Analysis of the butyrylcholinesterase gene and nearby chromosome 3 markers in Alzheimer disease

The K-variant of butyrylcholinesterase (BCHE-K) recently has been reported to be associated with Alzheimer disease (AD) in carriers of the epsilon4 allele of the apolipoprotein E (APOE) gene. We have re-examined the frequency of the BCHE-K allele in a large data set of both sporadic and familial cases of AD disease, and we have also examined the segregation of three genetic markers on chromosome 3 near BCHE . Our data neither support an association of BCHE-K with sporadic or familial AD, nor do they suggest the existence of another gene nearby on chromosome 3 as a common cause of familial AD.     

No association between the K variant of the butyrylcholinesterase gene and pathologically confirmed Alzheimer's disease

The polymorphic K variant of the butyrylcholinesterase ( BCHE-K ) gene recently has been demonstrated to have an elevated frequency in Alzheimer's disease (AD) patients carrying the epsilon4 allele of the apolipoprotein (APO E) gene when compared with a control population. We therefore genotyped a large series of pathologically confirmed AD patients and controls to confirm this association. We found no change in the frequency of this genetic variant, either in the AD group as a whole or in early- or late-onset patients when compared with age-matched controls. Stratification of these groups with reference to the APO E epsilon4 allele also showed no difference between AD and control groups. To determine if a biological effect were present, we also looked at senile plaque and neurofibrillary tangle densities in the frontal, temporal, parietal and occipital cortices in AD patients either carrying or not carrying a copy of the K variant. We found no difference in plaque or tangle load between these two groups in either the total, late-onset or early-onset AD subjects. Stratification of the total AD group in terms of APO E epsilon4 allele possession, and further comparison of plaque and tangle load between carriers and non-carriers of BCHE-K still failed to disclose a relationship between BCHE-K and AD. We conclude that in the population studied here there is no association between BCHE-K and AD, or that if such a relationship exists it is precluded by another, as yet unknown factor.     

18O exchange in suspensions of red blood cells: determination of parameters of mass spectrometer inlet system

A variety of anatomic and functional neuroimaging findings are associated with Alzheimer's disease (AD). One of the strongest imaging associations identified is between AD and hippocampal atrophy. The epsilon4 allele of the apolipoprotein E (ApoE) gene increases the risk of developing AD and lowers the mean age of onset of the disease. The purpose of this study was to assess the association between hippocampal volume and ApoE polymorphisms in elderly control subjects and in patients with probable AD. We performed magnetic resonance imaging-based volume measurements of the hippocampus in 125 cognitively normal elderly controls and 62 patients with probable AD. ApoE genotyping was performed by using standard methods. Hippocampal volumes were significantly smaller in AD cases than in control subjects. Hippocampal volumes did not differ significantly within either clinical group on the basis of ApoE genotype. Both the epsilon4 allele of ApoE and hippocampal atrophy were significantly but independently associated with AD.     

Microvasculopathy is associated with the number of cerebrovascular lesions in hereditary cerebral hemorrhage with amyloidosis, Dutch type

BACKGROUND AND PURPOSE: Microvascular changes such as microaneurysms and fibrinoid necrosis have been found in the presence of cerebral amyloid angiopathy (CAA). These CAA-associated microvasculopathies (CAA-AM) may contribute to the development of CAA-associated hemorrhages and/or infarcts, hereafter referred to as "cerebrovascular lesions." Hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCHWA-D) is an autosomal dominant form of CAA, in which the amyloid angiopathy is pathologically and biochemically similar to sporadic CAA associated with aging and Alzheimer disease. To determine the significance of CAA-AM for CAA-associated cerebrovascular complications, we investigated the association between CAA-AM and cerebrovascular lesions in HCHWA-D patients. METHODS: In a previous autopsy study we semiquantitatively scored CAA-AM in 29 HCHWA-D patients. In the present study we reviewed clinical charts and autopsy protocols of these same patients. We investigated whether CAA-AM was associated with age at death, number of cerebrovascular lesions, duration of clinical illness, hypertension, and atherosclerosis. RESULTS: An association was found between CAA-AM and the number of cerebrovascular lesions (P = 0.009). The presence of microaneurysmal degeneration was most strongly associated with the number of cerebrovascular lesions (P < 0.001). In addition, we found an association between atherosclerosis and the CAA-AM score (P = 0.047). Hypertension was not associated with CAA-AM. CONCLUSIONS: Our findings support previous reports suggesting an important role of secondary microvascular degenerative changes in CAA-associated cerebrovascular lesions and suggest an aggravating effect of systemic atherosclerosis, but not hypertension, on the evolution of CAA-AM. These findings may be of relevance to understanding cerebrovascular complications of sporadic or Alzheimer disease-associated CAA.     

