INTRODUCTION:

Alzheimer’s, a common cause of dementia, is a neurodegenerative disease caused by brain cell death. It is a progressive disease which does memory destruction and diminishes other important mental functions. An Alzheimer’s patient find it difficult to remember things, they may forget people and even their close relatives in their lives and has a certain dramatic personality change. The brain cells degenerate which progress to a decline in mental function and causes memory loss¹. The brain size of an Alzheimer’s patient shrinks in size and has compressed nerve cells. Microscopic tangles and plaques are present within the brain of a diseased person.

These are tiny inclusions in the nerve tissue which are only observed in an autopsy or postmortem and cannot be seen otherwise in a living individual’s brain². The reason being that plaques are seen in the dying cells of a brain due to the accumulation of a protein called beta amyloid, which may also refer the plaques as ‘amyloid plaques’. Whereas the brain neurons show tangles due to the disintegration of a protein called³.

The damage to the brain starts long before the development of the disease. The patients appear symptom free in the beginning while the toxic changes take place in the brain⁴. Deposits of amyloid plaques and tau tangles are formed abnormally in the brain which prevents the healthy neurons to stop functioning properly and cause them to lose connection with each other ultimately causing the cell death⁵. This damage appears to happen in the hippocampus which is an essential part of the brain that store memories. Brain is affected additionally as more neurons die therefore causing the brain to shrink and by the final stage of the disease the brain tissue significantly shrinks⁶.

Alzheimer’s disease varies from person to person. In some patients, a decline such aspects like vision issues, word finding or judgement are the early stages⁷. With the disease progression, patients face greater memory loss and cognitive difficulties such as wandering and getting lost, repeating questions, taking longer to complete tasks, behavioral and personality changes, all these symptoms fall in the mild stage of Alzheimer’s disease⁸. In the moderate stage, damage occurs in the specific areas of the brain, involved in reasoning, consciousness and sensory processing. Patients find it hard to recognize family members and are unable to learn new things, behave impulsively and may also have hallucinations^8,9. And when plaques and tangles are spread throughout the brain, the severe Alzheimer’s stage occurs in which the disease individual become dependent on others completely as they no longer are able to communicate as their body shuts down, therefore they remain in bed most of the time¹⁰.

Globally, the prevalence of Alzheimer’s disease has been estimated to be as high as 24 million and is believed to double every 20 years till 2050^10,11. As the time is passing by and the population is ageing day by day, the risk of developing Alzheimer’s disease is also increasing among the very old. The AD prevalence has been observed to be increasing with the increasing number of old individuals, markedly 65 years¹². A 15 fold of increase among the ages 60 and 85 has been studied. 4.6 million cases report annually. Overall, North America and Western Europe have the highest AD prevalence i.e. 6.4% and 5.4% of the total population specifically of age 60, Latin America has a prevalence rate of 4.9% and in China it’s 4%¹³.

Risk Factors leading to Alzheimer’s disease:

High cholesterol levels, diabetes, smoking, obesity and high blood pressure are major risk factore that lead to Alzheimer’s disease¹⁴. Smoking has an adverse effect causing dementia in patients. Increased risk of Alzheimer’s can be avoided by quitting smoking. High blood pressure also increases the risk of developing Alzheimer’s disease particularly vascular dementia. Type 2 diabetes in midlife also leads to memory loss in later life^15,16. Similarly high cholesterol, obesity and lack of physical inactivity lead to certain factors that stimulate Alzheimer’s disease. Other risk factors include consumption of alcohol, head injuries, aging, family genetics and also depression which has been found to have shared links with Alzheimer’s disease^15,16,17.

Depression is critically an important factor for those attending an elderly especially those with Alzheimer’s disease^[18]. It has been observed to be greatly linked with cognitive function. Its behavioral aspect is significantly associated with Alzheimer’s disease that affects the cognitive status of patients¹⁹. Depression is a common disorder; about 20% of all individuals go through a depressive phase during their lifetime. The depressive disorder prevalence in individuals with 60 plus age, also known as late-life depression ranges from 8% to 16%. LLD is associated with Alzheimer’s which is a common type of dementia found in elderly²⁰. The symptoms of depression are common in AD patients, out of which 50% have both the diseases. It is now believed that depression is a reaction to early cognitive impairment and may lead to cognitive defects later on in patients²⁰.

