Mutations In Amyloid Precursor Protein Gene Research Articles

Probable Novel APP Met671Leu Mutation in a Chinese Han Family with Early-Onset Alzheimer's Disease.

Familial Alzheimer's disease (AD) is a rare disease caused by autosomal-dominant mutations. APP (encoding amyloid precursor protein), PSEN1 (encoding presenilin 1), and PSEN2 (encoding presenilin 2) are the most common genes cause dominant inherited AD. This study aimed to demonstrate a Chinese early-onset AD pedigree presenting as progressive memory impairment, apraxia, visual-spatial disorders, psychobehavioral disorders, and personality changes with a novel APP gene mutation. The family contains four patients, three carries and three normal family members. The proband underwent brain magnetic resonance imaging (MRI), 18F-fludeoxyglucose positron emission tomography (18F-FDG-PET), cerebrospinal fluid amyloid detection, 18F-florbetapir (AV-45) Positron Emission Computed Tomography (PET) imaging, whole-exome sequencing and Sanger sequencing. Brain MRI images showed brain atrophy, especially in the entorhinal cortex, temporal hippocampus, and lateral ventricle dilation. The FDG-PET showed hypometabolism in the frontotemporal, parietal, and hippocampal regions. 18F-florbetapir (AV-45) PET imaging showed cerebral cortex Aβ protein deposition. The cerebrospinal fluid amyloid protein test showed Aβ42/Aβ40 ratio decreases, pathological phosphor-tau level increases. Whole-exome sequencing detected a new missense mutation of codon 671 (M671L), which was a heterozygous A to T point mutation at position 2011 (c.2011A > T) in exon 16 of the amyloid precursor protein, resulting in the replacement of methionine to Leucine. The co-separation analysis was validated in this family. The mutation was found in 3 patients, 3 clinical normal members in the family, but not in the other 3 unaffected family members, 100 unrelated normal subjects, or 100 sporadic patients with AD. This mutation was probably pathogenic and novel in a Chinese Han family with early-onset AD.

A populational review of the amyloid precursor protein gene mutations relevant to alzheimer’s disease

IntroductionThe genetic component of Alzheimer’s disease was previously studied and more than sixty amyloid precursor protein (APP) gene mutations were identified. However, the populational aspects of this component were scarcely discussed despite that many of the reports mentioned the demographic ancestry of the carriers or probands.ObjectivesIn this short study, we aimed to review the APP gene mutations relevant to Alzheimer’s disease from a Populational Genetics point of view by evaluating the current literature for the demographic description of the carriers or families in which the mutations were identified.MethodsIn this regard, multiple genetic studies on the APP gene mutations relevant to Alzheimer’s disease were reviewed and the incidence of the mutations was analyzed considering the ancestry of the patients.ResultsWe found many possible scenarios regarding the incidence of the APP gene mutations in Alzheimer’s disease patients and general population. On the one hand, we could identify several mutations which were present in more than one population (eg. V615M, V717I, V717L) and on the other hand, some mutations could be observed in certain populations (eg. E693delta, the Osaka mutation, which was until now observed in Japanese patients, while E693G was found in a Swedish family). One particular case is that of the isolated populations (eg. the Icelandic population in which an APP mutation protecting against Alzheimer’s disease is more frequent in the general population as compared to the patients).ConclusionsWe were able to identify several mutations which were characteristic to many populations, but also some population-specific features regarding the APP genotypes.DisclosureNo significant relationships.

Presenilin 1 and APP gene mutations in early‐onset AD families from a southeast region of China

AbstractBackgroundEarly‐onset familial Alzheimer’s disease (EOFAD) has been reported to be associated with presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid precursor protein (APP) genes. The spectrum of mutations in Chinese patients with EOFAD was rarely investigated. Thus, this study intends to investigate the spectrum of mutations in patients with EOFAD in Chinese population.MethodWe performed a whole‐exome sequencing and described relevant clinical features in a total of 67 patients from 3 families with EOFAD.ResultA splice mutation (p.S290C) in PSEN1 and a missense mutation (p.V717I) in APP were identified.ConclusionThe variant p. S290C (c.869‐2>G) in PSEN1 in Chinese EOAD family revealed different clinical phenotype when compared with that of European.

Gene mutations associated with early onset familial Alzheimer's disease in China: An overview and current status.

