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Specialized web pages were used to search concepts, classifications and epidemiological data. It stands out:

With the aim of reducing the results in order to adapt perfectly the search to the objectives of this review, the following inclusion-exclusion criteria were used:

- Inclusion criteria: all articles in English or Spanish were taken into account. Because of all the technological and health advantages that are continually made, the search was limited to the last five years. This temporal limitation was not considered in some exceptional cases because of the relevance of some articles to the matter. Moreover, the aim was to filter the articles in order to obtain a varied, non-repetitive and complete final selection that provide a detailed view of the subject and that allow to point out controversies. Also, other articles and documents were taken from the bibliography of the selected ones.

- Exclusion criteria: all the articles published in a different language from English or Spanish, those which do not focus on the main topic of this review or without relevant information were dismissed.

Despite of realising a meticulous search on all the cited sources of information, the principal database that sustained this review was Pubmed because of the high quality and utility of its studies.

Relationship between depression and dementia:

The AD is related to several RF that can be classified in modifiable (low educational level, depression, vascular RF and physical inactivity) and not modifiable (age, ethnic group, genetic factors)^8,9,10.

Depression is included in the group of the modifiable RF in reference to numerous studies that demonstrated it. With all, as mentioned before, because of the current debate about the role of depression on the development of AD and other dementia types, we have to differentiate three different hypothesis^11,12:

1. Depression: risk factor for dementia:

First of all, it is necessary to clarify the concept of RF, that is any circumstance that increase the probability of develop a pathology¹³. Therefore, when it is mentioned depression as RF, it means that suffering from depression increases the probability of suffering, afterwards, AD or other type of dementia.

Memory problems are one of the most common symptoms on depressed people, being present in 40% of the cases¹⁴; those memory problems are objective confirmed by the realization of cognitive tests. Additionally, it is also proved that depression accelerates the cognitive deterioration when it occurs in patients that suffered, previously, from dementia¹¹.

In spite of all the explained before, in practice, the similarity between the symptoms of both pathologies makes the differential diagnosis very difficult. Therefore, when depression is analyzed as a RF, it is necessary to bear in mind several aspects that have influence in that relationship:

A. The nature of the depressive disorder:

It is necessary to differentiate, principally, between chronic depression or isolated depressive attacks; and between a first depressive attack or a recurring depression.

Several studies have proved that people with chronic depression show higher risk of developing any type of dementia (in particular AD) than those with only one isolated attack during their lives^11,15. In addition, the severity of the disorder has also a proportional influence, the higher it is the higher would be the risk¹⁴.

Specifically, a longitudinal study realised in Zaragoza in 2015 analyzed the relationship between AD and severe depression, persistent depression, first depressive attack and not treated depression. The results of that investigation proved an increase on the risk of developing AD in those individuals with severe depression or not treated depression. It was also found an increase on the risk,

even not as clear, in individuals with a first depressive attack, however it was not found association between persistent depression and AD⁹.

B. Symptomatology of depressive disorder:

In relation to the previous point it is the symptomatology, changing the relation between depression and dementia according to the pattern of depressive symptoms.

A prospective cohort study done in different cities of the United States between 2014 and 2015 concluded that high and raised symptoms of depression meant an independent RF for dementia, while moderate and raised symptoms were consequence of a dementia disorder already in progress¹⁶.

The studies focussed on the two previous sections stand out the importance of knowing the characteristics of the depressive disorder and the progression of its symptoms. However, this is the weak point of many studies that use, as diagnostic method for depression, uniform scales without making a difference between chronic depression, first attack, severity of the disorder, etc. In addition, these studies make the diagnosis in just one point of the study period without having in mind the changes that take place over time. The consequence of these is a greater variety on the results and less validity^12,13.

C-Onset / development moment of depression:

Several studies highlight the onset / development moment of the depressive disorder as a crucial point on the determination, or not, of depression as a RF. Based on this, it is necessary to make a difference between early depression (if it takes place before the old age) or late depression (if it takes place, for the first time, after 50-60 years old). Many studies conclude that early depression is a RF for dementia, while late depression, that takes place closer to the diagnosis of dementia, could be a prodrome of it¹¹.

Nevertheless, there is not consensus in this point. A study carried out with the objective of evaluating the relation between dementia and various modifiable RF, stood out depression as a RF on the development of all types of dementia and, in particular, late depression as a RF to AD⁸. In agreement with the previous one, Diniz and Cols. (2013)¹⁵, concluded that late depression is related with a higher risk of developing AD and vascular dementia. In contrast, Burke and Cols. (2016)¹⁷, found risk association regardless of the moment of development of depression.

2. Depression: prodrome of dementia:

In the same way as in the case of the concept of RF, it is important to clarify the definition of prodrome in order to analyze depression as one. A prodrome is an early manifestation of a pathological process, it means, a symptom that precede the onset of the pathology¹³.

