The Risk Factors for Alzheimer Disease with Identification of Depression as a Potential Risk Factor for the Disease

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1 Lithuanian University of Health Sciences

Faculty of Public Health

Department of Preventive Medicine

Author: Aya Ahmed Mohamed Hamid Eltahir

The Risk Factors for Alzheimer Disease with Identification of

Depression as a Potential Risk Factor for the Disease

Study programme: Faculty of Medicine

Supervisor: Dr. Loreta Strumylaitė

Kaunas, Lithuania

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1. SUMMARY

Author name and surname: Aya Ahmed Mohamed Hamid Eltahir

Research title: The Risk Factors for Alzheimer Disease with Identification of Depression as a

Potential Risk Factor for the Disease.

Aim: To investigate different factors and depression as a possible risk factor for Alzheimer

disease.

Objectives:

1. To assess socioeconomic, lifestyle, environmental, genetic factors and comorbidities as possible risk factors for Alzheimer disease.

2. To develop an inclusion criteria of the articles on depression as it is a risk factor for Alzheimer disease.

3. To perform a literature search and select suitable articles that meet the inclusion criteria. 4. To assess depression as a possible risk factor for Alzheimer disease.

Methods:

To achieve the outlined objectives, several scientific databases were used, such as PubMed, BMJ and ScienceDirect. The literature review was achieved by collecting different articles published from 2015 to 2020. Searched keywords included “Alzheimer’s disease”, “risk factors”, “environmental risks”, “lifestyle risks” and “genetic risks”. A total of 30 articles were included. For systematic review, a comprehensive search of the electronic databases was conducted. Articles published from 2011 to 2021 were collected. The search string “depression” AND “risk factor” AND “Alzheimer” was searched. After analysing and excluding all irrelevant articles, 16 articles were collected and reviewed.

Results:

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4 disease. The onset time of depression, patient’s age at the time of depression and its severity were all factors that increase Alzheimer development risk further.

Conclusions:

Many risk factors were found to contribute to the development of Alzheimer disease, supporting the theory that it is a multifactorial disease. Older age, female gender, occupation, smoking, diet, decreased physical activity, exposure to chemicals, drugs, food insecurity, apolipoprotein E4 allele, infections, disturbed sleep, head injury, food insecurity and depression proved to be risk factors for Alzheimer disease. A more recent history of depression, onset of the disease in late-life, and more severe depression increased Alzheimer disease predisposition. Identifying predisposing factors for Alzheimer’s can highlight the most at-risk members of society and help improve disease prevention measures.

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2. ACKNOWLEDGEMENTS

I would like to express my deepest gratitude to Dr. Loreta Strumylaitė for her continuous support and academic supervision.

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4. ABBREVIATION LIST

AD: Alzheimer Disease RF: Risk Factors

APOE: Apolipoprotein E CI: Confidence Interval

DASH: Dietary Approach to Stop Hypertension L.C: Locus Coeruleus

HR: Hazard Ratio

PPI: Protein Pump Inhibitors MCI: Mild Cognitive Impairment

PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analysis OR: Odds Ratio

BZD: Benzodiazepine

MMSE: Mini-Mental State Exam

SGDS: Short Geriatric Depression Scale

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5. TERMS

Amyloid-Beta: Amino acid peptides that accumulate to form plaques. Locus Coeruleus: The main site for brain production of norepinephrine.

Neurofibrillary tangles: Paired helical filaments, abnormal accumulations of tau protein that collects inside of neurons.

Tau: A protein that stabilizes neuronal microtubules in normal functional conditions

The Centre for Epidemiological Studies Depression (CES-D) Scale: A short scale that measures self-reported symptoms associated with depression that were experienced in the past week. The items of the scale are symptoms linked with depression that have been used in already validated, longer, scales.

The Short Geriatric Depression Scale (SGDS): A screening tool for depression used in the elderly. It is a form that consists of 15 questions.

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6. INTRODUCTION

Alzheimer’s disease (AD) is a chronic progressive condition, it is a neurodegenerative disease and the most common type of dementia. This disease is a global health concern with huge implications for individuals and their communities. It causes problems with memory and progresses to deterioration in cognitive function. AD is one of the fastest rising conditions and it is a major cause of years of life lost, globally [1].

