Variant Alzheimer Research Articles

Apolipoprotein E gene in Parkinson's disease, Lewy body dementia and Alzheimer's disease.

Apolipoprotein E (Apo E) epsilon 4 allele is a risk factor for early and late onset Alzheimer's disease. This prompted us to examine other neurophyschiatric phenotypes. Epsilon 4 allele was significantly enriched in Lewy body dementia (n = 39) but not in Parkinson's disease (n = 50) or Schizophrenia (n = 175) compared to aged non-demented controls (n = 47) and the Scottish population (n = 400). We conclude that Lewy body disease should be regarded as a variant of Alzheimer's but not Parkinson's disease.

Vascular variant of Alzheimer's disease characterized by severe plaque-like beta protein angiopathy.

In the neuropathological investigations of 32 demented patients with severe cerebral amyloid angiopathy (CAA), we found an unusual case, a 90-year-old woman, presenting with the pathology of atypical Alzheimer's disease (AD). The case showed severe plaque-like angiopathy, in which all the senile plaques except for some diffuse plaques were formed around amyloid beta (/A4) protein-laden vessels. Analysis of the amyloid beta protein precursor gene from the patient revealed no mutation. Our results have indicated that, among demented patients with severe CAA, there is the vascular variant of AD characterized by severe plaque-like beta protein angiopathy.

Psychiatric symptoms and behavioural disturbances in the dementias.

This contribution will summarise the relationship between psychiatric symptoms and behavioural disturbances in dementia. The different types of symptoms will be discussed with particular relation to Alzheimer's and Parkinson's disease and results will be presented in relation to clinical symptomatology in the Lewy body variant of Alzheimer's disease.

Heterogeneity in the atypical variants of Alzheimer's disease: A case study of isolated bilateral sensorimotor impairment

Heterogeneity in the atypical variants of Alzheimer's disease: A case study of isolated bilateral sensorimotor impairment

Rate of cognitive decline in Alzheimer's disease is not affected by the alpha-1-antichymotrypsin A allele or the CYP2D6 B mutant

Patients with Alzheimer's disease (AD) show considerable heterogeneity in the rate at which they decline cognitively. The biological basis for this heterogeneity is unknown. We genotyped 86 subjects with diagnoses of probable AD to determine if they carried the alpha-1-antichymotrypsin (ACT) A allele, which has been associated with AD, or the CYP2D6 B mutant, found at increased frequency in the Lewy body variant (LBV) of AD. We then examined longitudinally-collected cognitive data to determine if these genetic markers were associated with rate of cognitive decline. Our results indicate that neither the ACT A allele nor the CYP2D6 B allele have a significant association with rate of decline on the Folstein Mini Mental State examination. Further, subjects with both the ACT A allele and the apolipoprotein ϵ4 allele showed no evidence of accelerated decline. These findings suggest that any increased risk of developing AD or LBV conferred by these markers is not necessarily accompanied by a more rapid rate of decline.

Rate of cognitive decline in Alzheimer's disease is not affected by the alpha-1-antichymotrypsin A allele or the CYP2D6 B mutant

Patients with Alzheimer's disease (AD) show considerable heterogeneity in the rate at which they decline cognitively. The biological basis for this heterogeneity is unknown. We genotyped 86 subjects with diagnoses of probable AD to determine if they carried the alpha-1-antichymotrypsin (ACT) A allele, which has been associated with AD, or the CYP2D6 B mutant, found at increased frequency in the Lewy body variant (LBV) of AD. We then examined longitudinally-collected cognitive data to determine if these genetic markers were associated with rate of cognitive decline. Our results indicate that neither the ACT A allele nor the CYP2D6 B allele have a significant association with rate of decline on the Folstein Mini Mental State examination. Further, subjects with both the ACT A allele and the apolipoprotein ϵ4 allele showed no evidence of accelerated decline. These findings suggest that any increased risk of developing AD or LBV conferred by these markers is not necessarily accompanied by a more rapid rate of decline.