Herpes simplex virus type 1 in brain and risk of Alzheimer's disease

BACKGROUND: The apolipoprotein E epsilon 4 (APOE-epsilon 4) allele is a risk factor for Alzheimer's disease (AD), but it is neither essential nor sufficient for development of the disease. Other factors-genetic or environmental-must therefore have a role. By means of a PCR we have detected herpes simplex virus type 1 (HSV1) in latent form in brains of elderly people with and without AD. We have postulated that limited reactivation of the virus causes more damage in AD patients than in elderly people without AD because of a difference in the hosts. We now report the APOE genotypes of AD patients and non-AD sufferers with and without HSV1 in brain. METHODS: DNA was extracted from 84 samples of brain from 46 AD patients (39 temporal lobe, 39 frontal lobe, three hippocampus) and from 75 samples of brain from 44 non-AD elderly people (33 temporal lobe, 36 frontal lobe, six hippocampus). PCR amplification was used to detect HSV1 thymidine kinase gene and the host APOE gene. FINDINGS: By multiple logistic regression, the APOE-epsilon 4 allele frequency was significantly higher in the patients positive for HSV1 in brain than in the HSV1-negative AD group, the HSV1-positive non-AD group, or the HSV1-negative non-AD group (52.8% vs 10.0%, 3.6%, and 6.3%, respectively). The odds ratio for APOE-epsilon 4 in the HSV1-positive AD group compared with HSV1-negative non-AD group was 16.8 (95% CI 3.61-77.8) and in the HSV1-negative AD group, 1.67 (0.21-13.4). We also compared APOE genotypes of 40 people who had recurrent cold sores and 33 non-sufferers; the APOE-epsilon 4 allele frequencies were 36% and 9%, respectively (p < 0.0001). INTERPRETATION: These findings suggest that the combination of HSV1 in brain and carriage of an APOE-epsilon 4 allele is a strong risk factor for AD, whereas either of these features alone does not increase the risk of AD. The findings in people with cold sores support our hypothesis that APOE-epsilon 4 and HSV1 together are damaging in the nervous system.     

Quantification by additive RT-PCR of HIV-1 RNA plasma levels in different stages of HIV-1 infection

Recent reports have shown an association between an intronic polymorphism of the presenilin-1 (PSEN1) gene and late-onset (age at onset > 65) familial and sporadic (no family history) Alzheimer disease (AD). The reported association was independent of the effect of the only previously identified gene associated with late-onset AD, APOE. Blood samples were obtained from members of 122 multiplex AD families, 42 unrelated cases of AD with positive family histories of dementia, 456 sporadic cases of AD, and 317 controls of similar ages at examination to the cases. These samples were genotyped for an intronic polymorphism of the PSEN1 gene, located 3' to exon 8, and the data analyzed for evidence of association or linkage. The samples were also genotyped for APOE and the data analyzed to see if the association or linkage changed when controlling for APOE genotype. There was no statistically significant increase (at alpha = .01) in allele 1 (199 bp) or genotype 1/1 in the sporadic AD cases, or in a random sample of one affected from each multiplex family, compared to controls. When examining the effect of the PSEN1 polymorphism while controlling for APOE genotype, APOE genotype was strongly associated with AD, but the PSEN1 polymorphism genotype was not. Model-trait dependent (lod score) and independent (Sim1BD) methods detected no evidence of linkage between PSEN1 and AD. In this independent dataset, the previously reported association between the intronic PSEN1 polymorphism and AD cannot be confirmed, and the conclusion that PSEN1 is a major susceptibility gene for late-onset AD is not supported.     

