The genes associated with early-onset Alzheimer’s disease

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that accounts for the most cases of dementia, which is characterized by the deposition of dense plaques of amyloid beta (Aβ) plaques and neurofibrillary tangles consisting of hyperphosphorylated tau. The two main types of AD can be classified as early-onset AD (EOAD, onset < 65 years) and late-onset AD (LOAD, onset ≥ 65 years). Evidence from family and twin studies indicate that genetic factors are estimated to play a role in at least 80% of AD cases. The first milestone with linkage analysis revealed the mutations in APP, PSEN1, and PSEN2 genes that cause EOAD. But pathogenic mutations in these three genes can only explain a small fraction of EOAD families. The additional disease-causing genes have not yet been identified. This review provides an overview of the genetic basis of EOAD and the relationship between the functions of these risk genes and the neuropathologic features of AD. A better understanding of genetic mechanisms underlying EOAD pathogenesis and the potentially molecular mechanisms of neurodegeneration will lead to the development of effective diagnosis and treatment strategies for this devastating disease.

Anagliptin protects neuronal cells against endogenous amyloid β (Aβ)-induced cytotoxicity and apoptosis

“…Familial-associated APP and PS1 mutations cause excessive secretion of Ab and are intensively linked with cytotoxicity in AD brains [19]. Transgenic (Tg) mouse models that overexpress familial AD-associated APP mutant or PS1 mutant have been widely used in preclinical studies of AD [20].…”

Exercise-Induced Modulation of Neuroinflammation in Models of Alzheimer’s Disease

“…Attempts to mimic in rodents the pathology of AD seen in the post-mortem human brain have been informed mainly by identification of the amyloid composition of AD plaques and by genetic information garnered from patients with familial Alzheimer’s Disease (FAD), now commonly referred to as Early Onset Alzheimer’s Disease (EOAD). EOAD, which usually becomes symptomatic in patients under the age of 65, is a rapidly progressing form of the disease and accounts for only 5–10% of all AD cases [ 45 ]. Mutations in three genes encoding APP, and the γ -secretase complex subunits presenilin 1 (PS1) and presenilin 2 (PS2), are causal in EOAD and are considered diagnostic [ 4 ], although these gene mutations account for only a small number of families with EOAD, indicating that additional AD-causing genes remain to be identified [ 45 ].…”

“…EOAD, which usually becomes symptomatic in patients under the age of 65, is a rapidly progressing form of the disease and accounts for only 5–10% of all AD cases [ 45 ]. Mutations in three genes encoding APP, and the γ -secretase complex subunits presenilin 1 (PS1) and presenilin 2 (PS2), are causal in EOAD and are considered diagnostic [ 4 ], although these gene mutations account for only a small number of families with EOAD, indicating that additional AD-causing genes remain to be identified [ 45 ]. The sporadic form of AD, although influenced by environmental factors, is also impacted by genetics, the major gene investigated thus far being the ɛ 4 allele of the apolipoprotein gene (APOE) [ 46–48 ].…”

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“…This group represents approximately about 3% of the diseased patients. The other classification group is late-onset AD (LOAD), also known as sporadic, which is due to polymorphisms of apolipoprotein E (APOE) 4, accounts for the remaining 97% of the cases [4,5]. The sign and symptoms are categorized into mild, moderate, and severe, including memory loss, language problems, mood swings, behavioral changes, unable to learn new info, agitation, aggression, ataxia (loss of muscle control and balance), aphasia (impairment of language), amnesia (forgetfulness), loss of visuospatial function (ability to recognize faces and objects), praxis (ability to perform purposeful movements), confusion, and motor disturbances [6,7].…”