P. C. Gaskell

Specificity, sensitivity, and predictive value of apolipoprotein-E genotyping for sporadic Alzheimer's disease

BACKGROUND We aimed to determine the specificity, sensitivity, and predictive value of apolipoprotein E (APOE) genotyping in 67 consecutive patients with clinical diagnoses of sporadic Alzheimers disease (AD) who underwent necropsy. METHODS We studied patients who attended the Duke Memory Disorders Clinic and were diagnosed as having probable AD. These patients were followed up until they died. APOE genotyping was done during life in most cases, but in some brain tissue obtained at necropsy was used. Members of known AD families were excluded. FINDINGS After neuropathological examination 57 (85%) of 67 of our patients were confirmed as having AD including all 43 who had at least one APOE-epsilon 4 allele. None of the patients found not to have AD carried an epsilon 4 allele. In this series, the specificity of the epsilon 4 allele was 100%, the sensitivity 75%, the positive predictive value 100%, and the negative predictive value 42%. In this necropsy-confirmed series, the epsilon 4/epsilon 4 genotype predicted AD with 100% accuracy. The epsilon 3/epsilon 4 and epsilon 2/epsilon 4 genotypes were also unexpectedly highly specific for AD. INTERPRETATION Data from hundreds of necropsy-confirmed non-AD patients in other longitudinal necropsy series will allow the predictive value of APOE genotypes to be assessed with useful confidence limits.

Hereditary motor and sensory neuropathy, X‐linked A half century follow‐up

The existence of an X-linked sensorimotor peripheral neuropathy has been debated. We reevaluated the original family, and present data on 13 affected males and 25 obligate or probable heterozygous females, documenting the devastating nature of the disease in the men and the extremely variable degree of clinical involvement in the carriers. Use of DNA probes indicates that the gene lies in the DXYS1-p58-1 region of the X-chromosome.

Lewy body and Alzheimer pathology in a family with the amyloid-β precursor protein APP717 gene mutation

Abstract Mutations in the amyloid precursor protein (APP) gene cause one form of early onset familial Alzheimer’s disease (AD). One such family has been studied genetically and neuropathologically and represents the basis of the present report. Four siblings with the APP717 Val to Ile mutation, aged 59, 65, 61 and 64 years, apolipoprotein E (APOE) genotyped 2,4 (first three) and 2,3 respectively, had severe AD, Braak stage VI with frequent neurofibrillary tangles in the primary visual cortex, Brodmann area 17. The first one also met McKeith criteria for the limbic stage of dementia with Lewy bodies but did not have substantia nigra Lewy bodies. The second two met McKeith criteria for the neocortical stage of dementia with Lewy bodies and both had substantia nigra Lewy bodies. The fourth had AD but no Lewy bodies. A cousin without the APP717 mutation who was APOE 3, 4, developed dementia at age 60 and died at age 75. She had severe cerebrovascular atherosclerosis, less severe AD, Braak stage V, with sparing of area 17. She also had Lewy bodies in the substantia nigra and in the cortex and met McKeith criteria for neocortical stage of dementia with Lewy bodies. Extrapyramidal features were present in all five. Lewy bodies have been described in 53% of reported autopsies on individuals with the APP717 Val to Ile mutation coincident with dementia and AD neuropathologic changes. These observations suggest an association between the chromosome 21 APP mutation and Lewy body formation, possibly mediated by other environmental or genetic factors.

Neuropathological features of frontotemporal dementia and parkinsonism linked to chromosome 17q21-22 (FTDP-17): Duke family 1684

Frontotemporal dementia with parkinsonism (FTDP-17) is an autosomal dominant disorder that presents clinically with dementia, extrapyramidal signs, and behavioral disturbances in mid-life and progresses to death within 5 to 10 years. Pathologically, the disorder is characterized by variable neuronal loss and gliosis in the frontal and temporal lobes, limbic structures, and the midbrain. Autopsied individuals from some kindreds display abundant neurofibrillary change while others, including a single affected individual from Duke Family 1684, lack distinctive histological features and exhibit only mild neuronal loss and gliosis in limbic structures and subcortical nuclei when examined by routine silver stain. Recently, mutations in the microtubule associated protein tau have been shown to segregate with the disease in this family and in many other affected kindreds. In order to examine the distribution of tau deposits, we performed tau immunohistochemistry, immunoblotting, and immunoelectron microscopy of tau-containing filaments. Immunohistochemistry revealed numerous tau deposits within glial cells and within neurons. Twisted ribbon-like filaments observed by immunoelectron microscopy were immunodecorated with tau AT8 antibody. Sarkosyl-insoluble tau extracted from the hippocampus and cortex migrated as 2 major bands at 64 and 68 kilodaltons and a minor band at 72 kilodaltons, which after alkaline phosphatase treatment appeared to contain mainly tau isoforms with 4 repeats. Furthermore, the ratio of soluble tau with 4 to 3 microtubule-binding repeats was increased. The role of tau mutations in this disorder is discussed in this paper.