Links between Depression and Alzheimer’s disease:

The mechanisms of the shared links between Alzheimer’s disease and depression are not clearly understood but research has shown that AD and depression can be heritable²¹. The heritability factor of major depressive disorder is 31-42%. Depression is thought to be influenced by multiple risk factor genes while their inheritance factor is extremely complex, epistatic and polygenic. 50% risk factors are contributed genetically whereas the heritability is calculated to range from 58% to 74%²².

Some specific susceptibility genes have been found to be linked with AD. Depending upon the genetic components in LLD and AD, it has been observed that shared risk genes for the two diseases have been reported²².Genetic polymorphisms of brain derived neurotrophic factor (BDNF), Apolipoprotein E (ApoE) and methylenetetrahydrofoloate reductase (MTHFR) have been observed to confer risks to both LLD and AD. These genes have been studied through various researches on both the diseases; depression and AD and are being further investigated along with other genes²³.

Role of BDNF gene in depression in AD:

Brain Derived Neurotrophic Factor (BDNF), is the most abundant neurotrophin in brain and has an influence on the function and survival of various neurotransmitter systems. This gene is located on chromosome 11. A SNP resulting in the substitution at valine 66 to methionine, declines the BDNF production, which is important for modulation of human memory and hippocampal function²⁴.

A direct link between BDNF and depression has been studies through various examinations. More LLD patients carry the Met allele than healthyindividuals²⁵. In addition, the risk of LLD to be developed increases by roughly 2-fold for people who carry the Met allele in contrast with those who are homozygous for the Val allele. In depressive-disorder Met-allele carriers, a prior time of illness beginning has been found in contrast with homozygous Val allele transporters²⁶. In any case, a relationship between Val allele homozygosity and a higher seriousness of depressive side effects has been noted, recommending that an alternate neuronal pathway may lead to depression onset in the two genotypes. Not all examinations support the fact that there is a relationship between the BDNF Val 66 Met polymorphism and LLD. One study concluded that the BDNFV a l66 Metpoly morphism isn't related with significant depressive disorder^26,27. However, anotherstudy suggested that the BDNF Val66Met polymorphism assumes a noteworthy part in the etiology of real depressive issue in males more than in females. Alternate meta-analysis has concentrated on LLD patients speciﬁcally and has demonstrated that Met allele carriers have a higher hazard for LLD than Val allele homozygous²⁷. These outcomes show that the Val66Met polymorphism may present an expanded hazard for LLD as people age. A few examinations have researched the potential neurobiological instruments by which the BDNF polymorphism may be connected to LLD pathogenesis. To start with, hippocampal weakening is believed to be included^[28]. The BDNF polymorphism may affect mental health, bringing about changeless neuronal development and plasticity damage, there byraising the neurobiological and additionally psychosocial dangers of melancholy. Significant depressive issue is joined by hippocampal decay in both young and elderly people^28,29. Moreover, smaller hippocampal volumes have been found in mice conveying the Met allele, and reduced dendritic arbor unpredictability has been found in BDNF Met/Met thump in mice²⁹. Essentially, depression patients and healthy subjects possessing the Met allele have smaller hippocampal volumes than homozygous Val allele carriers. Asecondline of evidencelinking BDNF and depression is the modulation of serotonergic neuro transmission. Shrinkage of serotonergic ﬁbers and diminished dendritic spine density in the hippocampus has been appeared in animal models of depression³⁰.