BackgroundMutations of three causative genes, namely presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid precursor protein (APP), have been identified as the major causes of early‐onset familial Alzheimer's disease (EOFAD). The prevalence of causative gene mutations in patients with EOFAD has been reported in previous studies worldwide but remains unclear in China. The patients with these known mutations always show considerable clinical phenotypic variability. However, to date, there have been no detailed descriptions of the clinical phenotypes associated with these Chinese EOFAD mutations. Thus, the aim of this study was to describe all of the known mutations in three EOFAD causative genes and genotype–phenotype correlations in Chinese patients with EOFAD.MethodWe systematically searched the PubMed, MEDLINE, CNKI, VIP, and WAN‐FANG databases to find Chinese EOFAD mutations in reports from inception through May 2020.ResultWe identified 31 studies reporting mutations of three causative genes in China. 10 mutations in APP gene, 27 mutations in PSEN1 gene and six mutations in PSEN2 were discovered in Chinese EOFAD. This review summarized all these probably pathogenic mutations as well as its clinical features. To the best of our knowledge, this is the first systemic review of causative gene mutations in patients with EOFAD in China.ConclusionThe analysis of the genetic and clinical phenotype correlations in this review supports the idea that the clinical phenotype might be influenced by specific genetic defects. It also suggests genetic testing and genotype–phenotype correlations are important for the accurate diagnosis and for understanding disease‐associated pathways and might also improve disease therapy and prevention.

Presenilin 1 and APP Gene Mutations in Early-Onset AD Families from a Southeast Region of China.

Early-Onset Familial Alzheimer's Disease (EOFAD) has been reported to be associated with Presenilin 1 (PSEN1), Presenilin 2 (PSEN2), and Amyloid Precursor Protein (APP) genes. The spectrum of mutations in Chinese patients with EOFAD was rarely investigated. To investigate the spectrum of mutations in patients with EOFAD in Chinese population. We performed whole-exome sequencing and described relevant clinical features in a total of 67 subjects from 3 families with EOFAD. A splice mutation (p.S290C) in PSEN1 and a missense mutation (p.V717I) in APP were identified. The variant p. S290C (c.869-2>G) in PSEN1 in Chinese EOAD family revealed different clinical phenotypes when compared with that of Europeans.

Effects of gene mutation and disease progression on representative neural circuits in familial Alzheimer\u2019s disease

BackgroundAlthough structural and functional changes of the striatum and hippocampus are present in familial Alzheimer’s disease, little is known about the effects of specific gene mutation or disease progression on their related neural circuits. This study was to evaluate the effects of known pathogenic gene mutation and disease progression on the striatum- and hippocampus-related neural circuits, including frontostriatal and hippocampus-posterior cingulate cortex (PCC) pathways.MethodsA total of 102 healthy mutation non-carriers, 40 presymptomatic mutation carriers (PMC), and 30 symptomatic mutation carriers (SMC) of amyloid precursor protein (APP), presenilin 1 (PS1), or presenilin 2 gene, with T1 structural MRI, diffusion tensor imaging, and resting-state functional MRI were included. Representative neural circuits and their key nodes were obtained, including bilateral caudate-rostral middle frontal gyrus (rMFG), putamen-rMFG, and hippocampus-PCC. Volumes, diffusion indices, and functional connectivity of circuits were compared between groups and correlated with neuropsychological and clinical measures.ResultsIn PMC, APP gene mutation carriers showed impaired diffusion indices of caudate-rMFG and putamen-rMFG circuits; PS1 gene mutation carriers showed increased fiber numbers of putamen-rMFG circuit. SMC showed increased diffusivity of the left hippocampus-PCC circuit and volume reduction of all regions as compared with PMC. Imaging measures especially axial diffusivity of the representative circuits were correlated with neuropsychological measures.ConclusionsAPP and PS1 gene mutations affect frontostriatal circuits in a different manner in familial Alzheimer’s disease; disease progression primarily affects the structure of hippocampus-PCC circuit. The structural connectivity of both frontostriatal and hippocampus-PCC circuits is associated with general cognitive function. Such findings may provide further information about the imaging biomarkers for early identification and prognosis of familial Alzheimer’s disease, and pave the way for early diagnosis, gene- or circuit-targeted treatment, and even prevention.