Late-onset AD is the most common type, where the disease is diagnosed when patients are over 65 years old. However, AD can also occur in people under the age of 65, this type of AD is known as early-onset AD. [2]

In 2006, it was found that roughly 26.6 million patients had AD worldwide. Current estimates calculate that this number will reach 106.8 million by 2050 as the elderly population is predicted to continue to increase in the future. According to a 2017 study, the prevalence of AD is calculated to be 5.05% in Europe. AD incidence in Europe was 11.08 per 1,000 people. The prevalence in men was 3.31% and in women was 7.13%. The prevalence rises with age in both genders. The total societal costs of dementia in Europe were estimated to 103 billion euros. AD is a huge social and financial burden, in America, the yearly socioeconomic cost per person suffering from AD was $19,144.36. In 2015, the total cost of the disease amounted to $167.74 billion. The total yearly cost of AD was estimated to reach $507.49 billion in 2030 and is suspected to increase further to approximately $1.89 trillion in 2050 [1]

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7. AIMS AND OBJECTIVES

The work aims to investigate different factors and depression as a possible risk factor for Alzheimer disease.

Objectives:

1. To assess socioeconomic, lifestyle, environmental, genetic factors and comorbidities as possible risk factors for Alzheimer disease.

2. To develop an inclusion criteria of the articles on depression as it is a risk factor for Alzheimer disease.

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8. METHODS

8.1. Strategy of search for simple review

Search strategy:

To achieve my objectives for this literature review, a comprehensive systematic search was conducted, Articles were gathered from different global databases such as Pubmed, BMJ and ScienceDirect. The first search was done on April 26th_{, 2019. A time filter of 5 years was} used so that articles published before the year 2015 were excluded from this review. The English language filter was also applied.

Searched String included terms such as “risk factors”, “Alzheimer disease”, “environmental risks”, “lifestyle risks”, “genetic risk”, ”lifestyle risk”, socioeconomic risk”, “environmental risk”, “main causes”, “prevalence”, “incidence”. Articles that had the specified keywords from the searched string were selected.

After all duplicates were removed, the full text of the remaining articles was read and assessed for the identification of the most relevant articles, 30 articles were collected, analysed and reviewed in the literature review.

8.2 Strategy of search for a systematic review and PRISMA table

Search strategy:

A comprehensive search for relevant articles was conducted using electronic databases such as BMJ, Pubmed and Sciencedirect. The search string “depression” AND “risk factor” AND “Alzheimer” was searched. The final literature search was conducted on the 30th_{of March 2021.} Study selection:

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11 in this review. Systematic reviews, books and documents and case reports were excluded from the review.

Study legibility

Table 1. Inclusion and exclusion criteria for systematic review

Inclusion Criteria Exclusion Criteria

English languages Other languages

Published Unpublished

Published after 2011 Published before 2011

Studies performed on humans Studies performed on animals

Randomized controlled trials, cohort studies, case-control studies, cross sectional studies, clinical trials, meta-analyses.

Systematic reviews, books and documents, case reports

Full text available Non-full texts available

Alzheimer disease and depression

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9. RESULTS

9.1. Review on socioeconomic, lifestyle, environmental and genetic factors as well as comorbidities as possible risk factors Alzheimer disease

9.1.1. Socioeconomic risk factors 9.1.1.1. Age

Most scientists agree that ageing has been maintained to be the biggest predisposing factor for the development of the disease, it is an important, non-modifiable, risk. The prevalence of AD is higher with increased age, 0.97% for ages 65-74, 7.66% for ages 75-84, and 22.53% for people over 85 years. The breakdown of myelin and cell loss in brain nuclei such as the locus coeruleus (L.C) are two processes that occur in the brain due to ageing. As well as this, neurofibrillary tangles begin to form in the L.C. This is believed to contribute to the age-related damage of the blood-brain barrier, this vascular damage is commonly believed to lead to AD [1, 4].

9.1.1.2. Gender

Three articles reviewed highlighted that being of female gender increased AD predisposition. One factor that could contribute to this is the fact that females tend to live longer than males. Women have a greater life expectancy of 4.5 years on average, as demonstrated in fig. 2 [5]. The loss of oestrogen that occurs during menopause could be another factor for this phenomenon. Research supports the hypothesis that oestrogen has neuroprotective qualities. It was found that women who experienced early menopause were more likely to develop AD. Women who are exposed to oestrogen for a longer period were found to be protected from AD [6].