Numerous studies have investigated the potential connection between the BDNF Val 66 Met polymorphism and AD. Many researchers have announced no relationship amongst AD and the BDNF Val 66 Met polymorphism³¹. Whereas, others have demonstrated that the BDNF Val66Met polymorphism expands the hazard for AD. Inaddition, age-dependenteffects on the allelic affiliation have been recommended. Val allele homozygotes are related with an expanded hazard for growing AD in elderly individuals, however the Met allele seems to give helplessness to AD in more young individuals^31,32. BDNF might be engaged with numerous parts of AD pathogenesis, including amyloid alpha collection, synaptic brokenness, and even Tau pathology. Several ADanimal model studieshavedemonstrated that A treatment can diminish BDNF levels in the cortex and hippocampus, which are likewise the regular regions of a consumption^32,33. Then again, BDNF has been appeared to decrease the amyloidogenic procedures of the amyloid-protein antecedent (APP), in this way upsetting an arrangement. Synapse loss and synaptic dysfunction are additionally firmly identified with AD pathogenesis anddirect in fusion of BDNF into the entorhinal cortexofamyloid-transgenicmice has been shown to turn around neurotransmitter misfortune and reestablish learning and memory deﬁcits³³. Another possible connection amongst BDNF and AD pathogenesis might be in Tau pathology arrangement. During aging, Tau phosphorylation and aggregation begins in the entorhinal cortex and after that spreads to the subiculum and CA1 region followed by the basal fore brain, theamygdala, and in the long run finishing off with some cortical ranges; in any case, this is precisely inverse to the BDNF transport pathway³¹.

Role of ApoE gene in Depression:

ApoE regulates lipoprotein digestion and plays a major role in complex processes of CNS, including lipid transport and repair and reugulation of neuronal cells. The ApoE gene is situated on chromosome 19 and is separated by 3 alleles: ε2, ε3, and ε4³⁴. Studies have shown an association between the ApoE ε4 allele and increased AD hazard, a few examinations have explored the ApoE ε4 allele as a possible risk factor for other neuropsychiatric illnesses, including LLD^34,35.

Recent studies have confirmed the association between ApoE gene and depression. A population based investigation exhibited that the presence of the ApoE ε4 allele anticipated future LLD³⁵. Since depression might be a prodromal symptom of dementia, the examination rejected depressed subjects who later acquired dementia, thus featuring the relationship between ApoE ε4 and LLD³⁶. An investigation demonstrated that elderly subjects with the ApoE ε4 allele have up to a 4.7 fold higher hrisk for creating LLD in contrast with subjects without the allele. Besides, a current meta-investigation found that the ApoE ε2 allele goes about as a defensive factor for depression in the Caucasian populace while the ApoE ε4 allele increases the risk for depression in elderly subjects. Together, these outcomes propose that the ApoE ε4 allele can possibly distinguish individuals who are at high hazard for LLD^34,36. A few studies have exhibited a connection between the ApoE ε4 allele and brain atrophy, which is believed to be a hazard factor for LLD. Non-demented LLD patients conveying the ApoE ε4 allele demonstrate a noteworthy decline in hippocampal volume. More articulated hippocampal shape variations have additionally been seen in depressed patients with the ApoEε4 allele in contrast with patients without the allele. ApoE ε4 allele transporters have demonstrated a quicker rate of hippocampal or entire mind decay than non-carriers. This information proposes that brain atrophy might be an intermediating factor that connects the ApoE ε4 allele to LLD³⁷. ApoE gene is involved in the onset of Alzheimer’s disease. The allele ε4 is the largest known genetic risk factor for this disorder³⁸. It has been observed that the amyloid interactions with ε4 allele have dramatic effects on Alzheimer patients as the disease is characterized by the aggregate build ups of the peptide beta amyloid³⁷.

ApoE also induces the proteolytic breakdown of peptide beta amyloid between and within the cells. The allele ε4 is not as effective as the rest at promotion of these reactions thus having an increased vulnerability to Alzheimer’s disease patients with gene variation. Approximately 40-60% of AD patients possess one copy of the ε4 allele, so it is not a determinant of the disease. One third of Alzheimer patients are ApoE4 negative and some ApoE4 carrying homozygotes do not possess the disease. However, there are chances up to 20 times for developing AD if a person is Apoε4 homozygote^37,38. ApoE ε4 may likewise influence the pathological depositiont of Tau. Studies have revealed that ApoE ε4 may advance Tau phosphorylation by inﬂuencing speciﬁc phosphorylation oatterns, yet this should be additionally explored³⁸.