Neuropsychological Deficits Associated with Diffuse Lewy Body Disease

Diffuse Lewy body disease (DLBD), in its pure form, is a neuropathologic condition in demented patients that is characterized by subcortical and diffusely distributed neocortical Lewy bodies with little or no concomitant Alzheimer's disease (AD) pathology. Clinically, DLBD patients initially present with dementia of insidious onset and subsequently develop mild extrapyramidal motor dysfunction. The present study retrospectively examined the neuropsychological test performance of five patients with DLBD and compared their performance to that of equally demented patients with neuropathologically confirmed “pure” AD. The results showed that the DLBD patients were globally demented with deficits in memory, attention, language, psychomotor performance, and “executive” functions, and a strikingly severe deficit in visuospatial and visuoconstructive abilities. The visuoconstructive and psychomotor impairments of the DLBD patients were significantly worse than those of the AD patients, whereas the memory performance of the AD patients was worse than that of the DLBD patients. These results indicate that DLBD without concomitant AD pathology can produce a global dementia with aspects of both cortical and subcortical dysfunction and suggests that Lewy body pathology contributes importantly to the clinical manifestation of the Lewy body variant of AD.

Corticobasal degeneration syndrome: a case of Lewy body variant of Alzheimer?s disease

Corticobasal degeneration syndrome (CBDS) is a well-described entity, although there are some cases in which clinical manifestations do not link with pathological findings. We present a 60-year-old man with a clinical course of CBDS. Postmortem examination demonstrated the features of the Lewy body variant of Alzheimer disease (LBVA). Different neurological evaluations showed a progressive motor disorder with alien hand and parkinsonism affecting mainly the left side. His neuropsychological examination was comparable with biparietal dysfunction, especially apraxias and signs of Gertsmann's syndrome. MRI and SPECT imaging revealed parietal, temporal and occipital involvement. We conclude that the CBDS is a heterogeneous pathological entity.

Diagnostic accuracy of Alzheimer's disease: a neuropathological study.

This prospective study focused on the accuracy of diagnosis of Alzheimer's disease (AD). We recruited 100 dementia patients and 20 controls who underwent a systematic evaluation. The clinical diagnosis of probable AD or possible AD according to the NINCDS-ADRDA criteria was assigned in 69% of the patients, 21% had vascular dementia (VaD) (DSM-III-R) and 8% had mixed AD-VaD; only 2 patients (2%) had the Lewy body variant of AD (AD-LB). During a 3-year period 57 patients died, 53 of them (93%) being autopsied. Neuropathological examination according to the CERAD criteria showed definite AD in 27 out of 28 (96%) patients diagnosed as probable AD. In the possible AD group, the diagnostic accuracy was also high, 86% showed at least some degree of AD pathological alterations. The neocortical senile plaque scores correlated significantly with tangle scores in patients with AD pathology, and there was a significant negative correlation between age of onset and neocortical tangle scores. The concordance between the clinical diagnosis and pathological findings was clearly lower in VaD than in AD. In the clinical VaD group, 8 of 10 patients had at least some degree of AD changes together with vascular changes and only 2 of 10 patients had pure VaD. This study confirms the high accuracy of the NINCDS-ADRDA criteria for diagnosing AD. In contrast, uncertainty in the clinical diagnosis of VaD should be taken into account, for example, in drug trials with VaD patients.

Apolipoprotein E polymorphism in patients with different neurodegenerative disorders

Apolipoprotein E (ApoE) is associated with Alzheimer's disease (AD) neurofibrillary tangles and β-amyloid protein in senile plaques. There are three common alleles of ApoE, designated ϵ2, ϵ3 and ϵ4. We studied Finnish patients with neurodegenerative disorders: AD, vascular dementia (VAD), Parkinson's disease (PD), PD + dementia (PDD), Lewy body variant of AD (LB), frontal dementia (FD), and Down's syndrome (DS), as well as control individuals (C). The ApoE genotypes and corresponding allele frequencies of 188 patients and 60 controls were determined by digestion of ApoE polymerase chain reaction products with the restriction enzyme Hha I. The ApoE ϵ4 allele frequency was 0.17 for C, 0.44 for AD, 0.35 for VAD, 0.10 for PD, 0.38 for PDD, 0.28 for LB, 0.39 for FD, and 0.17 for DS. We found significant differences in genotype frequency between AD/C, AD/PD and AD/DS. Our results suggest that, beside AD, an increased frequency of ε4 may also be involved in other dementing neurological disorders.

Apolipoprotein E alleles and brain vascular pathology in Alzheimer's disease.