Memory profiling with paired associate learning in Alzheimer's disease, mild cognitive impairment, and healthy aging.

Mild cognitive impairment (MCI) is associated with increased risk of developing Alzheimer's disease (AD), but up to 40% of cases do not develop AD. Examining a case's specific memory profile may help distinguish which MCI cases will progress to AD: An encoding profile is suggestive of incipient AD, whereas a retrieval profile suggests an alternative etiology. Paired associate learning (PAL) tasks are sensitive for preclinical and early detection of AD, but existing tasks do not enable memory profiling. We developed a novel PAL task enabling the differentiation of memory profiles in 19 people with AD, 17 people with amnestic MCI, and 33 normal elderly controls. Unexpectedly, the AD group demonstrated a retrieval profile for PAL using yes-no recognition, although an encoding profile was evident for forced-choice recognition and for the California Verbal Learning Test--Second Edition (Delis, Kramer, Kaplan, & Ober, 2000). There was considerable heterogeneity within the AD and MCI groups as well as intraindividual discordance for memory profiles. The findings challenge the clinical application of memory profiling in the differential diagnosis of AD, and, by extension, question its potential application in the assessment of MCI. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

No association between the low density lipoprotein receptor-related protein (LRP) gene and late-onset Alzheimer's disease in a community-based sample

It is now commonly known that possession of the epsilon4 allele of the apolipoprotein E (APOE) gene confers an increased risk for both familial and sporadic Alzheimer's disease (AD), in a dose-dependent way. Other genes that may play a role in AD, either through independent association with the disease or through modification of the existing APOE risk, have been reported with conflicting results. One such gene, the low density lipoprotein receptor-related protein (LRP) gene, was recently reported by two groups to be associated with AD, although the groups identified different risk-conferring alleles. Both studies were based on clinic-derived AD populations (one American, one French), and both reported only marginally significant results. We have genotyped a community-based AD and control population at this LRP polymorphism and find no association between the variants at that polymorphism and the occurrence of AD. Further, despite the biochemical relationship between LRP and the ApoE protein, we find no significant statistical interaction between the alleles at these loci.     

A newly identified polymorphism in the apolipoprotein E enhancer gene region is associated with Alzheimer's disease and strongly with the epsilon 4 allele

Apolipoprotein E allele 4 (apoE epsilon 4) is a major risk factor for late-onset AD. Inheritance of this allele is associated with an earlier age of onset of dementia in individuals with AD. It is unknown whether other polymorphisms in the apoE gene may influence the effect of apoE epsilon 4 on AD. We screened portions of the promoter enhancer element and of the apoE receptor binding domain for other polymorphisms that could affect risk of AD. In particular, a C/G polymorphism at position +113 of the apoE mRNA in the apoE intron 1 enhancer element (IE1) has been recently identified. We found no other polymorphisms. We studied the relationship of the two alleles of the IE1 polymorphism with AD and found an apparent association between IE1 G and AD (n = 94; p = 0.0515). However, the IE1 G allele is also closely associated with apoE epsilon 4 (p < 0.0001). When the presence of apoE epsilon 4 is covaried, the association between the IE1 G allele and AD is no longer statistically significant (odds ratio = 1.29, 95% confidence interval: 0.44, 3.78). In contrast, epsilon 4 is still highly associated with AD when IE1 G is controlled for (odds ratio = 5.91, 95% confidence interval: 3.29, 10.63). Furthermore, there is no significant association between the age of onset of dementia and the inheritance of the G allele. We believe that the apparent association between IE1 G and AD is a consequence of the association between the epsilon 4 and IE1 G alleles.     

