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Study of hereditary cases of disease resistance reveals possible Alzheimer's treatment.

Illustration of the influence of a combination of various hereditary traits on the development of the disease.
For example, Family members who carry a rare gene mutation called Presenilin 1 (PSEN1) E280A, have a 99.9% risk of developing early-onset Alzheimer's disease.
The researchers confirmed that the woman in this case carried the PSEN1 E280A mutation, which caused early-onset Alzheimer's in her other family members. However, she also had two copies of the APOE3ch gene variant, while no other affected family member carried two copies of this variant.

However, she did not develop signs of the disease until her seventies, nearly three decades after her expected age of onset. The researchers suspect that she may have been protected because in addition to the gene mutation causing early-onset Alzheimer's in her family, she also had two copies of the APOE3 Christchurch (APOE3ch) gene variant.

Imaging tests showed that the woman had only minor neurodegeneration. She did have large amounts of amyloid protein deposits, a hallmark of Alzheimer's disease, in her brain. But the amount of tau tangles, another hallmark of the disease, and the one more correlated with how thinking and memory are affected, was relatively low.

A list of hereditary mutations in genes
that lead to various biological and physiological effects on the development of Alzheimer's disease.

This section contains detailed examples of how inherited mutations in genes lead to various physiological effects, such as the early onset of Alzheimer's disease, as well as less pathogenic forms of amyloid peptides.
The figure shows a diagram of an amyloid peptide indicating hereditary mutations that have different distinctive features at the physiological level, and also have different characteristics in the studied physical interactions with other molecules (with amyloid peptides, oligomers, molecular complexes).

The figure shows those hereditary mutations that will be studied in detail for resistance, toxicity, aggregation kinetics, manifestations of Alzheimer's disease and other diseases.
Fig.1. Amino acid sequence of the ABeta(11–42) peptide, with its missense mutations being indicated. AAR numbering is given in two variants: for the peptide itself and relative to its predecessor protein APP.


APP encodes amyloid precursor protein, a transmembrane protein which is cleaved to form amyloidogenic Aβ peptides. Mutations in APP are associated with familial forms of early onset Alzheimer's disease as well as with Cerebral Amyloid Angiopathy (CAA). Pathogenic mutations generally alter processing by secretases, leading in an overall increase in Aβ production and/or a change in the ratio of specific Aβ peptides.
The mutation was described in an individual affected by a form of early onset dementia consistent with Alzheimer's disease. The patient presented with progressive deficits across several cognitive domains, including short-term memory, mathematical ability, and verbal fluency. (Kaden et al., 2012).

In vitro, this mutation makes APP a poor substrate for cleavage by α-secretase, with reduced production of total sAPP, and especially sAPPα. Although mutations in the Aβ region typically enhance Aβ toxicity, the Aβ42 K16N peptide was less harmful to neuroblastoma cells than wild-type Aβ42. However, the mutant peptide was highly toxic when mixed in equimolar amounts with wild-type Aβ, the expected situation in a patient heterozygous for the mutation. Similarly, although the mutant Aβ peptide formed predominantly low-n oligomers in vitro, when mixed with wild-type Aβ it aggregated into high-n oliogmers. The Aβ K16N peptide was also much less efficiently degraded by neprilysin (Kaden et al., 2012).
A21G APP A692G (Flemish)
Affected individuals were diagnosed with Alzheimer's disease or cerebral hemorrhage associated with cerebral amyloid angiopathy. The mean age at onset in this family was 45.7 ± 7.3 years (Hendriks et al., 1992).

Neuropathologic examination confirmed AD, congophilic angiopathy, and hemorrhagic infarction. In this family, dementia onset ranged from 39 to 54 years of age (Brooks et al., 2004).

Biological Effect
Aβ peptides carrying the Flemish mutation have relatively low aggregation propensity in vitro, including dimerization (Murakami et al., 2002; Meinhardt et al., 2007; Huet et al., 2006). Conformational changes are thought to explain the Flemish mutation's inhibitory effect on self-assembly and nucleation. However, fibril formation was promoted through interaction with gangliosides in the vascular wall, which may partly explain the propensity of Flemish Aβ to deposit in the vasculature (Yamamoto et al., 2005; Yagi-Utsumi and Dobson 2015). Flemish mutation A21G (A692G in full-length APP) leads to AD accompanied by extensive Aβ deposition

E22G APP (Arctic mutation)
Aβ deposition in the brains was wide-spread and profuse. Virtually all parenchymal deposits were composed of non-fibrillar. Most cerebral cortical plaques appeared targetoid with centres containing C-terminally (beyond aa 40) and variably N-terminally truncated Aβ surrounded by coronas immunopositive for Aβx-42.