Role of MTHFR gene in depression in AD:

Methylenetetrahydrofoloate is an important enzyme that regulates DNA synthesis, folate metabolism and nucleic acid synthesis³⁹. This gene MTHFR is located on chromosome p36.3. A SNP (C to T) at position 677 in the MTHFR gene resulting in the substitution of an amino acid alanine for valine has been studied to diminish the enzymatic activity⁴⁰. Decreased activity of this gene results in a significant elevation in plasma homocysteine and a decline in S-adenosyl methionine which is essential for CNS myelination. MTHFR mutations are linked to several disorders including AD and depression⁴⁰.

The relationship between the MTHFR C677T polymorphism and depression has been examined by various examinations⁴¹. A few studies have exhibited that the MTHFR C677T polymorphism is related with depression in the elderly population. The consequences of meta-investigations to evaluate the connection amongst depression and the MTHFR C677T polymorphism have been conflicting⁴². Two meta-analysis give proof to help the conclusion that genetic vulnerability for depression is intervened by the MTHFR C677T genotype in any case, other meta-examinations did not study such an affiliation. In the studies wherein an affiliation was discovered, Asian populaces were appeared to be at a more serious danger of developing depression that was connected to the MTHFR C677T polymorphism contrasted with Caucasian populaces, and ethnicity was decidedly related with the chances proportions^42,43. Moreover, a current report investigated the impacts of gene condition cooperations and uncovered that the MTHFR C677T polymorphism associated with traumatic childhood occasions to increase the risk of recurrence of depression in patients following a 5.5-year follow-up period. Folate mediated one-carbon metabolismis a pathway that has been recently proposed to underlie weakness to depression onset, recurrence and symptomatology. This mind boggling pathway manages DNA methylation and nucleic acid synthesis⁴⁴. The MTHFR C677T polymorphism produces a thermolabile protein that may bring about degraded DNA methylation and upgraded oxidative stress⁴⁵. The improved oxidative stress may alter state of mind control and cognitive function, thereby giving a conceivable natural clarification to the potential relationship between the MTHFR quality polymorphism and depression⁴⁶.

The MTHFR C677T polymorphism causes direct hyper homo-cysteinaemia, and this is known to cause cognitive impairment. Epidemiological examinations have likewise revealed that the MTHFR C677T polymorphism gives increased risk for AD beginning⁴⁷. Two late meta-investigations reasoned that the MTHFR C677T polymorphism is identified with AD in Asians however not in Caucasians, proposing a potential part of ethnicity in genetic studies. The recurrence of the T allele is signiﬁcantly higher in Asians than it is in Caucasians⁴⁸. Moreover, the eating methodologies of AD patients in these two populaces are diverse in light of provincial and ethnic varieties, leading to different levels of patient presentation to vitamin B12, folate, and homocysteine. Together, these distinctions may add to the connection between the MTHFR C677T polymorphism and AD⁴⁹. In thought of the significant part of the ApoE ε4 allele in AD pathogenesis, a subgroup examination of ApoE ε4 allele non-transporters was performed, and it was found that the MTHFR C677T polymorphism is related with an increased risk of AD in Asians without the ε4 allele; be that as it may, this isn't seen in Caucasians^49,50. There are a few conceivable clarifications for the relationship between the MTHFR C677T polymorphism and AD⁵⁰. Firstly, in light of the fact that the MTHFR C677T polymorphism is connected to direct hyper homocysteinemia, it is conceivable that expanded homocysteine levels may potentiate amyloid depositions and this may cause an increase in cytosolic calcium, increased oxidative stress, and debilitations in DNA repair that could eventually lead to neuron apoptosis^[51]. Second, the digestion of homocysteine produces homocysteic corrosive and upgrades intraneuronal aggregation of neurotoxic A 42⁵². Diminished MTHFR movement may bring about mind district speciﬁc modifications in the methylation of Ser/Thr protein phosphatase 2 A, which is known to adjust Tau phosphorylation and gathering⁵³ Interestingly, a current neuroimaging study demonstrated that the MTHFR C677T polymorphism may advance brain atrophy by raising homocysteine levels⁴². The investigation additionally recommended that healthy life style, for example, increased intake of vitaminB12 and folate, may postpone brain atrophy, particularly in elderly T allele transporters with mild cognitive impairment⁵⁴.