Establishment of induced pluripotent stem cell line (ZZUi010-A) from an Alzheimer's disease patient carrying an APP gene mutation

Alzheimer's disease (AD) is one of the most common neurodegenerative disorders. Previous studies have identified mutations in several genes, such as amyloid precursor protein (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2), in patients with early-onset (<65years) familial AD. Recently, a patient with an APP gene mutation was identified; the dermal fibroblasts of the patient were obtained and a line of induced pluripotent stem cells (iPSCs) was successfully generated using the Sendai-virus (SeV) delivery system. The iPSC line will be useful for further study of the pathomechanism and drug screening for AD.

P3-221: Familial Alzheimer's disease associated with the V717L amyloid precursor protein gene mutation: Neuropathological characterization

Mutations in the amyloid precursor protein (APP) gene are associated with familial Alzheimer Disease. Here we report the neuropathological findings observed in the brain of an affected carrier of the V717L APP mutation. The proband presented with short-term memory loss and mild behavioral changes at age 35. He died at age 44, following a 9 years disease duration. His family history is remarkable for his father who died of heart attack at age 42 after having experienced memory loss and depression, and a sister who developed similar symptoms at age 38 and died at age 51. The proband's brain was processed for histology and immunohistochemistry (IHC). Aβ IHC was carried out using antibodies recognizing Aβ3–7, AβN3pE, Aβ10–16, Aβ17–24, AβN-40 and AβN-42. IHC for α-synuclein was also carried out. The brain (approximately 1183 grams) displayed moderate atrophy of the frontal lobe, mild atrophy of the remaining lobes, and extensive atrophy of the hippocampus and parahippocampal gyrus. Neuritic plaques (CERAD stage C) were abundant in the intermediate neocortical layers. Abundant diffuse Aβ deposits were observed in the remaining cortical layers as well as in the subpial zone. Mild amyloid angiopathy was seen, predominantly in penetrating vessels. Braak VI-tau pathology was observed, particularly affecting layer V and VI. Neuritic plaques were immunoreactive against the full panel of Aβ antibodies except for the anti-AβN-40. Diffuse deposits contained AβN-42 species but did not react with antibodies recognizing epitopes located before position 11. In the cerebellum, a few Aβ-immunoreactive diffuse deposits were seen. Occasional neuritic plaques were observed in the brainstem. IHC for α-synuclein was negative in all the examined sections. The proband's ApoE genotype was ϵ3/ϵ3. Our data suggest a heterogeneous involvement of the cortical layers by the deposition of Aβ species with specific immunohistochemical pattern. They also suggest that diffuse deposits, in the upper and lower cortical layers, are composed by N-terminally truncated Aβ species. Supported by AG10133 and Alzheimer's Association.

Atypical early-onset Alzheimer's disease caused by the Iranian APP mutation

Approximately 1% of all cases of Alzheimer's disease are inherited autosomal dominantly, and to date, three causative genes have been found, the Presenilin 1 (PSEN1) gene, the Presenilin 2 (PSEN2) gene and the Amyloid precursor protein (APP) gene. We describe atypical phenotypic features in a family with a pathogenic APP gene mutation and discuss possible explanations for these atypical features. We report a family with a history of dementia compatible with autosomal dominant transmission. The disease course in the proband was not typical for Alzheimer's disease as the diagnosis was preceded by 8 years of an isolated amnesia. Further, the proband had epilepsy with complex partial seizures and central degenerative autonomic failure as determined by clinical physiology. Sequencing the three known causative Alzheimer genes revealed a pathogenic missense mutation, APP Thr714Ala (the Iranian mutation). The atypical clinical phenotype with long prodromal phase, autonomic failure and seizures in this new proband with the APP Thr714Ala mutation illustrates the clinical heterogeneity in families with identical pathogenic mutations.

Identification of PSEN1 and APP Gene Mutations in Korean Patients with Early-Onset Alzheimer's Disease

Although mutations in three genes, amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2), have been identified as genetic causes of early-onset Alzheimer's disease (EOAD), there has been a single report on a PSEN1 mutation in Koreans. In the present study, we performed a genetic analysis of six Korean patients with EOAD. Direct sequencing analysis of the APP, PSEN1 and PSEN2 genes revealed two different mutations of the PSEN1 gene (G206S and M233T) and one mutation of the APP gene (V715M) in three patients with age-at-onset of 34, 35, and 42 yr, respectively. In addition, two patients with age-at-onset of 55 and 62 yr, respectively, were homozygous for APOE ε4 allele. One woman had no genetic alterations. These findings suggest that PSEN1 and APP gene mutations may not be uncommon in Korean patients with EOAD and that genetic analysis should be provided to EOAD patients not only for the identification of their genetic causes but also for the appropriate genetic counseling.