In Arctic AD brain differentially truncated abundant Aβ is deposited in plaques of variable numbers and shapes in different regions of the brain. The extracellular non-fibrillar Aβ does not seem to cause overt damage to adjacent neurons or to induce formation of neurofibrillary tangles, supporting the view that intracellular Aβ oligomers are more neurotoxic than extracellular Aβ deposits. Finally, similarly as the cotton wool plaques in AD resulting from exon 9 deletion in the presenilin-1 gene, the Arctic plaques induced only modest glial and inflammatory tissue reaction [5].
Neuropathology No signs of strokes or vascular lesions were found by brain imaging (Nilsberth et al., 2001). Neuropathology was available for only one mutation carrier and showed neuritic plaques and neurofibrillary tangles consistent with a diagnosis of AD (Kamino et al., 1992). Cortical PiB retention was very low in two Arctic mutation carriers compared with both noncarrier siblings and two individuals with other pathogenic mutations (APP Swedish and PSEN1 H163Y).

Arctic Aβ40 forms protofibrils at an increased propensity and faster rate compared with wild-type Aβ40 (Nilsberth et al., 2001).
E22K APP E693K (Italian)
Neuropathology Neuroimaging showed small to large hematomas, subarachnoid bleeding, scars with hemosiderin deposits, small infarcts, and leukoaraiosis. Aβ immunoreactivity was detected in the walls of leptomeningeal and parenchymal vessels and in the neuropil. This disease is distinguished from Alzheimer's disease with CAA by the absence of neurofibrillary changes and neuritic plaques (Tagliavini et al., 1999; Bugiani et al., 2010).
CAA caused by the Italian or Dutch Aβ variants is uniquely characterized by deposition of Aβ in the smooth muscle cells surrounding the cerebral vasculature as compared to the typical Aβ pathology in sporadic AD, which is found mostly in brain parenchyma
The absence of neuritic plaques and tangles made it possible to distinguish the disease from familial AD with CAA and to call it hereditary cerebral hemorrhage with amyloidosis (HCHWA).

Biological Effect It is possible that this variant affects the conformation of Aβ peptides changing their rate of fibrillization. Indeed, a variant in this same position and associated with a similar phenotype, E693Q, accelerates polymerization into protofibrils and fibrils.

E22Q APP E693Q (Dutch)

The discovery of this mutation was an early demonstration that a variant in the APP gene could cause severe amyloid deposition (Levy et al., 1990; van Broeckhoven et al., 1990; Fernandez-Madrid et al., 1991).

Neuropathology This mutation is associated with severe amyloid deposition in cerebral vessels, hemorrhages, and diffuse plaques in brain parenchyma (Timmers et al., 1990). Extensive Aβ accumulates in the cerebral vessels, especially the meningeal arteries and the cerebro-cortical arterioles. In people with HCHWA-D, the amount of CAA is correlated with dementia, whereas parenchymal plaque density and intraneuronal neurofibrillary tangles are not (Natté et al., 2001).

Biological Effect This mutation results in the accumulation of Aβ in cerebral vessel walls. This pathology leads to cell death and loss of vessel wall integrity, which in turn makes the vessels prone to obstruction and rupture, manifesting clinically as hemorrhages and infarcts. In vitro, this mutation accelerates Aβ aggregation, leading to increased fibril formation (Wisniewski et al., 1991).This mutation is associated with high levels of β-sheet conformation and induction of apoptosis in cerebral endothelial cells compared with wild-type Aβ (Miravalle et al., 2000)
Affected individuals presented with a hereditary syndrome involving hemorrhagic stroke, dementia, leukoencephalopathy, and occipital calcifications. Age of onset in this family was 58 to 66 years.
Overall, symptom onset in this family ranged from 38 to 47 years of age.

Neuropathology Neuropathological examination of the original Iowa proband revealed severe cerebral amyloid angiopathy, widespread neurofibrillary tangles, and abundant Aβ40 in plaques. The proband and an affected brother also had microscopic hemorrhagic lesions and cortical calcifications in the occipital lobe (Grabowski et al., 2001). Neuropathological examination in the Irish patient, LM, confirmed a large occipital hemorrhage with severe amyloid angiopathy of meningeal, cerebro-cortical, and cerebellar parenchymal arteries and veins.
L34V APP L705V
The proband and three affected cousins carried the mutation while an unaffected 74-year-old cousin did not, suggesting cosegregation of the mutation with disease.
At age 62, the carrier suffered multiple, large intracerebral hemorrhages over a four-month period, the last of which was fatal. Notably, except for brief periods immediately following each hemorrhage, her cognition remained intact. As in the original report of this mutation, there is a family history of hemorrhagic strokes in individuals in their 40s to 70s that is consistent with an autosomal dominant pattern of inheritance.

Neuropathology. The amyloid deposition appeared to selectively affect vessel walls. There was no evidence of Aβ parenchymal deposits (either diffuse or neuritic plaques), nor were neurofibrillary tangles or dystrophic neurites observed (Obici et al., 2005).
This variant was detected in one out of 188 individuals with Parkinson's disease with dementia (Schulte et al., 2015). This individual presented with resting tremor, and also developed bradykinesia, rigor, postural instability, and dementia. An uncle also had PD. The variant was absent in 188 PD cases without dementia and 376 controls.
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