Tight linkage of apolipoprotein C2 to myotonic dystrophy on chromosome 19

The cDNA and genomic probes for apolipoprotein C2 detect two restriction fragment length polymorphisms on chromosome 19. The combined estimated percentage of heterozygosity, assuming equilibrium, is approximately 75%, ie, apolipoprotein C2 is informative in 75% of matings. We have analyzed over 350 individuals in large multigenerational families for linkage of apolipoprotein C2 to myotonic muscular dystrophy. The maximum lod score was 16.29 with the maximum recombination fraction (𝛉) of 0.02, with 95% confidence limits for 𝛉 of 0.001 to 0.065. Thus, apolipoprotein C2 is useful in carrier detection and prenatal diagnosis with an accuracy of about 98%.

No association or linkage between an intronic polymorphism of presenilin-1 and sporadic or late-onset familial alzheimer disease

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 α = .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 (SimIBD) 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. Genet. Epidemiol. 14:307–315,1997.

No association between very low density lipoprotein receptor (VLDL-R) and Alzheimer disease in American Caucasians

The very low density lipoprotein receptor gene (VLDL-R) is a receptor for apolipoprotein-epsilon (APOE)-containing lipoproteins, and thus has been suggested as a possible risk factor for Alzheimer disease (AD). Recently, Okuizumi et al. [Nature Genet, II (1995) 207-209] reported an association between the 96 bp allele at the VLDL-R locus and AD in a Japanese population. The association resulted in a two-fold increase of risk that decreased with increasing age. We have examined this association in 316 Caucasian sporadic AD patients, comparing their findings to 160 Caucasian AD spouse controls. We also investigated 53 late-onset Caucasian AD families for association and linkage. Our data failed to confirm linkage and/or association to the VLDL-R locus. Stratification by age at onset or APOE genotype also failed to show significant results.

Maternal lineages and Alzheimer disease risk in the Old Order Amish

Old Order Amish, founded by a small number of Swiss immigrants, exist in culturally isolated communities across rural North America. The consequences of genetic isolation and inbreeding within this group are evident by increased frequencies of many monogenic diseases and several complex disorders. Conversely, the prevalence of Alzheimer disease (AD), the most common form of dementia, is lower in the Amish than in the general American population. Since mitochondrial dysfunction has been proposed as an underlying cause of AD and a specific haplogroup was found to affect AD susceptibility in Caucasians, we investigated whether inherited mitochondrial haplogroups affect risk of developing AD dementia in Ohio and Indiana Amish communities. Ninety-five independent matrilines were observed across six large pedigrees and three small pedigrees then classified into seven major European haplogroups. Haplogroup T is the most frequent haplogroup represented overall in these maternal lines (35.4%) while observed in only 10.6% in outbred American and European populations. Furthermore, haplogroups J and K are less frequent (1.0%) than in the outbred data set (9.4–11.2%). Affected case matrilines and unaffected control lines were chosen from pedigrees to test whether specific haplogroups and their defining SNPs confer risk of AD. We did not observe frequency differences between AD cases compared to controls overall or when stratified by sex. Therefore, we suggest that the genetic effect responsible for AD dementia in the affected Amish pedigrees is unlikely to be of mitochondrial origin and may be caused by nuclear genetic factors.

Locus heterogeneity, anticipation and reduction of the chromosome 2p minimal candidate region in autosomal dominant familial spastic paraplegia.

ABSTRACTWe examined 11 Caucasian pedigrees with autosomal dominant ‘uncomplicated’ familial spastic paraplegia (SPG) for linkage to the previously identified loci on chromosomes 2p, 14q and 15q. Chromosome 15q was excluded for all families. Five families showed evidence for linkage to chromosome 2p, one to chromosome 14q, and five families remained indeterminate. Homogenity analysis of combined chromosome 2p and 14q date gave no evidence for a fourth as yet unidentified SPG locus. Recombination events reduced the chromosome 2p minimum candidate region (MCR) to a 3 cM interval between D2S352 and D2S367 and supported the previously reported 7 cM MCR for chromosome 14q. Age of onset (AO) was highly variable, indicating that subtypes of SPG are more appropriately defined on a genetic basis than by AO. Comparison of AO in parent-child pairs was suggestive of anticipation, with a median difference of 9.0 years (p <0.0001).

Linkage studies in Charcot‐Marie‐Tooth disease type 2 Evidence that CMT types 1 and 2 are distinct genetic entities

Charcot-Marie-Tooth disease (CMT), the most common inherited peripheral neuropathy, is a progressive sensorimotor neuropathy divided into types 1 and 2 based upon electrophysiologic and neuropathologic differences. The more common autosomal dominant form of CMT type 1 (hereditary motor and sensory neuropathy type I) is genetically heterogeneous, with genes located on chromosomes 1 (type 1B) or 17 (type 1A). However, no locus for CMT type 2 is known. We have performed linkage studies on three large multigenerational CMT type 2 families using probes from chromosome 1 and chromosome 17, which span their respective linkage regions. Multipoint analysis of the chromosome 17 markers excluded linkage over an area of 45 cM—15 cM proximal and 30 cM distal to the region containing CMT type 1A. Multipoint analysis of the chromosome 1 markers exclude linkage 15 cM proximal and 20 cM distal to FC-gamma-RII in the region of CMT 1B. These data indicate that CMT type 2 is genetically distinct from CMT type 1.