Other Pathogenic Synergestic Factors:

Neuropathological studies tells about two abnormal proteins; beta amyloid and tau in which beta amyloid is linked to senile plaques and tau protein is linked to neurofibrillary tangles⁵⁵. The Amyloid Plaques and Neuro fibrillary Tangles (NFT) are regarded as two of the most prominent reasons of neuronal damage that can lead to the appearance of symptoms related to Alzheimer’s disease (AD)⁵⁶. The brain of an AD patient is characterized on the microscopic level by the presence of two classes of aberrant structures. These are the amyloid plaques present in extracellular region and neurofibrillary tangles which resided intraneuronally⁵⁴. Amyloid-β peptides are the main soluble components or building blocks of amyloid plaques whereas the tau proteins are for Neurofibrillary Tangles⁵⁷. Amassing of plaques and tangles directly correlated with the symptoms of AD.

Depression is a risk factor for the development of AD and a depressive symptomatology can regularly be found at the beginning of or during dementia⁵⁸. These depressive manifestations are not inferable to emotional reactions, but rather they could be a result of neurobiological changes in particular brain areas⁵⁹. Most likely due to the technique obtrusiveness, there is an absence of CSF contemplates evaluating Aβ levels in depression patients. Comparative CSF Aβ levels in AD and depression patients were observed, speculating the presence of normal pathophysiological components^60,61. Following examinations on elderly non demented women announced more elevated amounts of CSF Aβ levels in the individuals who were depressed. It has been studied that the lessening in CSF levels of Aβ42 might be identified with increased brain Aβ plaques or decreased soluble Aβ production in elderly people with major depression⁶².

The tau protein is the marker for NFT as discussed earlier. Scientists have sought to look for the aggregation of these proteins in AD patients. There have been reports indicating that an overall increased concentration of tau proteins have been found in Cerebrospinal Fluids (CSF) of AD patients compared to those found in the healthy controls⁶¹. These results were also upheld in studying mildly demented patients⁶². The increased tau protein concentration in CSF has also been linked to various other nervous disorders creating an overlap, however, they can be distinguished from AD on clinical grounds. It was reported in 2001 that Tau proteins are linked to Amyloid-β where injecting synthetically produced amyloid-β into the brains of the mice resulted in a five-fold increase in the formation of tangles along the areas adjacent to the sites of injection⁶³. Neuritic plaques and neurofibrillary tangles are more articulated in the hippocampus of patients with AD with a lifetime history of major depressive issue, as contrasted and patients with AD without depression history⁶⁴.

CONCLUSION:

Genetic Polymorphisms for BDNF, ApoE and MTHFR have been studied to have an enhanced risk to both depression and Alzheimer’s disease. Multiple neurobiological and pathophysiological mechanisms link these genes to both the diseases which involve defects in nerve growth factors, dysregulation in metabolism of lipoprotein and folate and inflammatory changes. Studies have examined the role of Val 66 Met BDNF polymorphism in both depression and AD, which increases the risk for developing depression in Alzheimer’s patients. Similarly association between ApoE and AD has also been studied. An AD patient with depression has a higher frequency of ApoE ε4 allele than the AD patient without depression. ApoE, however modifies the AD and depression link. The association of AD and MTHFR gene has also been examined the same way and has found the association links between both the diseases depending upon the frequency of gene the present gene. Polymorphs of these two genes can identify the development of depression in AD patients. Patients with depression who express the mentioned susceptibility genes are more prone to Alzheimer’s disease. Prophylactic treatments in future may be developed by the insights of depression leading to Alzheimer’s disease. Development of antidepressants may also be done keeping in view the comorbidity of depression and AD which may also have disease modifying effects in AD.

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Received on 20.07.2017 Modified on 11.10.2017

Research J. Pharm. and Tech 2018; 11(10): 4317-4323.

DOI: 10.5958/0974-360X.2018.00790.4