Another multimodality brain investigation also supported this theory. The results of the study indicated that as females undergo menopause and endocrinal ageing, the ageing of the brain also speeds up. This makes such women more likely to develop neurodegenerative diseases such as AD in comparison to men of the same age [7].

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14 positive APOE 4 had similar risks of developing AD. However, younger women with positive APOE 3/APOE 4 had a higher chance of developing the disease compared to men with APOE 4 [8].

Figure 2. Incidence of Alzheimer disease by gender. Source: Riedel et al. [5]

9.1.1.3. Occupation

In a two-phase epidemiological study of 3883 healthy individuals (over the age of 55), the risk of developing AD was compared according to the people’s career choice. It was found that both males and females that worked as farmers had the lowest risk of developing AD from the list of career choices. Male farmers had 66% decreased chance of developing the disease compared to men with office jobs hazard ratio (HR) was 0.34 (95% CI: 0.08–1.33). Female farmers had 45% fewer risks compared to female homemakers HR=0.55 (95% CI: 0.17–1.78), however with a medium effect size (Cohen’s d = 0.46). These results demonstrate the significance of different lifetime occupations and how they may influence the risk of developing AD [9].

Therefore, according to studies, older aged individuals and people of females are predisposed to the disease. Certain occupation types such as office increased AD risk more than others.

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9.1.2.1. Smoking

Two articles that were reviewed concluded that smoking is a risk factor for AD. To investigate the effects of vascular RF on the brain, a cohort longitudinal study that consisted of a patient follow-up for three years, discovered that multiple vascular risks have summative effects on the development of AD, especially in people who were already carriers of the APOE 4 gene [10].

A magnetic resonance imaging study that was conducted in 2018 compared the images of smokers and non-smokers. The results provided additional evidence that vascular injury and AD are connected. The results highlighted that smoking cigarettes is associated with cortical thinning in regions of the brain that are shown to atrophy in early AD. There was also evidence showing that more cigarette pack-years were associated with thinner cortex in multiple regions [11].

9.1.2.2. Diet

According to the studies reviewed, it can be concluded that complex dietary patterns with multiple components such as the Mediterranean diet, the Dietary Approach to Stop Hypertension (DASH), and the Mediterranean-DASH diet intervention for neurodegenerative delay tend to have a better effect on preventing cognitive decline and AD. Single nutrient supplementations such as vitamin B12, folic acid, vitamin E, and vitamin D supplements were found to be less effective. However larger scale clinical trials are needed to more accurately assess the benefits of these diets over time. Fig. 3 demonstrates the general level of evidence scientists have found for certain nutritional strategies in AD prevention [12].

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16 Figure 3. Nutritional patterns in cognition and Alzheimer disease risk. Source:

Pistollato et al. [12]

9.1.2.3. Physical activity

Self-reported data about leisurely physical activity was collected, this information was used to make a conclusion about leisure-time physical activity and its effect on AD progression. The study demonstrated that people who exercised leisurely both throughout life and at older ages are less likely to develop AD compared to others [15].

The studies show that smoking cigarettes increases predisposition to AD and is associated with the cortical thinning that occurs with AD. Diet and nutrition also can influence the risk of AD, evidence shows that complex dietary patterns can help prevent AD. Another finding is that people who were more physically active have a reduced risk of developing AD compared to less active individuals, implying that it may have a protective role.

9.1.3. Environmental risks 9.1.3.1. Chemicals

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17 such as nitrogen dioxide, nitrogen oxide, carbon monoxide, and ozone, the more likely they are at risk of developing AD [16].

Increased environmental exposure to arsenic and heavy metals has long been recognized as factors that contribute to cognitive decline. More recently, there has been more research conducted to help identify the possible link between blood metal levels and the development of AD. A case-control study consisting of measuring blood levels of metals such as cadmium, lead, and mercury, and the urinary arsenic profile was conducted in Taiwan in which a significant connection was found between arsenic metabolized and the risk of developing AD disease. The research found that low selenium and high arsenic level in urine tripled the AD risk [17].

Accumulative lead exposure has already been proven to be connected with cognitive decline. A longitudinal study that aimed to investigate the link between blood lead levels and AD mortality was done using information from the US National Health and Nutrition Examination Survey and mortality files from the National Centre for Health Statistics. A positive however not a statistically significant association was found [18].