Clinical and Neuropathological Features of the Arctic APP Gene Mutation Causing Early-Onset Alzheimer Disease

A majority of mutations within the beta-amyloid region of the amyloid precursor protein (APP) gene cause inherited forms of intracerebral hemorrhage. Most of these mutations may also cause cognitive impairment, but the Arctic APP mutation is the only known intra-beta-amyloid mutation to date causing the more typical clinical picture of Alzheimer disease. To describe features of 1 Swedish and 1 American family with the previously reported Arctic APP mutation. Affected and nonaffected carriers of the Arctic APP mutation from the Swedish and American families were investigated clinically. In addition, 1 brain from each family was investigated neuropathologically. The clinical picture, with age at disease onset in the sixth to seventh decade of life and dysfunction in multiple cognitive areas, is indicative of Alzheimer disease and similar to the phenotype for other Alzheimer disease APP mutations. Several affected mutation carriers displayed general brain atrophy and reduced blood flow of the parietal lobe as demonstrated by magnetic resonance imaging and single-photon emission computed tomography. One Swedish case and 1 American case with the Arctic APP mutation came to autopsy, and both showed no signs of hemorrhage but revealed severe congophilic angiopathy, region-specific neurofibrillary tangle pathological findings, and abundant amyloid plaques. Intriguingly, most plaques from both of these cases had a characteristic ringlike character. Overall, our findings corroborate that the Arctic APP mutation causes a clinical and neuropathological picture compatible with Alzheimer disease.

Familial Early-Onset Dementia With Tau Intron 10 + 16 Mutation With Clinical Features Similar to Those of Alzheimer Disease

Frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) owing to the tau intron 10 + 16 mutation usually occurs with a prototypical frontotemporal dementia phenotype with prominent disinhibition and affective disturbances. To report a new FTDP-17 pedigree with the tau intron 10 + 16 mutation demonstrating a clinical phenotype suggestive of Alzheimer disease. Case reports. Regional neuroscience centers in northwest England. Patients We examined 4 members of a kindred in which 8 individuals were affected in 3 generations. All 4 patients reported memory difficulty. Marked anomia was also present, but behavioral disturbances were conspicuously absent in the early stages of disease. All patients had an initial clinical diagnosis of Alzheimer disease. No mutations were found in the presenilin or amyloid precursor protein genes. Pathologic examination of the proband showed features typical of FTDP-17, and tau gene analysis showed the intron 10 + 16 mutation. This pedigree illustrates the phenotypic variability of tau intron 10 + 16 mutations. In pedigrees with a clinical diagnosis of Alzheimer disease but without presenilin or amyloid precursor protein gene mutations, tau gene mutations may be found.

Environment- and mutation-dependent aggregation behavior of Alzheimer amyloid beta-protein.

The deposition of amyloid beta-protein in the brain is a fundamental process in the development of Alzheimerís disease; however, the mechanism underlying aggregation of amyloid beta-protein remains to be determined. Here, we report that a membrane-mimicking environment, generated in the presence of detergents or a ganglioside, is sufficient per se for amyloid fibril formation from soluble amyloid beta-protein. Furthermore, hereditary variants of amyloid beta-protein, which are caused by amyloid precursor protein gene mutations, including the Dutch (E693Q), Flemish (A692G) and Arctic (E693G) types, show mutually different aggregation behavior in these environments. Notably, the Arctic-type amyloid beta-protein, in contrast to the wild-type and other variant forms, shows a markedly rapid and higher level of amyloid fibril formation in the presence of sodium dodecyl sulfate or GM1 ganglioside. These results suggest that there are favorable local environments for fibrillogenesis of amyloid beta-protein.

Mutations in presenilin 1, presenilin 2 and amyloid precursor protein genes in patients with early-onset Alzheimer's disease in Poland

Mutations in three causative genes have been identified in patients with an autosomal-dominant form of early-onset Alzheimer's disease (EOAD). To determine the spectrum of mutations in a group consisting of 40 Polish patients with clinically diagnosed familial EOAD and 1 patient with mild cognitive impairment (MCI) and family history of AD, we performed a screening for mutations in the presenilin 1 ( PSEN1), presenilin 2 ( PSEN2) and amyloid precursor protein ( APP) genes. Four previously recognized pathogenic mutations in PSEN1 gene (H163R, M139V) and APP gene (T714A, V715A), and three novel putative mutations in PSEN1 gene (P117R and I213F) and PSEN2 gene (Q228L) were identified. The 34 patients with no mutations detected were older than the patients with mutations. A frequency of APOE4 allele was higher in this group. Frequency of mutations is relatively low (17%), possibly due to used operational definition of a patient with familial EOAD (a patient having at least one relative with early-onset dementia). It could be concluded that screening for mutations in the three genes could be included in a diagnostic program directed at patients with a positive family history or age of onset before 55 years.