Genetic susceptibility and head injury as risk factors for Alzheimer's disease among community-dwelling elderly persons and their first-degree relatives

We performed a community-based study to investigate the relationship of genetic susceptibility and head injury to Alzheimer's disease (AD) in 138 patients with AD and 193 healthy elderly control subjects. Data concerning presence or absence of dementia and certain exposures were also obtained from 799 first-degree relatives of the patients and 1,238 first-degree relatives of the control subjects. Adjusting for age, gender, and other risk factors, the odds ratio for AD associated with head injury was 3.7 (95% confidence interval [CI], 1.4-9.7). The association was highest for head injuries that occurred after age 70. The risk of AD was higher in first-degree relatives of patients with onset prior to age 70 than in relatives of control subjects (risk ratio [RR] = 2.5; 95% CI, 1.1-5.6). The risk was not increased for relatives of patients with onset of AD at age 70 or older. Compared with relatives without head injury, the risk of AD was increased among both head-injured relatives of patients (RR = 5.9; 95% CI, 2.3-14.8) and head-injured relatives of control subjects (RR = 6.9; 95% CI, 2.5-18.9). Our results are consistent with the hypothesis that severe head injury and genetic susceptibility are associated with AD. Both associations concur with current concepts regarding the role of amyloid in AD. Although we regard head injury, like genetic susceptibility, to be a putative risk factor for AD, the temporal relationship between head injury and AD warrants further investigation.     

Cerebral amyloid angiopathy. A review

Cerebral amyloid angiopathy (CAA) is a condition characterized by amyloid deposition in cerebral blood vessels. It occurs most frequently in association with clinical Alzheimer's disease but also occurs in some nondemented elderly people. CAA is a cause of spontaneous cerebral hemorrhage and may therefore present as a sudden unexpected death in an elderly person. The amyloid is deposited in cortical blood vessels, and on hematoxylin-eosin sections takes the form of pink hyaline thickening of arteries and arterioles, often with narrowing of the lumina. For diagnosis apple-green birefringence after Congo red staining is the most widely practiced and reliable tool. CAA-related hemorrhage may also occur in any lobe of the cerebrum close to the external surface and may occur at multiple sites and at the same or different times. CAA-related hemorrhage may occur in the setting of trauma necessitating distinction between the two and raising the question of whether it precipitated trauma or vice versa. Usually CAA-related hemorrhage is infrequent in sites where traumatic hemorrhages occur, and traumatic hemorrhages are often associated with other hemorrhages in sites typical for trauma. Five cases demonstrating many of the clinical and pathological features of CAA-related hemorrhage are presented. In two of the five cases, the hemorrhage followed trauma, suggesting that trauma as a precipitating factor for CAA-related hemorrhage may be more common than is generally recognized. CAA-associated hemorrhage should be considered in the differential diagnosis of cerebral hemorrhage in the elderly whether or not dementia is present.     

Effect of a chronic high-salt diet on whole-body and organ sodium contents of Dahl rats

A prior history of depression and the epsilon 4 allele of apolipoprotein E (APOE) have each been associated with development of Alzheimer's disease (AD). In a sample of 142 elderly twins from a large study of dementia, we examined the relation of major depression, APOE genotype and AD using time-dependent proportional hazards models. Compared against the risk for AD with no history of depression and no epsilon 4 allele, the risk ratio for AD with two epsilon 4 alleles was 2.87 (C.I. = 1.56-5.28), with one epsilon 4 allele, 1.82 (C.I. = 1.09-3.04) and with late-onset depression and no epsilon 4 allele, 2.95 (C.I. = 1.55-5.62). There was no suggestion of an interaction between prior depression and APOE genotype in their effects on AD risk. Results were similar when the sample was stratified by twin pair, so that a single genetic marker is unlikely to explain the relation among depression, APOE, and dementia. Risk ratios declined substantially with increasing intervals between the onset of depression and AD. Thus, for many individuals, the association of depression and AD may reflect the occurrence of prodromal depressive symptoms rather than a true risk relationship.     

ApoE allele frequencies in Italian sporadic and familial Alzheimer's disease

Recent studies have provided evidence of association of apolipoprotein E (ApoE) epsilon 4 allele and late onset familial and sporadic Alzheimer's disease (AD). Epidemiological studies have established allelic variation at the ApoE locus. We have analyzed the ApoE gene polymorphism in a sample of 446 Italian subjects. Our data confirm a significant association between epsilon 4 allele and sporadic AD. The frequency of epsilon 4 allele in early onset familial AD patients was comparable to control values suggesting that epsilon 4 allele does not represent a risk factor for early onset familial AD (EOFAD). Moreover, we found a not previously reported association between ApoE epsilon 2 allele and sporadic AD and EOFAD.     