Mercury is an even more toxic heavy metal that has also been linked with AD. In 2019, the effects of mercury on the brain were cross-referenced with 70 other factors that can be associated with the disease in a literature review. Many changes that occur in Alzheimer’s patients were found to occur in the case of mercury toxicity. Typical signs of AD in the brain such as plaque build-up, neurofibrillary tangles, and beta-amyloid protein as well as symptoms of memory loss can all occur due to mercury poisoning. Additionally, mercury was found to inhibit neurotransmitters similarly as in the case with AD. The study also demonstrated that Immune responses that occur when exposed to mercury also occur with AD. Furthermore, many other similarities between the conditions were found in the study. The results of the study indicated strongly that mercury poisoning may lead to AD [19].

9.1.3.2. Drugs

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18 in a community-based cohort study. Although a slight increase in non-AD dementia was observed, the study found that PPI use does not increase the risk of AD [20].

9.1.3.3. Food insecurity

One study investigated the association between food insecurity and cognitive dysfunction. The study which used a sample of 1823 over 60-year-olds, found that food insecurity was inversely associated with cognitive function, this could mean that over time, such individuals with lack of food security for example due to lower socioeconomic class were more at risk of developing cognitive impairment and AD [21].

Inhaling environmental pollutants as well as exposure to heavy metals such as lead and mercury increase AD predisposition. Lack of food security was also found to be related with the development of AD.

9.1.4. Inherited predisposition and comorbidities 9.1.4.1. The Apolipoprotein E gene

Having a variation of the Apolipoprotein E gene (APOE) on chromosome 19 has been recognised as RF for AD. This gene’s normal function is to transports triglycerides and cholesterol, this is required to mobilize cholesterol between cells, which is needed for the maintenance of myelin and neuronal membranes. One of the most important variations in question is APOE 4, having this allele increases the risk for the disease, especially if it is inherited from both parents. One study found that people who have AD were roughly 3 times more likely to have the APOE 4 allele compared to normal control cases. It is thought that this allele could speed up the development of AD. This could explain why APOE 4 is often linked to earlier disease onset [4].

Another study proposed that plasma APOE can be used as an early biomarker for AD. After analysis of cross-sectional data, the level of APOE in plasma was found to change in cases of AD. This change was found to correlate with the disease pathology level [22].

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9.1.4.2. Infections

Infectious agents have also been linked with AD. According to one meta-analysis study, being infected with toxoplasma gondii is significantly related to AD. The analysis of this association included four eligible studies. An association risk of 1.3 was found, with a 95% confidence interval (CI) of 0.99-1.92. However, to understand the mechanism of the pathogenesis linking the infection to AD, more research is needed [23].

Another study found that being diagnosed with a herpesvirus infection increased the risk of AD by approximately 30% in people over the age of 65. However, vaccination against the viruses was not found to reduce the risk of AD in the studied sample [24].

One review found roughly 100 publications indicating that the herpes simplex virus 1 is a major predisposing factor for AD. This virus, chlamydia pneumoniae and spirochetes are known to remain latent in the central nervous system. It was proposed that once they are reactivated, for example, due to declination of the immune system that occurs with ageing, they can lead to AD [25].

An American cohort study found a significant association between testing seropositive for helicobacter pylori and AD mortality. However, this link was restricted to men and people in higher socioeconomic status groups [26].

9.1.4.3. Sleep disturbance

One meta-analysis found that impaired or poor-quality sleep increases the risk of cognitive dysfunction and AD. Interrupted sleep was associated with a higher probability of developing AD and people with high sleep fragmentation (in the 90th percentile) had a 1.55 times more risk of developing AD (95% CI: 1.25-1.93) compared to those with a better quality of sleep [27].

9.1.4.4. Head Injury

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20 Another study looked at this association in detail and found that the connection between head injury and AD also depended on the time between injury exposure and outcome. The study concluded that head injuries with a five-year time gap or shorter had a higher risk of AD than longer time gaps [29].

9.1.4.5. Depression

Depression, another predisposing factor, is a particularly significant disease for the geriatric population because of the large proportion of elderly people it affects. Studies have found that depending on cultural situations, the prevalence of depressive disorders in the elderly population is between 10% and 20% globally [30].

