasma Zn concentrations may compromise the immune response and favor oxidative stress in older adults. Oxidative stress is a recognized factor associated with AD and has been frequently observed in the brains of individuals in the early stages of the disease and appears to play a critical role in its severity and spread³,³³.

The total body content of Zn is labile, especially those present in plasma and body fluids, so the presence of factors that increase losses or raise the organic demand for this mineral is rapidly reflected in its plasma concentrations. However, the body content of Zn can be rapidly controlled by dietary intake and intestinal absorption capacity²⁶,³⁴,³⁵.

Despite the absence of a specific reserve of Zn, erythrocytes’ uptake and exchange of this nutrient occurs more slowly and is possibly observed in chronic processes of dietary deficiencies or high metabolic needs³⁴,³⁵. Although it has not yet been established whether the imbalance of this mineral is a cause or consequence of AD, it is believed that Zn deficiency may contribute directly and indirectly to the onset and progression of the disease⁴.

Considering that AD is a chronic and progressive pathological process, the determination of zincrelated nutritional status in this context requires a multi-compartmental assessment. In this research, the highest frequency of older adults with low levels of Zn in red blood cells was observed in the AD group, and after adjusting for age, gender, and education, only the plasma concentration of Zn was associated with the diagnosis of the disease.

Thus, it is possible to admit that Zn deficiency in older adults with Alzheimer’s disease may be a consequence of multiple associated chronic processes that are maintained over the years and that may assist in the perpetuation and progression of the disease.

This study presents a methodological design (cross-sectional) that did not allow researchers to identify a causal connection. To better elucidate the relationship between Zn and Alzheimer’s disease and to determine whether Zn represents a candidate early biomarker for cognitive impairment, longitudinal studies are needed to identify causal and risk factors associated with impaired cognition, the development of dementia, and Zn deficiency, including assessment of metabolic and oxidative stress, dietary intake (this being an important limitation of the study that could help better to elucidate the possible association between Zn concentrations and AD), medication use, presence of other diseases, and/or use of supplements.

Therefore, some questions remain unanswered, especially about the temporality of the factors studied. In addition, the small number of older adults diagnosed with the disease is still a limiting factor not only here but in several research studies. And finally, considering the characteristics of AD, the answers to some questions about the sociodemographic variables researched here required the participation of caregivers and/or family members, which may have contributed to possible biases of memory or accuracy of information.

CONCLUSION

Low Zn concentrations in plasma, characterizing a current imbalance between organic supply and demand, and in erythrocytes, suggesting that such imbalance exists chronically, were observed in older adults with Alzheimer’s disease. Although the determinants of these low concentrations are multifactorial and may contribute from age, this factor alone could not justify the low Zn concentrations in older adults with Alzheimer’s disease found in the present study. After statistical adjustment, only plasma Zn was associated with the diagnosis of AD, suggesting that the deficiency of this mineral increases the chances of older adults presenting the disease.

• Funding: Programa de apoio a pós graduação (PROAP) (Universidade Federal de Ciências da Saúde de Porto Alegre - UFCSPA).

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Edited by

Edited by: Diôgo Vale

Publication Dates

• Publication in this collection
  01 Dec 2023
• Date of issue
  2023

History

• Received
  24 May 2023
• Accepted
  13 Sept 2023