The effects of Alzheimer disease on driving-related abilities

Ten Alzheimer disease (AD) patients and 12 healthy elderly controls were evaluated on two tests of driving-related abilities: the Driver Performance Test (DPT) and the Driving Advisement System (DAS). Subjects were administered a battery of neuropsychological tests to determine if severity of dementia in AD correlates with driving performance. On the DPT, the AD patients scored in the average range in two of five skill areas (predicting the effects of a hazard, deciding how to avoid it); below average in two areas (searching for a hazard, executing evasive actions); and poorly in one area (identifying hazards). The elderly controls scored at an average level in all five skill areas. On the DAS, AD patients were significantly slower than the elderly controls on simple, two-choice, and conditional reaction time tests and were much slower than drivers in general. The AD patients' performances on two cognitive tests, the Mini-Mental State Examination (MMSE) and the Category Fluency Test, correlated significantly with aspects of performance on the DPT and the DAS. Although these are preliminary results from a pilot investigation, they suggest that AD patients' driving-related abilities are adversely affected by the disease and that driving-related performance tests and neuropsychological tests may be useful in assessing the impact of AD on driving.     

Comparative evolution of Alzheimer disease, vascular dementia, and mixed dementia

OBJECTIVE: To compare the evolution of Alzheimer disease (AD), vascular dementia (VaD), and mixed dementia by cognitive domain. SETTING: The University of Western Ontario Dementia Study, which is a registry of cases of dementia seen for secondary and tertiary assessment in a university memory disorders clinica with extensive follow-up data and histopathological confirmation of clinical diagnoses. PATIENTS: One hundred twenty-nine patients with definite or probable AD, 12 patients with definite or probable VaD, and 36 patients with definite or probable mixed dementia. METHODS: Patients were grouped as having an early, moderate, or advanced stage of disease according to the extended scale for dementia (ESD). The ESD was subdivided into cognitive domains, and the domain scores were compared for each stage of disease by diagnostic category with the use of a 2-way analysis of variance with repeated measures. RESULTS: As expected, the scores in all domains decreased significantly with increasing severity. There was a significant difference in the decline in memory among the diagnostic groups (P = .02) that was mostly attributable to the difference between AD and mixed dementia (P = .03), with the difference between AD and VaD only approaching significance (P = .06). There was a similar finding for praxis. The interaction between diagnosis (AD and VaD) and severity was significant only for memory (P = .02), showing a less severe memory deficit at onset but a proportionately more rapid progression in VaD and arithmetic ability (AD and mixed dementia [P = .03]). CONCLUSIONS: Alzheimer disease, VaD, and mixed dementia evolve similarly as assessed using cognitive domains obtained by subdivision of the ESD in a patient population derived from a memory clinic and by analyzing VaD as a single entity. Only memory impairment evolves differently between AD and VaD, with this depending on the severity. Memory is more severely impaired in the early stage of AD; however, with increasing severity of dementia, memory impairment in VaD accelerates and catches up with AD at the level of moderate impairment. The differences between AD and mixed dementia are greater than those between mixed dementia and VaD, suggesting an important role for the ischemic component of mixed dementia. Simple neuropsychological tools (eg, the ESD) may be incapable of distinguishing between AD and VaD, and more focused instruments may be required. Inherent bias in case selection may prevent extrapolation of these results to VaD in general, but the neuropsychological criteria for VaD may need to vary, depending on the severity.     