Depression has often been linked with poor cognitive function. Having depression and symptoms of depression has been revealed to be significantly common amongst AD patients. The two diseases also share many symptoms, often making it difficult to differentiate between them. Very often, depressive symptoms have been found to occur before the development of AD. Although the association between depression and AD has been found, it is not yet clear what the nature of this link is. Studies imply that the timing of depression onset may be crucial in defining the nature of the association between the diseases. After extensive research, scientists have proposed that having a personal history of depression could be a potential risk factor for the development of AD. However, findings supporting this belief have not been universal. More information is required in order to confirm this hypothesis and to identify if suffering from depression predisposes patients to AD [31].

Given the massive projected increase of AD prevalence and the elderly population in the future, the result of such research could prove to be very beneficial and could have important implications in targeting disease intervention, prevention, and health care needs [32].

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9.2. A systematic review on depression as a risk factor for Alzheimer disease

The search to identify if depression is a risk factor for AD, yielded 1369 articles, of which 16 were eligible for review. 3 case-control studies, 11 longitudinal studies and 2 meta-analyses studies (table 2).

Table 2. Characteristics of included studies Study Time of study Design Place Participant

number

Factors adjusted for Statistical index

Tapiainen et al., 2017 [33].

The study was conducted on members of the population who have a history of mental and behavioural disorders since the year 1972 and if participants were alive in 2005. Case-control study Finland 27,948 case-control pairs Modified Charlson

Comorbidity Index, Modified Charlson Comorbidity Index and substance abuse.

Having depression or mood disorder was found to increase AD risk with a 5-year window, adjusted odds ratio (OR) was 1.17, 95% CI was 1.05–1.30.

However, this finding was not there with a 10-year adjusted window OR= 1.08, (95% CI: 0.96–1.23).

Rosenberg et al., 2015 [34].

Participants were followed for at least six years before being matched with controls with the

Case-control study Canada 1796 Participants and 7184 controls

Anxiety, depression and sleep disorders.

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22 same duration of

follow-up.

>180 doses (95% CI: 1.62 - 2.08) and with the use of long-acting BZD OR= 1.70 (95% CI: 1.46-1.98). Billioti De Gage et al., 2014 [35]. Participants were members of a drug plan from 1 January 2000 to 31 December 2009. Case-control study Canada 1796 participants 7184 controls

High blood pressure, use of antihypertensive drugs, myocardial infarction, stroke, use of platelet inhibitors or oral anticoagulants,

hypercholesterolemia or use of lipid-lowering drugs, diabetes mellitus, use of antidiabetic drugs, anxiety, depression, insomnia. Charlson comorbidity index chronic pulmonary disease, rheumatic disease, peptic ulcer, hemiplegia or paraplegia, renal disease, malignancy or metastatic solid tumour, liver disease, and AIDS/HIV.

Any use of BDZ was associated with an increased risk of AD adjusted OR was 1.51 (95% CI: 1.36-1.69). The association with AD was stronger for long-acting BDZ (OR=1.70, 95% CI: 1.46-1.98) than for short-acting ones (OR=1.43, 95% CI: 1.27-1.61). Burke et al., 2018 [36]. Participants were under observation until an AD Longitudinal study

United States 12,053 APOE 4 carrier status, high blood pressure cholesterol.

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23 diagnosis was received. Data was collected from September 2005 till September 2015. They were observed for at least 208 days. The maximum observation interval was 3458 days.

developing AD than those who did not, (HR= 2.32, 95% CI: 1.87–2.88) Sacuiu et al., 2016 [37]. Participants were investigated every 6 months during the first 2 years. Afterwards, investigations were performed annually, the median follow-up was 3 years. Longitudinal study

United States 94 Sex, age, education and APOE.

Participants with chronic depressive

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24 Gracia-García et al., 2015 [38]. This three-wave epidemiologic study followed up participants at 2.5 years and 4.5 years. Longitudinal study

Spain 3864 Age, gender, and educational studies, Mini-Mental State Exam (MMSE) score,

functional disability, vascular risk factors and diseases.

Compared to people without depression, incidence rate of AD was significantly higher in severely depressed participants, incidence ratio was 3.59 (95% CI: 1.30–9.94). A

consistent, significant association was observed between severe depression and incident AD (HR=4.30, 95% CI: 1.39–13.33). Kim et al., 2021

[39].

Older adults with normal cognition, who visited memory clinics in between September 2005 and December 2019, were

followed until their first diagnosis of AD or follow up was lost.

Longitudinal study

United States 10,739 Demographic (age, MMSE score, education, APOE status, visual and hearing impairment) and medical history (cardiac arrest , stroke, hypertension).