The presence of apolipoprotein E (ApoE)-E4 allele has been implicated as a risk factor for Alzheimer's disease (AD). We examined the occurrence of ApoE 4 alleles in AD associated with cerebral amyloid angiopathy and other vascular lesions. We found significantly high frequency of the ApoE 4 allele in AD with moderate to severe CAA. The frequency of the allele was also high in AD cases with other vascular lesions such as multiple infarcts and lacunes. As previously reported, we confirm a greater frequency of the ApoE 4 allele in the diffuse Lewy body variant of AD. Our results suggest ApoE 4 allele to be a significant factor in the development of CAA in AD. While this may be related to increased brain amyloid load as a consequence of ApoE genotype, the possibility exists that ApoE may be a specific factor in vascular abnormalities associated with AD.

Spastic tetraplegia as an initial manifestation of familial Alzheimer's disease.

Two sisters with familial Alzheimer's disease developed spastic gait disturbance as an initial manifestation. Their gait disturbance progressed gradually, followed by dementia a few years later. Post-mortem examination of one of the patients disclosed degeneration of the thalamus and corticospinal tract in addition to numerous senile plaques and neurofibrillary tangles in the neocortex, both of which were confirmed by immunohistochemistry. This is the first report in which clinicopathological evaluation is sufficient to establish a new variant of Alzheimer's disease presenting initially as spastic tetraplegia.

Cortical Lewy body-containing neurons are pyramidal cells: laser confocal imaging of double-immunolabeled sections with anti-ubiquitin and SMI32.

To characterize neurons containing cortical Lewy bodies (LBs), vibratome sections of the superior temporal cortex from eight patients with the LB variant of Alzheimer's disease (LBV) were double-immunolabeled with anti-ubiquitin (a marker of LBs) and anti-nonphosphorylated neurofilament (SMI32; a marker of pyramidal cells) or parvalbumin (PV; a marker of interneurons) and were viewed with a laser-scanning confocal microscope. Almost all (96.1%) the LB-containing neurons were positive for SMI32, but not for PV. Furthermore, the average numbers of SMI32-immunoreactive neurons in layers 3 and 5 were 63% and 77% of those in controls, respectively. PV-immunoreactive neurons showed a greater than 40% decrease. These findings indicate that cortical LB-containing neurons are pyramidal cells and suggest that in LBV, there may be some differences in the degenerative processes effecting pyramidal cells and interneurons.

The α-Helical to β-Strand Transition in the Amino-terminal Fragment of the Amyloid β-Peptide Modulates Amyloid Formation

Amyloid-beta peptide (A beta) consists of a hydrophobic C-terminal domain (residues 29-42) that adopts beta-strand conformation and an N-terminal domain (amino acids 10-24) whose sequence permits the existence of a dynamic equilibrium between an alpha-helix and a beta-strand. In this paper we analyzed the effect of the alternate N-terminal conformations on amyloid fibril formation through the study of the analogous A beta peptides containing single amino acidic substitutions. The single mutation of valine 18 to alanine induces a significant increment of the alpha-helical content of A beta, determined by Fourier transform infrared spectroscopy and circular dichroism and dramatically diminishes fibrillogenesis, measured by turbidity, thioflavine T binding, Congo red staining, and electron microscopic examination. In hereditary Dutch cerebral hemorrhage with amyloidosis (a variant of Alzheimer's disease), the substitution of glutamine for glutamic acid at position 22 decreased the propensity of the A beta N-terminal domain to adopt an alpha-helical structure, with a concomitant increase in amyloid formation. We propose that A beta exists in an equilibrium between two species: one "able" and another "unable" to form amyloid, depending on the secondary structure adopted by the N-terminal domain. Thus, manipulation of the A beta secondary structure with therapeutical compounds that promote the alpha-helical conformation may provides a tool to control the amyloid deposition observed in Alzheimer's disease patients.

The CYP2D6B mutant allele is overrepresented in the Lewy body variant of Alzheimer's disease

Approximately one-fourth of neuropathologically confirmed cases of Alzheimer's disease (AD) also have brainstem and neocortical Lewy bodies, constituting a Lewy body variant of AD. Because Lewy bodies are a pathologic hallmark of Parkinson's disease (PD), this subpopulation of AD subjects may have the same risk factors as PD subjects. Analyses of the cytochrome P450 CYP2D6-debrisoquine 4-hydroxylase mutant B allele, a susceptibility gene for PD, revealed a higher representation of this allele in the Lewy body variant of AD than in pure AD or non-AD without Lewy bodies.