The temporal aspect, explained in the previous section, is the base of the studies that affirm that depression is not an independent RF, if not a prodrome of dementia.

Several studies affirm that depression as a prodrome is the result of the self-assessment of the individual that, conscious of his own loose of cognitive functions, develop, as an answer, a depressive disorder. The difficulty in this point is that the prodrome period of dementia is not well delimited and could spread throughout ten, or more, years before the diagnosis^11,16. As a consequence, it is very difficult to differentiate which depressive symptoms are in that prodome period and could be a result of a dementia disorder in progress and which not.

In a cohort study, realised by Singh-Manoux and Cols. (2017)¹², about the progression of the depressive symptoms previous to the diagnosis of dementia, it was done a retrospective analysis of the results throughout 28 years. Those results did not support the hypothesis of depression as a RF, concluding that depression is a consequence of the preclinical phase of dementia. This happens because it was only found relation between dementia and depression, regardless of the depressive characteristics (chronic, recurrent etc.), when the symptoms appeared in the previous decade of the dementia diagnosis.

In agreement with the results of the previous study, another investigation, focussed on AD, concluded that if depression is a prodrome of AD it has to be temporal proximity between the onset of depression and the onset of dementia instead of depressive symptoms that remit and reappear later. Based on this, late depression has to be a prodrome of AD¹³.

Therefore, to establish depression as a consequence of the dementia development and not as a RF, it is necessary to have in mind that the disorder could not be detected at its beginning. It means, to accept that the temporally proximity between the onset of both pathologies define the relationship between them do not have to be correct if the diagnosis is done late¹³.

In relationship with the previous, Ownby and Cols. (2006)¹⁸ set out as one of their objectives to study the importance of the temporally period between the diagnosis of both pathologies. Their hypothesis established that if the association was negative, it means, the smaller the temporal period between diagnosis of both disorders was, the biggest would be the risk of AD, then depression would be a prodrome. In contrast, if the relationship was positive and, therefore, the bigger the temporal period between them was, the bigger would be the risk, so depression would be an independent risk factor to AD. After the realisation of their investigation, they concluded that the relation was positive and, therefore, depression would be an independent RF to AD.

3. Depression and dementia independent pathologies:

The third hypothesis is based on the fact that depression and dementia are two pathologies of the old age and, therefore, simultaneous.

To this is necessary to add that these pathologies have common risk factors and symptomatology. Some of these common symptoms are memory problems and sleep disturbances; while among the common risk factors stood out the low economic level, social isolation and vascular RF, among others.

On the other hand, both pathologies also share neurobiological characteristics: inflammation, neurodegeneration, variations in the hypothalamic-pituitary-adrenal axis, etc.^11,12. Those common characteristics could cause errors on the diagnosis. Because of that, a depressive person could be mistakenly diagnosed from dementia or, on the contrary, it could be associated the symptoms to a depressive disorder being, in fact, a dementia process¹³.

Despite the previous, it does not exist enough evidences that support this third hypothesis. Several studies that had had in mind, in the moment of analyzing the results, the common RF for both pathologies, still concluding that depression is an independent RF¹¹.

Neurobiological explanation:

All the explained before has a neurobiological basis. The development of both pathologies, depression and AD, is related with some genetic aspects and pathological processes that provide consistency to the hypothesis that relates them.

Genetic aspects:

First of all, it is necessary to mention the genetic role in the appearance of both disorders, especially in AD as in its development is crucial the genetic transmission¹⁷.

The way in which individuals answer to the ambient factors would depend, partially, of their genetic information. Like this, the existence or not of different genotypes could determine a higher risk of development a pathology. In the case of AD a gene implicated on its development is APOE¹⁷. It is, therefore, a not modifiable RF, but it is important to bear in mind the risk that mean its presence in combination with other modifiable RF as depression.

There are three variants of the genotype APOE: e2, e3, e4. The presence of e2 is considered neuroprotector and, even, has been pointed out that could delay the onset of AD. However it is demonstrated that e3 and, above all, e4 increase the risk of its development¹⁷. In addition, it is estimated that 40-65% of the people who suffer from AD have one or two copies of the genotype APOE-e4³.

A study carried out with the aim of determining the association between depression, sleep disturbances, APOE and dementia, concluded that even there was not found a direct relation between depression and the genotype APOE, the risk of developing AD is higher in people who have the genotype APOE-e4 and depression jointly than in those who only have one of the variables¹⁷.

The importance of this is that, despite there are some RF not modifiable, like the genotype APOE, it is possible to act against other modifiable that increase the effect of the not modifiable, like depression.

Neuropathology mechanisms:

Several investigations connect depression and dementia by different pathological mechanisms at the neurological level. The principal ones are explained in table 1.

These pathological processes are not mutually exclusive, that is, they are connected and usually happen simultaneously. Because of this, the investigation at neurobiological level is really diverse and varied, taking place, again, controversies¹¹.

