Alzheimer and Autism: A tale of shifting hypothesis
The Alzheimer disease is rewarded as one of the most prevalent neurodegenerative disease in the world. It is characterized in medical literature as a progressive form of dementia, typically known as loss of brain function. The disease is immedicable and begins with slight and poorly recognized loss of memory, which become more severe over time and eventually leads to death. The common symptoms include difficulty in remembering recent events, perplexity, thinking and judgement, language disorder, agitation, and hallucinations. The regional specificity of neurological abnormality in Alzheimer disease is linked with higher level cognitive functions in the neocortex and hippocampus. Clinical diagnosis of Alzheimer disease is based on signs of gradually progressive dementia and usually relies on behavioural/judgment examination, neuro-imaging and clinical-neuropathologic evaluation. Neuropathologic observations such as intra-neuronal neurofibrillary tangles (containing tau protein), β-amyloid neuritic plaques and gross cerebral cortical atrophy (on CT and MRI) and diffuse cerebral hypometabolism (on PET) by neuroimaging are some of the accurate standards for diagnosis of Alzheimer disease. Molecular and genetic testing in early-onset familial Alzheimer disease (EOFAD, caused by mutations in one of three genes APP, PSEN1, PSEN2) are also considered affirmative for diagnosis. The cause and progression of disease is a subject of debate and poorly understood. Supportive treatment such as medication is used to hold up the disease progression rate. The presently available drug therapies for Alzheimer are based on drugs that boost cholinergic activity by inhibiting acetylcholinesterase. The fundamental theory behind their usage is based on the fact that Alzheimer disease is caused by reduced synthesis of the neurotransmitter acetylcholine. The use of these drugs have been reported to generate a modest but useful cognitive benefit in a minority of affected individuals (e.g., donepezil, rivastigmine, galantamine etc).
Genetic basis of Alzheimer’s disease
Majority of studies suggests sporadic nature of Alzheimer disease (~ 75%). However, nearly 25% of all cases of Alzheimer’s disease are familial and out of which around 95% cases are observed at late onset (age >60-65 years) and remaining 5% at early onset (age <65 years). It has been observed that hereditary (chromosomal and genetic) factors are directly involved in the pathogenesis of the disease. A number of genes have been reported to be directly involved in increasing the risk of disease. The most well studied and established genetic association came from familial early-onset Alzheimer disease (FEOAD). The familial early-onset Alzheimer disease is inherited in an autosomal dominant pattern and credited due to mutations beta-amyloid precursor protein (APP) and presenilins (PSEN1 and 2) genes. The beta-amyloid precursor protein after cleavage produces amyloid β. It has been observed that mutations in APP gene results in abnormal cleavage of beta-amyloid precursor protein, thus generating a close relative of the beta-amyloid protein that results in plaque formation. It has been observed that ~10-15% cases of familial early-onset are due to mutation in beta-amyloid precursor protein (APP). The proteins encoded by PSEN (presenilin) genes work in cleavage of amyloid precursor protein. Mutations in either one or both PSEN1 and PSEN2 gene result in inaccurate cleavage of APP. Thus, PSEN (presenilin) genes are also allied with advancement of familial early-onset Alzheimer disease. It has been observed that mutations in PSEN1 and PSEN2 account for around 30%-70% and 5% of familial early-onset Alzheimer disease. However, mutations in PSEN (1 and 2) and APP are not always associated with all cases of familial early-onset Alzheimer disease. Therefore, it is noteworthy that other genes (yet not described) may play an essential role in familial early-onset Alzheimer disease.