Oxidative stress and reduced antioxidant defenses in peripheral cells from familial Alzheimer's patients.

We have measured the levels of typical end products of the processes of lipid peroxidation, protein oxidation, and total antioxidant capacity (TAC) in skin fibroblasts and lymphoblasts taken from patients with familial Alzheimer's disease (FAD), sporadic Alzheimer's disease (AD), and age-matched healthy controls. Compared to controls, the fibroblasts and lymphoblasts carrying amyloid precursor protein (APP) and presenilin-1 (PS-1) gene mutations showed a clear increase in lipoperoxidation products, malondialdehyde (MDA), and 4-hydroxynonenal (4-HNE). In contrast, the antioxidant defenses of cells from FAD patients were lower than those from normal subjects. Lipoperoxidation and antioxidant capacity in lymphoblasts from patients affected by sporadic AD were virtually indistinguishable from the basal values of normal controls. An oxidative attack on protein gave rise to greater protein carbonyl content in FAD patients than in age-matched controls. Furthermore, ADP ribosylation levels of poly(ADP-ribose) polymerase (PARP) nuclear substrates were significantly raised, whereas the PARP content did not differ significantly between fibroblasts carrying gene mutations and control cells. These results indicate that peripheral cells carrying APP and PS-1 gene mutations show altered levels of oxidative markers even though they are not directly involved in the neurodegenerative process of AD. These results support the hypothesis that oxidative damage to lipid, protein, and DNA is an important early event in the pathogenesis of AD.

Genetic testing for Alzheimer's disease.

Genetic factors are important in the development of Alzheimer's disease (AD). Familial AD can result from rare mutations in some genes. Other genes, such as the apolipoprotein E gene (APOE), operate as risk factors for late-onset sporadic AD. On a background of advances in the genetics of AD we suggest a way in which genetic information may be used in the diagnosis of AD. If there is a positive family history of early-onset dementia and the clinical features suggest AD, patients may be tested for presenilin and amyloid precursor protein gene mutations with appropriate pretest and post-test counselling. Predictive testing should be performed under guidelines developed by the World Federation of Neurology and the Human Genetics Society of Australasia. The usefulness of APOE genotyping as an adjunct to conventional diagnostic tests is unknown; data suggest it has low sensitivity and specificity and may have little predictive value in an individual patient. APOE genotyping should not be performed in asymptomatic individuals, except as part of an ethically approved research project; this recommendation is supported by a number of international consensus statements. APOE testing should not be used as a diagnostic test without adequate pretest and post-test counselling, education and support. APOE testing should not be used as a sole diagnostic test in the work-up of patients with AD. Genetic risk factors other than APOE require validation and should not be used routinely, except as part of an ethically approved research protocol.

Translation of the Alzheimer Amyloid Precursor Protein mRNA Is Up-regulated by Interleukin-1 through 5′-Untranslated Region Sequences

The amyloid precursor protein (APP) has been associated with Alzheimer's disease (AD) because APP is processed into the beta-peptide that accumulates in amyloid plaques, and APP gene mutations can cause early onset AD. Inflammation is also associated with AD as exemplified by increased expression of interleukin-1 (IL-1) in microglia in affected areas of the AD brain. Here we demonstrate that IL-1alpha and IL-1beta increase APP synthesis by up to 6-fold in primary human astrocytes and by 15-fold in human astrocytoma cells without changing the steady-state levels of APP mRNA. A 90-nucleotide sequence in the APP gene 5'-untranslated region (5'-UTR) conferred translational regulation by IL-1alpha and IL-1beta to a chloramphenicol acetyltransferase (CAT) reporter gene. Steady-state levels of transfected APP(5'-UTR)/CAT mRNAs were unchanged, whereas both base-line and IL-1-dependent CAT protein synthesis were increased. This APP mRNA translational enhancer maps from +55 to +144 nucleotides from the 5'-cap site and is homologous to related translational control elements in the 5'-UTR of the light and and heavy ferritin genes. Enhanced translation of APP mRNA provides a mechanism by which IL-1 influences the pathogenesis of AD.