Recent depression (active within the last 2 years) had increased risk of AD (HR= 2.0, 95% CI: 1.5–2.6).

Remote history of depression was not associated to the risk of AD (HR= 1.0, 95% CI: 0.7–1.5).

Barnes et al., 2012 [40].

Study participants consisted of people who took part in a local health

Longitudinal study

United States 13535 Demographic factors (sex, race, and education) and number of medical comorbidities.

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from1964 till 1973 when they were 40–55 years old (some members were excluded from this study).

did not have a significantly increased risk of AD (HR= 1.06, 95% CI: 0.85-1.33) Lenoir et al., 2011 [41]. Participants were recruited randomly and followed for four years. The first follow-up visit took place between 2001 and 2002. The second follow-up took place between 2003 and 2004. Longitudinal study France (cities of Bordeaux, Dijon, and Montpellier)

7989 Gender, education, vascular RF, history of cardiovascular events, APOE genotype, psychotropic drugs intake, functional limitation in

Instrumental activities of daily living, subjective memory complaint and self-perceived health.

No association between high levels of depressive symptoms and risk of AD was found (HR= 1.0, 95% CI: 0.7–1.6). Vialta-Franch et al., 2013 [42]. Information collected from initial cohort was

Longitudinal study

Spain 451 Age, gender, marital status, education, cognitive

impairment, executive function and stroke history.

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26 analysed after a

5‐year follow‐up.

increase the risk of AD with HR of 7.8 (95% CI: 1.57–38.89). In late‐onset minor

depressive disorders with depression‐

executive dysfunction syndrome. The HR was 6.1 (95% CI: 2.12–17.52).

Gallagher et al., 2018 [43].

Participants were followed until the development of AD or loss to follow-up.

Longitudinal study

United States 1965 Age, MMSE score, amnestic subtype, APOE 4 status, MCI amnesic subtype and onset time of depression.

39.7% of the older adults with depression progressed to AD over a short follow-up duration of roughly 27 months. HR= 1.44 (95% CI: 1.16–1.79, p < 0.001). 41.7% of the participants with mild cognitive impairment and active depression within the last two years developed AD compared to the 31.6% of those with a more remote history of depression. Chan et al., 2020 [44]. Participants were enrolled between 2002 and 2004. All participants were followed up until end of 2013. Longitudinal study Taiwan 3,345 participants and 13,380 controls

Demographic data, medical and psychiatric comorbidities.

Patients with depression were more likely to develop AD than controls. Amongst the participants with late-onset depression, difficult to treat patients had the highest risk for developing AD and faster disease

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27 Bae et al., 2015 [45]. Follow-up assessments were conducted from November 2011 to May 2012. Participants were followed up for 3.5 years. Longitudinal study

Korea 460 Gender, literacy, residential area, marital status, presence of depression, and diagnosis.

Depression was associated with the risk of AD (HR= 30.34, 95% CI: 2.43–378.75). The risk of AD was higher with increased severity of depression. In participants with a score of 8 or 9 in the Korean version of the Short Geriatric Depression Scale (SGDS) the HR was 10.71 (95% CI: 0.55–209.35). In

participants with a SGDS score of ≥10 points, HR was 51.18 (95% CI: 4.29–610.16).

Steenland et al., 2012 [46].

The study was conducted from September 2005 till January 2011. Longitudinal study United States 5607 participants with normal cognition and 2500 with MCI

Age, gender, race, education (high school or less), self-reported history of hypertension, history of diabetes, and history of heart disease.

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28 Diniz et al., 2013 [47]. The literature search of electronic databases was conducted in February 2012. Meta-analysis

Britain 28 746 Sociodemographic (age, education, gender etc.), cognitive function cardiovascular RF and medication use.

Late life depression was associated with significant risk of AD. OR= 1.65 (95% CI: 1.42-1.92, P<0.001 ). Cherbuin et al., 2015 [48]. Databases were searched through 28 February 2014. Meta-analysis

Australia 66 532 All studies were adjusted for age and education. Most studies were adjusted for age, sex and education

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10. DISCUSSION

This literature review found that multiple factors may predispose individuals towards developing AD. The risk factors can be modifiable or non-modifiable. The different types of risks found can be subdivided according to aetiology. They can be lifestyle and environment-related, genetic and socioeconomic factors or comorbidities. These findings support the belief that AD is a multifactorial disease.