Alzheimer and Autism: Associations between neurodevelopmental and neuropsychiatric disorder
At psychological level, both Autism and Alzheimer share a number of features including, catatonic state, disrupted sleep, difficulty with balance and language comprehension, and attention transition issues and a lot. Studies conducted on neurodevelopmental and neuropsychiatric disorders develop a strong belief of genetic overlapping between Alzheimer and Autism. There is growing interest among researchers and clinicians concerning association between Alzheimer and Autism, the two clinically divergent disorders. Both Alzheimer’s and Autism patients have significantly similar abnormal findings in the brain including, extreme deposition of metal ions such as mercury (Hg), reduced Acetylcholine (neurotransmitter), existence of viral or bacterial infection and markedly increase in ß-amyloid (1-42). Although, Alzheimer and Autism are caused by divergent mechanism but a number of genes have been found to be common among the two diseases. This conceptual framework of involvement of same genes is based on recent experimental evidences. A large number of genes have been proposed to contribute in pathology of both Alzheimer and Autism. These include, Catechol-O-methyltransferase (involved in degradation of catecholamines such as dopamine, epinephrine, and norepinephrine), Fragile X mental retardation protein (FMRP), Major histocompatibility complex, class I, A (HLA-A), Phosphatase and tensin homolog (PTEN), and Solute carrier family 6 member (SLC6A4, neurotransmitter transporter, serotonin).
However, the most extensively established hypothesis is centralized around the beta-amyloid (βA), widely studied in Alzheimer disease. Support for this assumption comes from the frequent studies which report the increased level of secreted beta-amyloid precursor protein (APP), in patients with autistic behaviour and aggression. Studies conducted by Lahiri and co-workers at Department of Psychiatry, Indiana University School of Medicine observed that plasma level of secretary beta-amyloid precursor protein- alpha form (sAPPa) was drastically higher in autistic patients. Furthermore, it has also been observed that brain-derived neurotrophic factor (BDNF) and sAPPβ levels are appreciably decreased in plasma of autistic patients. It is suggested that increased levels of sAPPα and decreased level of sAPPβ or imbalance in levels of sAPPα and sAPPβ (proteolytic products of APP by α- and β-secretase) directly contribute in brain overgrowth in autistic patients. These studies were further supported by Wegie and co-workers working at New York State Institute for Basic Research in Developmental Disabilities. They have observed the accumulation of beta-amyloid precursor protein (APP) in brain tissue of children with Autism. Wegie and co-workers reported the accumulation of intracellular N-terminally truncated Aβ-42 in brain neurons of cortex and cerebellar cortex and dentate nucleus. Taken together, these studies provide evidences of common similarities and active participitation of abnormal processing or defective non-amyloidogenic processing of APP in both Alzheimer and Autism disorder.
Another common link between Alzheimer and Autism is mercury relationship. It has been suggested that mercury directly affect the neurological system and causes disastrous neurological damage via disturbing immune system and lithium level in brain, inflicting oxidative burden and depleting glutathione level. It has been observed that mercury has a tendency to accumulate at very high levels in the cerebral cortex and hippocampus. Studies have shown that mercury concentration is found to be altered in the brain and body fluids in Alzheimer and Autistic patients. Furthermore, mercury toxicity induces subtle changes in brain morphology similar to that of Alzheimer and Autism disorder. Studies conducted by Hock and collageous at Psychiatric University Hospital, Basel, Switzerland highlighted a direct relationship between mercury toxicity and beta amyloid secretions. They have shown that mercury inflicts the release of beta-amyloid peptide 1-40 and 1-42 into cell culture supernatants and suggested mercury implication in pathophysiological mechanisms of Alzheimer diseases. Meanwhile, studies conducted by Geier and co-workers at Institute of Chronic Illnesses, USA suggested that mercury in synergism of toxins and pathogens inflicts brain pathology in ASD. Apart from this, elevated immune responses have been observed in the brain of patients from Alzheimer and Autism diseases. The underlying studies demonstrated that increased cytokines level in the brain tissue specially tumor necrosis factor alpha (TNF-alpha) can affect immune response, brain inflammation and possibly the susceptibility to Alzheimer and Autism disorders.
It has been a long time since the first case of Alzheimer and Autism were reported. A number of presumptions have been proposed so far concerning the molecular and genetic link of the two diseases. Conclusion materialize from literature studies suggested that abnormal processing or defective non-amyloidogenic processing of APP represent one of the most affirmative and frequent link between the Autism and Alzheimer disease. Thus, beta amyloid production could be a milestone in the pathophysiological mechanisms of Autism and Alzheimer disease.
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