Particularly, a study realised by Wilson and Cols. (2016)²¹, with the aim of determining if depression is related with the dementia pathological processes, concluded negatively. They studied the possible relation between depression and six dementia pathological marks: neurofibrillary tangles of protein tau, β-amyloid plaques, Lewy bodies, sclerosis of the hippocampus and microscopic infarcts. However, after the investigation, they only found relation between depression and the formation of β-amyloid plaques²¹.

In contrast, another investigation, which principal objective was to study the relation between synapsis degeneration, depression and AD, found a positive association and also stood out other common processes between the disorders such as neuroinflammation⁷.

Prevention and nurse role:

As it was mentioned before, with a pathology as Alzheimer’s Disease the prevention of its RF is crucial.

There are many studies that try to emphasize on this point. In particularly, one published on the Lancet Neurology journal and realised with the objective of reflecting the importance of prevention in AD, concluded that one third of AD cases can be attributed to modifiable RF. Throughout the mentioned investigation, it was calculated the attributable risk (proportion of AD cases attributable to a RF) of seven modifiable RF which association with the disease is scientific proved: diabetes, hypertension, obesity, physical inactivity, depression, smoking and low educational level. The results determined that a decrease, per decade, of the 10% in the prevalence of each RF, would reduce in a 8.3% the worldwide prevalence of AD estimated to the year 2050, which is estimated around 106.2 million cases. While a reduction in the 20% would reduce the AD prevalence in a 15.3%¹⁰. See figure 2.

Figure 2. Number of cases of AD estimated to the year 2050 if there is no action on RF versus if there is a reduction in a 10% or in a 20% on the prevalence of those RF. 

Modified from Norton and Cols. (2014)¹⁰. Alzheimer’s Disease (AD) Risk Factor (RF).

Despite the strength of the investigation results, at the moment of assessing them, it is necessary to have in mind certain limitations of the study. On one hand, the relation between AD and the studied RF could be altered by some unknown or not evaluated RF. And, on the other hand, the calculations were done in specific moments, without analyzing the variation that could happen throughout time and through the different generations. For example, the changes that could be carried out in the following years to improve the educational level would affect people younger than those who are really going to be in risk of developing AD in 2050, which is the year taken as a reference to calculate the results¹⁰.

Specifically, depression, RF of higher interest in this review, is defined as a pathology that could be prevented and, therefore, its early treatment could delay, at the same time, the development of dementia¹⁵. One point in which the investigations that study prevention agree is the importance of the role played by the health staff and, in particularly, the role of nurses^17,19.

In particularly, a study published in the Journal of Nursing Scholarship journal, (one of the journal edited by the Sigma Theta Tau International Honor Society of Nursing -Sigma- which is the second biggest nurse organization worldwide) about depression as a RF for different pathologies, among them AD, stood out the nurse function in the preventive area. It pointed out that, in the first place, it is necessary to know the nature and the principal signs and symptoms of depression to be able to detect it early or even be able to anticipate its development by adopting the most optimal preventive measures. In the same way, it is necessary to know the relation between depression and other pathologies, in this case AD, and its possible role as RF to be able to act directly on the depressive disorder and, at the same time, indirectly preventing the development of other pathology. For this it is crucial a good nurse-patient relationship¹⁹.

Another basic aspect on the preventive level is the health education¹⁷. An optimal educational level, the practice of physical activity, and good social relationships increase the cognitive reserves of the individuals¹⁴. In this point, primary attention is so important and nurses must assume their responsibility on the education of patients. This responsibility does not only consist on giving patients information about the adverse effects of theirs bad acts, but also on trying to help them to, gradually, change those bad habits for healthier ones that remain throughout time¹⁵.

Bearing in mind the nurse work, that does not only consist on take care of the person affected by the disease, but also of the family, we have to know the current characteristics of the caregivers and family; adapting our job to the emerge needs. Health education and prevention, therefore, has to focus not only in the patient but on the community where he/she lives. Relatives are, in many cases, the informal caregivers at home, which is a field that is gaining higher importance in the last years. The principal caregiver is represented, in most part of the cases, by a female figure, motivated by the gender role and its implications at home. In relation with this, the role of nurses gains, if it is possible, a higher importance on the context of the current care scene; it is still an activity that involves the binomial caregiver/patient and that is prolonged throughout time, being necessary to get used to it^22,23,24.

In conclusion, the strategies of prevention, early diagnosis and correct treatment of depression have a great importance to fight against AD. But also, they have a great general effect on the health system, because depression is a RF to many pathologies¹⁵. Because of this, being this another point in which most part of the examined studies are agree, it is very important to continue with the investigations about depression as a RF to AD in order to be able to also determinate the impact of the work on the preventive area^8,15-17.

Limitations and considerations: