Early-onset Alzheimer's disease in 2 large Belgian families

Familial Alzheimer's disease (FAD) is a dominantly inherited condition that may present with an early onset, and myoclonus occurs frequently in the course of the disease. We report clinical and neuropathologic data on 2 large Belgian families with FAD in which we obtained 17 autopsies of the CNS. In family A, each of 11 autopsies had the typical neuropathologic features of Alzheimer's disease (AD), and there were a few cerebellar plaques in the molecular layer. In family B, in addition to the typical characteristics of AD in 6 autopsies, there were numerous amyloid plaques in the cortical cerebellar layers. In both families, we immunostained the amyloid deposits for the A4 protein, and they were negative for prion-associated protein immunoreactivity.     

Phenotypic heterogeneity in familial Alzheimer's disease: a study of 24 kindreds

We report the clinical and neuropathological characteristics occurring in 180 demented individuals from 24 kindreds with familial Alzheimer's disease (FAD). Each family had at least two affected generations, and at least one autopsy or brain biopsy was compatible with the diagnosis of AD. Forty-nine neuropathological specimens or reports were reviewed. Mean age of onset for the total group was 54.7 years +/- 11.5, with a large range of 30 to 84 years. Mean age at death was 63.5 years +/- 12.2, with a range of 46 to 85. Mean duration of disease was 8.8 years +/- 4.4, with a range of 1 to 23 years. Six findings suggested phenotypic heterogeneity in FAD. (1) Five families represented an early age of onset group with mean onset at 42 years (range 30 to 51 years) and mean disease duration of 6.7 years. (2) Eight families represented a late onset group with mean onset at 68 years (range 59 to 78 years) and a mean duration of 8.5 years. (3) Seven families were of Volga German ancestry, all originating from the same two villages in Russia. Mean age of onset was 55.9 years (range 40 to 72 years), with a mean disease duration of 10 years. This group probably represents the genetic founder effect of an autosomal dominant gene for AD. (4) One family had the unusual characteristics of neurofibrillary tangles and granulovacuolar change but no amyloid plaques, a mean disease duration of more than 11 years, and a "schizophrenia-like" onset. (5) One family with late onset also had clinical and pathological evidence for anterior horn cell disease. (6) Two autopsies in 1 family both showed remarkable rarefaction of myelin and expansion of perivascular spaces in centrum semiovale (état criblé), with marked leptomeningeal and cortical amyloid angiopathy, distinct from the other FAD brains. It remains to be determined whether the clinical and pathological differences between these families represent genetic heterogeneity at the biochemical or molecular level.     

Early-onset familial Alzheimer's disease (EOFAD)

Early-onset familial Alzheimer's disease (EOFAD) is a condition characterized by early onset dementia (age at onset < 65 years) and a positive family history for dementia. To date, 230 mutations in presenilin (PS1, PS2) and amyloid precursor protein (APP) genes have been identified in EOFAD. The mutations within these three genes (PS1/PS2/APP) affect a common pathogenic pathway in APP synthesis and proteolysis, which lead to excessive production of amyloid β. Compared with sporadic Alzheimer's disease (AD), EOFAD has some distinctive features including early age at onset, positive familial history, a variety of non-cognitive neurological symptoms and signs, and a more aggressive course. There is marked phenotypic heterogeneity among different mutations of EOFAD. Studies in presymptomatic mutation carriers reveal biomarkers abnormalities. EOFAD diagnosis is based on clinical and family history, neurological symptoms and examination, biomarker features, as well as genotyping in some cases. New therapeutic agents targeting amyloid formation may benefit EOFAD individuals.     

Amyloid plaques in the cerebellum in Alzheimer's disease

The brains of patients with a clinical history of Alzheimer's disease were collected for study. In 57 cases the diagnosis of Alzheimer's disease was confirmed histologically. The disease was of senile onset (over the age of 65 years) in 40 cases, of presenile onset in 8 cases, and there were 9 cases of Down's syndrome with Alzheimer's disease. In each case the cerebellum was examined for the presence of amyloid plaques. Cerebellar amyloid plaques were found in 31 of the 57 cases (52%) and were present in all 3 clinical groups. Amyloid involvement of the cerebral and cerebellar arteries was marked in many but not all of the cases with cerebellar amyloid plaques. The significance of cerebellar plaques is uncertain, but their presence in Alzheimer's disease is by no means as rare as previously thought. The findings are described and some preliminary clinicopathological correlations are made.     

Inhibiting the conversion of soluble amyloid-β peptide into abnormally folded amyloidogenic intermediates: relevance for Alzheimer's disease therapy

Alzheimer's disease is a degenerative disorder of the brain for which there is no cure or effective treatment. Recent studies suggest that cerebral amyloid plaques are central to the disease process. However, it is not clear which of the species going from the normal soluble amyloid-β peptide to the mature amyloid plaque is the toxic agent in the brain. Therefore, an attractive therapeutic strategy for Alzheimer's disease is to block the early steps involving the pathological conversion of the soluble peptide into the abnormally folded oligomeric intermediate precursor of the amyloid fibrils. We have engineered synthetic β-sheet breaker peptides to bind amyloid-β peptide, stabilize the normal conformation and destabilize the β-sheet rich structure of the potentially toxic intermediates and hence the formation of amyloid plaques. Results in vitro , in cell culture and in vivo suggest that β-sheet breaker peptide may be useful for blocking the pathway that lead to the formation of cerebral amyloid deposits. It remains to be proved that inhibition of the defective folding of amyloid-β peptide and/or amyloid plaque deposition could be beneficial for the therapeutic treatment of Alzheimer's disease.     

Novel presenilin 1 mutation (S170F) causing Alzheimer disease with Lewy bodies in the third decade of life

BACKGROUND: Cases of early-onset Alzheimer disease (AD) with an autosomal dominant inheritance pattern (familial AD [FAD]) are rare but have greatly advanced our understanding of the molecular pathogenesis of AD. We describe herein a kindred with very early-onset FAD (age, <40 years) with unusual pathological features and a novel mutation in the presenilin 1 (PSEN1) gene (S170F) and review the existing literature on very early-onset FAD. OBJECTIVE: To analyze the neuropathological and genetic features of a family with onset of AD in the third decade of life. DESIGN, SETTING, AND PARTICIPANTS: The proband underwent full clinical assessment and postmortem examination at the Washington University Alzheimer's Disease Research Center, St Louis, Mo. Limited pathological samples and autopsy records of 2 affected family members were available. The proband underwent screening for mutations in genes linked with FAD. RESULTS: Dementia developed in 3 family members in this kindred at a mean age of 27 years; the proband had myoclonus, seizures, and rigidity, similar to findings in previously described kindreds with PSEN1 mutations. All 3 family members were confirmed to have AD by neuropathological examination. The proband also had widespread Lewy body pathology in the brainstem, limbic areas, and neocortex; specific staining for Lewy bodies was not performed in the other 2 family members. The proband had a single mutation (S170F) in exon 6 of the PSEN1 gene, which segregates with disease. CONCLUSIONS: A novel PSEN1 mutation causes very-early-onset FAD with associated Lewy bodies. To our knowledge, this kindred has the earliest reported onset of pathologically confirmed FAD and dementia with Lewy bodies.     

One novel presenilin-1 gene mutation in a Chinese pedigree of familial Alzheimer's disease

This study is to explore whether there is presenilin 1 (PS1) gene mutation in Chinese familial Alzheimer's disease (FAD). There has been no such systemic research before in China. Using polymerase chain reaction, single strand conformation polymorphism (PCR-SSCP), followed by denaturing high performance liquid chromatograph (DHPLC) and DNA sequencing, we analyzed a Chinese family with early onset AD. The patients in this family showed a novel missense mutation in exon 4 of the PS1 gene (G to T change in codon 97), altering valine to leucine acid substitution. Because the change occurred in conserved domains of this gene, and is not present in normal controls, this novel mutation is likely to be causative of Chinese FAD.     

Comparison of clinical characteristics between familial and non-familial early onset Alzheimer’s disease

Although familial Alzheimer's disease (FAD) is an early onset AD (EAD), most patients with EAD do not have a familial disorder. Recent guidelines recommend testing for genes causing FAD only in those EAD patients with two first-degree relatives. However, some patients with FAD may lack a known family history or other indications for suspecting FAD but might nonetheless be carriers of FAD mutations. The study was aimed to identify clinical features that distinguish FAD from non-familial EAD (NF-EAD). A retrospective review of a university-based cohort of 32 FAD patients with PSEN1-related AD and 81 with NF-EAD was conducted. The PSEN1 patients, compared to the NF-EAD patients, had an earlier age of disease onset (41.8?±?5.2 vs. 55.9?±?4.8?years) and, at initial assessment, a longer disease duration (5.1?±?3.4 vs. 3.3?±?2.6?years) and lower MMSE scores (10.74?±?8.0 vs. 20.95?±?5.8). Patients with NF-EAD were more likely to present with non-memory deficits, particularly visuospatial symptoms, than were FAD patients. When age, disease duration, and MMSE scores were controlled in a logistical regression model, FAD patients were more likely to have significant headaches, myoclonus, gait abnormality, and pseudobulbar affect than those with NF-EAD. In addition to a much younger age of onset, FAD patients with PSEN1 mutations differed from those with NF-EAD by a history of headaches and pseudobulbar affect, as well as myoclonus and gait abnormality on examination. These may represent differences in pathophysiology between FAD and NF-EAD and in some contexts such findings should lead to genetic counseling and appropriate recommendations for genetic testing for FAD.     

The Clinical phenotype of two missense mutations in the presenilin I gene in Japanese patients

We report the clinical and neuropathologic phenotypes associated with two different missense mutations in the presenilin 1 (PS-1) gene in Japanese patients with early-onset familial Alzheimer's disease (FAD). In the Ah4/JPN1 pedigree a missense mutation (C→T) was found at nucleotide 1102, which is predicted to cause an alanine-to-valine missense substitution at codon 260. In this family, the disease had a mean age of onset of 40.3 years and an indolent course (range, 8–19 years). Neuropathologic studies in 3 members of this pedigree showed widespread senile plaques, neurofibrillary tangles, and neuronal loss, as well as abundant perivascular subpial amyloid deposits in the Virchow-Robin spaces and the presence of Pick-like intraneuronal inclusions in the dentate gyrus. In the second pedigree, transmitting a C→T nucleotide substitution at position 1027, leading to the missense mutation of alanine to valine at codon 285, the disease had a later onset (mean, 51 years) but a more rapid course. Comparison of the disease phenotypes associated with other missense mutations in exon 9 of PS-1 reveals no clinical or pathological phenotype, which uniquely distinguishes Alzheimer's disease associated with PS-1 mutations from other forms of early-onset FAD, implying that direct mutation screening is required to identify these cases.     

Molecular and prospective phenotypic characterization of a pedigree with familial Alzheimer's disease and a missense mutation in codon 717 of the beta-amyloid precursor protein gene.

We present prospective clinical and neuropathologic details of a pedigree segregating familial Alzheimer's disease (FAD) associated with a mutation (G----A substitution) at nucleotide 2149 in exon 17 of the amyloid precursor protein (APP) gene. This mutation, which is predicted to cause the missense substitution of isoleucine for valine at codon 717 of APP, cosegregated perfectly with the FAD trait (lod score = 3.49 at theta = 0.00). The earliest clinical manifestations of the disease relate to deficits in memory function, cognitive processing speed, and attention to complex cognitive sets. These changes occurred in the absence of changes in nonmemory language and visuospatial functions. The neuropathologic features of FAD associated with the APP717 mutation in this family include severe neuronal loss, abundant neurofibrillary tangles, amyloid plaques, and amyloid angiopathy. These results provide independent confirmation that mutations in the APP gene are linked to the FAD trait in some families.     

Neuronal RNA oxidation is a prominent feature of familial Alzheimer's disease

An in situ approach was used to identify the oxidized RNA nucleoside 8-hydroxyguanosine (8OHG) in the frontal cortex of familial Alzheimer's disease (FAD) with a mutation in presenilin-1 (PS-1) or amyloid beta protein precursor (AbetaPP) gene (n = 13, age 47-81 years). Neurons with marked 8OHG immunoreaction in the cytoplasm were widely distributed in the superior/middle frontal gyrus of FAD. Relative intensity measurements of neuronal 8OHG immunoreactivity showed that there was a significant increase in FAD compared with controls (n = 15, age 59-81 years), while there was no difference in relative 8OHG between the PS-1 and the AbetaPP FAD. Interestingly, a presymptomatic case carrying a PS-1 mutation showed a considerable level of relative 8OHG, and the increased levels of neuronal 8OHG in FAD were more prominent in cases with a lower percentage area of Abeta42 burden. These results suggest that oxidative stress is an early event involved in the pathological cascade of FAD.     

Clinical phenotype of G206D mutation in the presenilin 1 gene in pathologically confirmed familial Alzheimer's disease

Familial Alzheimer's disease (FAD) is genetically heterogeneous, autosomal dominant, with nearly 100% penetrance. In FAD, most common causative genetic mutations are presenilin 1 (PSEN1), presenilin 2 and amyloid-β protein precursor. We demonstrate a family presenting as early-onset AD with a rapid deterioration course and seizure developed after 1.5 years of symptoms. A histopathological examination of the frontal cortex showed amyloid deposition and abundant phosphorylated tau deposition. In both cases, a single nucleotide mutation from guanine to adenine at exon 7 was found in PSEN1 (c.617G>A, codon change from GGT to GAT). Though G206D mutation in PSEN1 gene was found in FAD, no clinical phenotype or pathological finding was documented. This is the first report of PSEN1 mutation (Gly206Asp) with features of seizure and a rapid progressive cognitive decline in a pathologically confirmed case of FAD.     

Familial Alzheimer's disease

A family with familial Alzheimer's disease (FAD) inherited as an apparent autosomal dominant trait is presented. Twelve individuals (6 females; 6 males) in 4 generations were affected. The disease had its onset in the late 30's, early 40's with death by age 50. Although FAD which appears to be transmitted as an autosomal dominant trait is relatively rare, such families must be identified and carefully counselled with respect to recurrence risks for subsequent generations. In this family, there are currently 20 members of Generation IV, aged 15-37, and 9 members of Generation V, aged 1-11. The majority of these individuals appear to have a 50% risk for developing this disease.     

Familial Alzheimer's disease connected with mutation in presenilin gene 1 (P117L)

We describe a Polish family with Alzheimer's disease in some of its members. Two sisters were observed and examined--also neuropathologically in the Institute of Psychiatry and Neurology in Warsaw. The disease onset was in our patients at 32 and 33 years. The first symptoms were memory loss and disorientation. Later on myoclonus and extrapyramidal stiffness were noted in both cases. Neurovisualizing examinations performed in both sisters showed diffuse brain atrophy. The symptoms increased rapidly and in short time (several months) the patients became mute and bedbound. They died at age 35 and 37 years. We were informed that the father of the patients suffered from very similar illness and died at age of 37 years and their older brother had the some symptoms and died at the age of 28 years. Post-mortem brain examination disclosed in the both hospitalized cases diffuse atrophy of the cerebral hemispheres, particularly severe in the temporal lobes. Microscopically senile plaques of various types were found in the cortex. The density of the plaques was very high but Alzheimer's fibrillary degeneration was found occasionally only. The amyloid burden in cortex of the examined brains, estimated as the measure of parenchymal amyloidosis beta, was two to six-fold higher in most areas compared with changes in sporadic AD and Down-syndrome cases. DNA was isolated from blood and tissue of both cases and from blood of their 8 children as well. In both patients mutation in presenilin 1 (PS1) gene of Prol 117 Leu was found and it was discovered that 4 persons of their progeniture were carriers of this mutation. The described mutation causes one of the earliest so far reported onset and death in FAD kindreds. Presenilin isolated from both cases and transfected into cultures of murine neuroblastoma and human kidneys provoked production of beta amyloid with increased A-beta 42/40 ratio.     

Alzheimer's disease: a model from the quantitative study of a large kindred.

In an Italian kindred (family N), early onset Alzheimer's disease has been transmitted in a Mendelian autosomal fashion since the early 18th century. The age at death of affected members of the family varies widely, and was taken as an index of the age of expression, a measure of phenotypic variability. Either a gamma or a log-normal algorithm provides the best fit for the age at death distribution. Subsets of family N widely different as to time and place have the same age at death of patients: Environment appears to play a negligible role in the expression of disease. Pairwise correlation between an affected parent and child is zero: The disease is monogenic (no major expression gene). The same stochastic distribution of age of expression, but with late onset, and after correction for death from other causes, is compatible with the epidemiology of Alzheimer's disease in general. Mendelian genetics is a possible model for Alzheimer's disease etiology.     

Genetic linkage studies in Alzheimer''s disease families

Alzheimer's disease is a devastating neurological disorder and the leading cause of dementia among the elderly. Recent studies have localized the gene for familial Alzheimer's disease to chromosome 21 in a series of early onset AD families (mean age of onset less than 60). Familial late onset AD (mean age of onset greater than 60) is a more common clinical form of the disorder. Thirteen families with multiply affected Alzheimer's disease family members were identified and sampled. Ten of these families were of the late onset Alzheimer's disease type. Simulation studies were used to evaluate the usefulness of these pedigrees in linkage studies in familial Alzheimer's disease. Linkage studies undertaken to test the localization of both early onset and late onset Alzheimer's disease families to chromosome 21 failed to establish linkage and excluded linkage from a large portion of the region where the early onset Alzheimer's disease gene was localized. These findings suggest that more than one etiology may exist for familial Alzheimer's disease and indicate the need for continued screening of the genome in familial Alzheimer's disease families.     

Neuropsychological features of familial Alzheimer's disease.

It has been proposed that early-onset familial Alzheimer's disease (FAD) and sporadic Alzheimer's disease (AD) have different causes, with FAD due to a single dominant gene with disease onset before the sixth decade, whereas sporadic AD has a later onset and is not associated with a dominant pattern of inheritance. Given these differences, we questioned whether these etiologically distinct forms of AD also differ neuropsychologically. In this study we performed neuropsychological evaluations on patients from two well-documented families with FAD and a group of patients with sporadic AD. The groups were matched on global disease severity at entry. Two groups of education- and age-matched normal controls were recruited for comparison. The groups were analyzed for psychometric findings and pattern of deficits. Both patients with FAD and patients with sporadic AD showed a similar pattern of neuropsychological impairment relative to age-matched controls, i.e., mildly to moderately impaired verbal performance and concentration, severely slowed psychomotor speed, and severely impaired delayed recall of verbal material. There were no differences in pattern suggestive of disproportionately severe anomia, amnesia, agnosia, or apraxia in the early onset FAD group, as has been reported previously.     

Apolipoprotein E genotype and neuropathological phenotype in two members of a German family with chromosome 14-linked early onset Alzheimer's disease

Molecular genetic analysis was performed in two autopsy-confirmed cases of early-onset Alzheimer's disease belonging to a large German pedigree [FAD2, according to the nomenclature of St. George-Hyslop, et al. (1987) Science 235:885–890]. The disease in this family has been linked to chromosome 14. As gene interactions are considered to influence the age of onset and tissue pathology in Alzheimer's disease, we have studied three candidate genes that could modify disease progression. In this study a new polymerase chain reaction (PCR) assay was established for apolipoprotein E genotyping in archival neuropathological tissue, exon 17 of the amyloid precursor protein gene was directly sequenced, and a candidate mutation site at nucleotide (nt) 5460 of the mitochondrial NADH dehydrogenase subunit gene ND2 was analyzed employing PCR followed by HphI digestion. Whereas no sequence variations were detected in exon 17^APP or at nt5460 of mitochondrial DNA, the apolipoprotein E genotypes of the two cases differed. Neuropathological examination revealed a higher number of A4-positive amyloid plaques and a larger total tissue area covered by A4 deposits in the 3/3 homozygote. In contrast, the number of cortical neurofibrillary tangles and the number of plaques with tau-positive neurites appeared to be higher in the 3/4 heterozygote. Our findings support the view that the ahromosome 14 genetic defect, rather than apolipoprotein E genotype, is the preeminent factor determining Alzheimer's disease pathology in this family.     

Selective loss of inhibitory neurons in the cerebral cortex in motor neuron disease

Introduction:  The pattern of β-amyloid (Aβ) deposition in cerebral amyloid angiopathy (CAA) in Alzheimer's disease (AD) suggests that Aβ is eliminated along perivascular interstitial fluid drainage pathways. The age at which accumulation of Aβ in the brain becomes significant in AD coincides with the development of cerebrovascular disease (CVD) and increasing rigidity of artery walls through arteriosclerosis.
Hypothesis:  The distribution of Aβ deposits in Alzheimer brains is influenced by CVD.
Materials and methods:  Paraffin sections of frontal, parietal, temporal and occipital lobes from six cases with Alzheimer's disease were stained for reticulin and by immunocytochemistry for Aβ and GFAP.
Results:  Three distinct patterns of Aβ deposition were seen in relation to cortical blood vessels: (i) early deposition of Aβ in cortical parenchyma was related to individual cortical arterial territories; (ii) severe capillary amyloid angiopathy and an absence of Aβ plaques were associated with thromboembolic occlusion of the feeding artery; (iii) Aβ plaques were abundant in areas devoid of capillary amyloid angiopathy.
Conclusions:  The pattern of Aβ deposition corresponds to individual intracortical arterial territories, and hence periarterial ISF drainage territories. Cerebrovascular disease influences the pattern of Aβ deposition within brain parenchyma and in vessel walls in individual arterial territories. Failure of periarterial drainage of Aβ from the brain may be related to cerebrovascular disease and is possibly due to altered arterial pulsations.