Ophthalmological aspects of Alzheimer??s disease

Patients with Alzheimer's disease may present to the ophthalmologist with visual symptoms that precede or overshadow the features of dementia. This visual variant of Alzheimer's disease has been recognized only recently and typically appears in late middle age as progressive visuospatial and reading dysfunction, with normal visual acuity and fields. Common features include simultanagnosia and the other features of Balint's syndrome, and variable hemispatial neglect and hemianopia. The neuroimaging and neuropathological findings in this Alzheimer's variant are distinct and suggest disruption of occipitoparietal visual projections. The identification of the visually symptomatic patient who is destined to develop other signs of Alzheimer's disease depends on the use of appropriate screening tests, including text reading, figure-ground discrimination, and other bedside tests of visuospatial attention and perception.

Synapse alterations in the hippocampal-entorhinal formation in Alzheimer's disease with and without Lewy body disease

We quantified by microdensitometry the immunoreactivity (IR) to monoclonal antibodies (SP6, SP12, SP15 and SP18) against various synaptic proteins in the molecular layers of the dentate gyrus, CA4, CA3, CA1, subiculum and entorhinal cortex in Alzheimer's disease (AD), Lewy body variant of AD (LBV) and diffuse Lewy body disease (DLBD). A significant decrease in SP6 IR was observed in almost all regions in AD (28.4–70.1%, mean 41.3%), LBV (19.0–42.5%, mean 26.8%) and DLBD (19.9–31.7%, mean 27.1%) compared to controls. In addition, SP6 IR in the outer molecular layer of the dentate gyrus was strongly correlated with tangle count in the entorhinal cortex ( r = −0.70, P < 0.002), suggesting loss of perforant pathway projection. Although the decrease in SP12 and SP15 IR was less pronounced, the mean values were decreased in dementia. Furthermore, SP12 and SP15 labeled a large number of neuritic plaques, and SP15 occasionally stained cortical LBs. The present findings indicate (i) that in the hippocampal-entorhinal formation, the decrease of synapse protein IR in AD is more severe than that in LBV and DLBD, (ii) that synaptic markers detect a subset of dystrophic neurites in the plaques and (iii) that synapse proteins are involved in the formation of cortical LBs.

Apolipoprotein-E ε-4 is associated with increased neurofibrillary pathology in the Lewy body variant of Alzheimer's disease

Brains from demented patients with both Alzheimer's disease (AD) pathology and brainstem and neocortical Lewy bodies have fewer neurofibrillary tangles than pure AD, but share with AD an increased apolipoprotein-E ε-4 (APOE4) allelic frequency. We applied the Braak and Braak AD neuropathology staging protocol, based on entorhinal and neocortical neurofibrillary pathology, to 40 such Lewy body variants of AD (LBV) and 97 cases of pure AD and compared the results in APOE4 positive and APOE4 negative subgroups. APOE4 was associated with more severe neurofibrillary pathology in LBV but not in pure AD, where a ceiling effect appears to be operative.

The apolipoprotein E allele epsi;4 is overrepresented in patients with the Lewy body variant of Alzheimer's disease

We determined apolipoprotein E (ApoE) genotypes in 122 autopsied demented patients. The frequency of the ApoE epsilon 4 allele was 39.6% in Alzheimer's disease (AD), 29.0% in the Lewy body variant of AD (LBV), and 6.25% in diffuse Lewy body disease. For AD and LBV patients, the epsilon 4 frequency was significantly higher than that reported in nondemented controls (10 to 15%). Therefore, LBV and AD share ApoE epsilon 4 as a genetic risk factor, providing further evidence that these conditions overlap.

Relative abundance of Alzheimer A beta amyloid peptide variants in Alzheimer disease and normal aging.

The Alzheimer A beta amyloid peptide (A beta) is the principal proteinaceous component of amyloid associated with Alzheimer disease (AD). We have determined the relative abundance of A beta structural variants present in amyloid from brains of 10 individuals with sporadic AD, 2 individuals with familial AD carrying specific mutations in the Alzheimer amyloid precursor protein gene, and 5 nondemented elderly controls. A procedure of isolation based on the extreme insolubility of A beta amyloid was used. The purified, nondigested A beta was analyzed by N-terminal sequencing and electrospray-ionization mass spectrometry. Three principal A beta variants were detected--A beta-(1-40), A beta-(1-42), and A beta-(11-42)--in all brains analyzed. The predominant variant in sporadic AD was A beta-(1-40), whereas the principal A beta variant in nondemented elderly controls was A beta-(1-42). The ratio A beta-(1-40)/A beta-(1-42) differed by 10-fold between brains from nondemented controls and those with sporadic AD.