No increased incidence of Alzheimer's disease in elderly schizophrenics

There is currently controversy as to the morphological basis of cognitive impairment in elderly schizophrenics. In contrast to previous findings, recent studies have found no increased frequency of Alzheimer's disease (AD) pathology in elderly schizophrenics. We examined 99 consecutive autopsy cases of patients over the age of 55 years from a psychiatric hospital who met the DSM-III-R and ICD.10 criteria for schizophrenia (mean age 69.5 +/- 8.25 years; mean duration of illness 35.15 +/- 10.1 years), 56% showing moderate to severe dementia. All brains were blindly reviewed for evidence of AD using CERAD criteria and Braak staging of neuritic AD lesions. "Definite" AD (CERAD C, Braak stage V) was seen in 2 cases aged 56 and 67 years, respectively [2% of total or 1/68 (1.4%) of those over age 65]. "Probable" AD (CERAD B, Braak stages IV-V) were seen in 5 cases aged 71-89 years (mean 79 years; 5% of total or 7.3% of those over age 65), and 1 case each with multiple cerebral infarcts and with Parkinson's disease pathology. In addition, 2 females aged 82 and 89 years, respectively, revealed senile dementia with tangles (NIA, CERAD negative; Braak stage IV), 1 with hippocampal sclerosis. The total incidence of definite and probable AD in this cohort was 7.1% or 8.7% for those over age 65. This is in line with other recent studies showing that the frequency of AD in elderly schizophrenics may be equal or even less than in the general population. The reasons for this negative association and the basis of cognitive deficits in elderly schizophrenics--those with dementia usually showing significantly lower brain weight--await further elucidation.     

The apolipoprotein E gene, attention, and brain function.

The ε4 allele of the apolipoprotein E (ApoE) gene is associated with alterations in brain function and is a risk factor for Alzheimer's disease (AD). Changes in components of visuospatial attention with ApoE-ε4, aging, and AD are described. Healthy middle-aged adults without dementia who have the ApoE-ε4 gene show deficits in spatial attention and working memory that are qualitatively similar to those seen in clinically diagnosed AD patients. The findings support an association between ApoE polymorphism and specific components of visuospatial attention. Molecular mechanisms that may mediate the ApoE-attention link by modulating cholinergic neurotransmission to the posterior parietal cortex are discussed. Studies of attention and brain function in ApoE-ε4 carriers without dementia can advance knowledge of the genetics of visual attention, may enhance understanding of the preclinical phase of AD, and may lead to better methods for early AD detection. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

MR T2 relaxometry in Alzheimer's disease and age-associated memory impairment

A prolonged MR T2 relaxation time was proposed to mark the presence and severity of Alzheimer's disease (AD). We studied the value of T2 relaxometry in diagnosing early AD. T2 was measured from 54 patients with AD, 25 subjects with age-associated memory impairment (AAMI), 18 elderly and 16 young controls. The AD patients had longer T2 in the right hippocampal head (104 +/- 11 ms) and tail (98 +/- 10 ms) than age-matched controls (95 +/- 5 and 92 +/- 9 ms, respectively). This prolongation was not related to age. In the AD group, the T2 of the left hippocampal head also correlated with the clinical severity. The T2 of the amygdala did not differ across the groups. Increased T2 in the temporal and parietal white matter and the thalamus related to increasing age rather than to the diagnostic category. The AAMI subjects had T2 comparable with those of age-matched controls. Despite the prolongation of T2 in the AD group the possible diagnostic value was compromized by a substantial overlap between the study groups. We, thus, conclude that the T2 relaxometry is not a reliable method for diagnosing early AD.     

Complete-type DiGeorge syndrome treated by bone marrow transplantation

Since information concerning reflux oesophagitis in the elderly is limited, particularly in Japan, the severity and symptomatic profiles of reflux oesophagitis in elderly patients were investigated. One hundred and nineteen patients with reflux oesophagitis found among 2278 endoscopy cases between 1993 and 1996 were investigated in this study. The patients were divided into two groups, elderly and non-elderly. The severity of reflux oesophagitis was estimated by the Los Angeles classification. The presence or absence of typical symptoms (heartburn and regurgitation) was determined by interview. Reflux oesophagitis was not only more frequently found in the elderly group, but was more severe than in the non-elderly. Although the degree of manifestation of typical symptoms was similar between the elderly and the non-elderly with high-grade oesophagitis, the elderly patients with mild reflux oesophagitis were less symptomatic than the non-elderly. Mild reflux oesophagitis in the elderly may be missed due to its rarity of typical reflux symptoms and a substantial number of elderly persons might have subclinical reflux oesophagitis.