Table. 3. Different risk factors for Alzheimer disease

Socioeconomic Lifestyle Environment Inherited and comorbidities Age [1, 4] Smoking [10], [11] Chemicals [16-19] Apolipoprotein E allele [4, 22] Gender [5-8] Diet [12, 14] Drugs [20] Infection [23-26] Occupation [9] Physical activity [15] Food insecurity [21] Sleep disturbance [27] Head injury [28, 29] Depression [30-32]

The systematic review to identify if depression is a risk factor for AD, included 16 articles, 3 case-control studies, 11 longitudinal studies and 2 meta-analyses. From the articles collected, 2 found that suffering from depression increased progression from MCI to AD. 66% of the articles reviewed found a significant association between having depression or a history of depression and the development of AD.

In contrast, one longitudinal study conducted in 2011 found a link between high levels of depressive symptoms and other types of dementia, however, it reported no association between depression and risk of AD [41].

Two case controls looked at the relationship between the use of BZD and AD. Both studies discovered that the association was stronger in patients who took long-term acting BZD compared to short-acting drugs. Longer exposure time to BZD was also found to increase AD risk [34, 35].

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30 recent depression (active within the last 2 years) was associated with a higher predisposition to AD compared to having an older history of the disease. One longitudinal study which followed participants that were diagnosed with depression and MCI concluded that 41.7% of the participants with mild cognitive impairment and active depression within the last two years developed AD whereas only 31.6% of those with a more remote history of depression developed AD [36, 39, 43].

A case-control study of the nation of Finland found that depression increased predisposition to AD with a 5-year time window. However, this finding was not found for a 10-year time window, highlighting that time window width could affect the association between depression and AD [33].

People with late-life depression have a higher AD predisposition compared to those who at depression at a younger age. A meta-analysis found that late-life depression significantly increased the risk of AD, OR=1.65 (95% CI: 1.42-1.92, P<0.001). A longitudinal study conducted did not find midlife depressive symptoms to increase AD risk. However, late-life depression was found to double the risk of developing the disease. A cohort study concluded that both late-onset depression with depression‐executive dysfunction syndrome and late‐ onset minor depressive disorders with depression-executive dysfunction syndrome increased AD risk [47, 40, 42].

A clinic-based study whose participants were elderly MCI patients found that patients with chronic symptoms of depression had a 60% shorter conversion time from MCI to AD compared to those without depressive symptoms [38].

More severe depression was found to increase AD risk. A three-wave epidemiologic study found that participants with severe depression showed a consistent, significant association of developing AD compared to participants without depression. One meta-analysis study which grouped participants according to their scoring on CES-D scale found that elderly patients with a score higher than 20 showed a 97% increased risk of developing AD after follow-up (6 years on average). When scores were cut-off to 16 on the scale, patients had an increased risk of only 58%. The effect of severe depression on AD predisposition was also investigated in another study by Bae et al., it was discovered that higher scores on the SGDS increased the HR of AD [38, 48, 45].

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11. CONCLUSIONS

1. The findings support the theory that AD is a multifactorial disease with several risk factors.

2. Socioeconomic AD risks include age, gender and occupation. Lifestyle habits such as smoking, diet and decreased physical activity can also contribute to AD development. Environmental exposure to air pollutants and heavy metals as well as suffering from lack of food insecurity have the potential to increase AD risk. Additionally, APOE genetic predisposition, infections (herpesvirus, T.gondii and C.pneumoniae), sleep disturbance, head trauma and depression can also contribute to the development of AD.

3. Depression is a predisposing factor for AD. Patients who suffered from depression recently are more at risk of developing AD compared to those with a remote history of the disease. People with late-life depression have a higher AD risk compared to those who had depression at a younger age. More severe forms of depression lead to increased AD risk. Exposure to BZD was also found to directly increase AD risk.

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The Risk Factors for Alzheimer Disease with Identification of Depression as a Potential Risk Factor for the Disease

The Risk Factors for Alzheimer Disease with Identification of

Depression as a Potential Risk Factor for the Disease

Table of contents

1. SUMMARY

2. ACKNOWLEDGEMENTS

4. ABBREVIATION LIST

5. TERMS

6. INTRODUCTION

7. AIMS AND OBJECTIVES

8. METHODS

9. RESULTS

10.

DISCUSSION

11.

CONCLUSIONS

12.

REFERENCES