Presence of soluble amyloid β–peptide precedes amyloid plaque formation in Down's syndrome

Abnormal and excessive accumulation of the amyloid beta-peptide (A beta) in the brain is a major and common characteristic of all Alzheimer's disease (AD) forms irrespective of their genetic background. Insoluble aggregates of A beta are identified as amyloid plaques. These deposits are thought to form when the amount of A beta is increased in the brain parenchyma as a result of either overexpression or altered processing of the amyloid precursor protein (APP). Soluble A beta ending at carboxyl-terminal residue 40 (A beta 40) and, in lesser amount, the form ending at residue 42 (A beta 42), are normal products of the APP metabolism in cell cultures. Increased secretion of soluble A beta 42 has been observed in cells transfected with constructs modeling APP gene mutations of familial forms of AD (refs 4, 5). On the basis of these in vitro data it has been hypothesized that the presence of soluble A beta 42 plays a role in the formation of amyloid plaques. Subjects affected by Down's syndrome (DS) have an increased APP gene dosage and overexpress APP. Apparently because of this overexpression, they almost invariably develop amyloid deposits after the age of 30 years, although they are free of them at earlier ages. Moreover, it has been observed that A beta 42 precedes A beta 40 in the course of amyloid deposition in DS brain. Thus, DS subjects provide the opportunity to investigate in the human brain the metabolic conditions that precede the formation of the amyloid deposits. Here we report that soluble A beta 42 is present in the brains of DS-affected subjects aged from 21 gestational weeks to 61 years but it is undetectable in age-matched controls. It is argued that overexpression of APP leads specifically to A beta 42 increase and that the presence of the soluble A beta 42 is causally related to plaque formation in DS and, likely, in AD brains.

Phenotype of chromosome 14–linked familial Alzheimer's disease in a large kindred

We report the clinical and neuropathological features of chromosome 14-linked familial Alzheimer's disease (14qFAD) in affected members of the L family. Some clinical information on all 16 known affected individuals and detailed neuropathological findings in 6 family members were available for review. Common features of the phenotype of 14qFAD in the L family included onset of dementia before the age of 50, early progressive aphasia, early-appearing myoclonus and generalized seizures, paratonia, cortical atrophy, numerous and extensive senile plaques and neurofibrillary tangles, and prominent amyloid angiopathy. Descriptions of phenotypic features were available for six additional recently defined 14q-linked FAD kindreds: the findings in four of them (FAD4, FAD2, A, B) indicated a relatively consistently shared 14qFAD phenotype, conforming closely with the specific clinical and neuropathological characteristics noted in the L family. Comparisons also suggested several ostensible phenotypic variants in 14qFAD: (1) In two 14q-linked kindreds (SNW/FAD3, FAD1), affected individuals in some instances were noted to survive to age 70 or beyond and the mean age at onset (> 49 years) in these two kindreds was somewhat higher than in their five 14qFAD counterparts (< 48 years in each); (2) in the SNW/FAD3 kindred, seizures and myoclonus were absent in all 10 subjects examined; and (3) cerebellar amyloid plaques were variably present within and among several 14qFAD kindreds. Comparisons with phenotypic features recently detailed in three kindreds (TOR3, F19, ROM) with codon 717 amyloid precursor protein gene mutations (i.e., APP717 FAD) suggested several distinctions: Prominent progressive aphasia, myoclonus, seizures, and paratonia were all apparently less prevalent in APP717 FAD, with language function predominantly spared over the initial disease course. The extent of homogeneity and heterogeneity in the clinical and neuropathological phenotype of 14q-linked FAD and its possible meaningful distinctions from the phenotypes of APP717 FAD await further determination.

The apolipoprotein E epsilon 4 allele does not influence the clinical expression of the amyloid precursor protein gene codon 693 or 692 mutations.

In 31 symptomatic and 5 asymptomatic carriers of the amyloid precursor protein (APP) gene codon 693 mutation, 10 family members without mutation, and 5 carriers of the APP gene codon 692 mutation (3 with early-onset Alzheimer dementia, 2 with cerebral hemorrhage), a high frequency of the apolipoprotein E epsilon 4 allele was found. Age at onset, age at death, occurrence of dementia, and number of strokes did not differ between APP gene mutation carriers with or without epsilon 4 allele, showing that the clinical expression of these APP mutations is not influenced by the apolipoprotein E gene.