A clinical series with 13% of Alzheimer actually CJD
Compensated frequency of CJD
Alzheimer's and CJD ... overview by Michael Greger
The mechanism of TSE ... Dr. Allen Goldenthal
Mis-diagnosed: prion gene insertion instead of Alzheimer's.
3 sheepbreeders with multiple-sclerosis-like GSS
Atypical Alzheimer's : human mad cow gene altered.
Familial Alzheimer's: prion and APP gene mutations.
Remarkable similarities between Alzheimer's and CJD
Transition between the pathology of prion disease and that of Alzheimer's disease
Familial amyloidotic polyneuropathy, Alzheimer's, and CJD

Apo E alleles and risk for Alzheimer's
Neuroprotection afforded by Apo E2 is not confined to Alzheimer's disease
Apolipoprotein E alleles and susceptibility to CJD

A clinical series with 13% of Alzheimer actually CJD

Manuelidis, Elias E. and Laura Manuelidis
Alzheimer Disease and Associated Disorders_ 3 (1989): 100-109
Suggested Links between Different Types of Dementias: Creutzfeldt-Jakob Disease, Alzheimer Disease, and Retroviral CNS Infections

"In our own neuropathological material, in 46 cases diagnosed clinically as AD [(Alzheimer's)], 6 cases were proven to be CJD at autopsy [13%}."

Peiffer, J. : 
Gerstmann-Straussler's disease, atypical multiple sclerosis and carcinomas in a family of sheepbreeders.
Acta Neuropath. 56: 87-92, 1982.
Peiffer (1982) described a family of sheepbreeders in which a father and 2 sons had GSS. All 3 also had congenital hip dysplasia, as did at least 3 other members of the kindred, all females. Atactic symptoms, dysarthria, and personality changes characterized the clinical course of this disorder, which might be labeled atypical multiple sclerosis.

Like CJD , GSS is a form of subacute spongiform encephalopathy. Cases of GSS are clinically similar to the atactic type of CJD. Although there are many neuropathologic similarities, GSS differs from CJD by the presence of kuru-plaques and numerous multicentric, floccular plaques in the cerebral and cerebellar cortex, basal ganglia, and white matter. Whereas only 5 to 15% of CJD cases are familial, most cases of GSS are familial.

Mis-diagnosed atypical dementias.

Owen F; Poulter M; Collinge J; Leach M; Shah T; Lofthouse R; Chen YF; Crow TJ; Harding AE; Hardy J; et al. Exp Neurol 112: 240-2 (1991) Division of Psychiatry, Clinical Research Centre, Harrow, Middlesex, United Kingdom.

A number of mutations have been demonstrated in the open reading frame (ORF) of the prion protein (PrP) gene in patients with familial Creutzfeldt-Jakob disease or Gerstmann-Straussler syndrome. On the basis of detecting an insertion in the ORF of the PrP gene in a patient originally suspected to be suffering from familial Alzheimer-type dementia, we screened 101 individuals with atypical dementias for the known PrP gene mutations.

Insertions were found in five individuals, whereas none of the other reported mutations in the PrP gene was detected in the present study. One of the five insertions was larger than that described previously, suggesting that the individuals with these mutations are unlikely to be all lineally related and that insertions in the PrP gene may not be uncommon in prion diseases.

CJD and BSE: Exploring the Possible Link

by Allen E. Goldenthal, B.Sc.,DVM.
submitted to: New York Academy of Science for the Annals 7.1.96


It is recognized that a single host gene encodes the agent for scrapie, transmissible mink encephalopathy, bovine spongiform encephalopathy, kuru, GSS, Creutzfeldt-Jakob and other Transmissible Spongiform Encephalopathies. This gene is transcribed equally in both normal and diseased hosts.

The claim that rendered sheep offal fed to cattle was the initiator for BSE is not fully supported by the facts. Although recent revelations of the variant-CJD being possibly linked to BSE are still being debated, it is surprising considering past evidence of just such a cross species transmission.

It has been the author's experience as Director for the Animal Resources Department and Pathology of a leading biologics manufacturer in Canada that a more plausible explanation may be a pathway failure in which one of the host body's sophisticated production processes is interfered with. Through comparisons of pathologic lesions at an electronmicroscopic level, the author has discovered what he considers significant associated pathology that suggests mechanical destruction. The vacuolation resulting from the prion disease is not unlike many other neuropathogeneses. It may be more appropriate to evaluate prions on a cellular pathway level and thereby examine their development and spread more as a molecular epidemiology.

The author reviews the history of prion disease in order to provide a perspective and insight that cannot be gained when reports are read as isolated incidents. Only by examining prion disease as a logical process which does not require genetic material can the agent be recognized as to its true potential for neural destruction.


Upon review of articles and materials involving spongiform encephalopathies, certain hypotheses were expounded in this article suggesting that far more information on this family of disease agents can be extrapolated from current knowledge. The fact that thus far, prions have been unique in the behavior suggests that accepted principles that normally are applied to other micro organisms do not adhere well in when dealing with abnormal prions.

Certain species are more prone to TSE's than others. The high susceptibility of goats does not only apply itself to scrapie but to CJD as well. When CJD was injected into goats, the resultant disease was indistinguishable from naturally occurring scrapie either on the basis of clinical signs nor by histopathology. Whereas other species seem to rely heavily on a host-agent mechanism for determining severity and incubation period, this does not appear to be a restriction exhibited in goats.

The potential for human infection with prion disease is a distinct possibility wherever beef or dairy products are consumed and BSE exists. Since 85% of CJD cases are not familial based, there is the possibility that some of these cases as recently reported in Britain, are BSE related. A view of the CJD incidence worldwide reported in Mastersí paper of 1979 overlaid against a map of the beef and dairy industries would possibly suggest that a relationship between the disease was occurring prior to this decade and that BSE may have been present earlier than its recorded date in Kent, England.

The possibility of a closer relationship in mechanism between CJD and Alzheimerís Disease must be fully explored and identification of those cases of AD which were misdiagnosed must be done in order to acquire a more accurate knowledge of CJD incidence. If the hypothesis of prion disease being the result of an abnormal pathway resulting in human diseases such as CJD and AD, then it would be likely that the host would eventually encode the abnormality as in AD and propagate the disease in subsequent generations. Some indicator of BSE or V-CJD would arise in the present of near future in either an isolated cow or a human, respectively.

This would be considered a spontaneous case simply because the host was completely isolated from any of the same species harbouring the disease and not exposed to any products either ingested or injected that may cause the disease. Scott reports such a case, which he did label as 'spontaneous'occurring to a cow held in isolation at the University of Edinburghís pedigreed Holstein herd. The subject was a four year old Holstein that was eight months pregnant with her third calf. She had been born fourteen months after the introduction of the ban and had no exposure to any contaminated materials during its lifetime. Clinical signs began to manifest themselves after the second calving. Scott could only conclude that either the cow was accidentally fed contaminated feed from an unknown source that mysteriously appeared at the university or a prion mutation occurred in this particular cow giving rise to BSE spontaneously.

The alteration of prions as they passage through various host species would indicate that there was a common origin for prion diseases and that host specificity was a result of continued passage within the same species. This would also suggest that a genetic susceptibility or recognition process would also be achieved within the host species over time. The process of alteration would increase the opportunity for further prion dysfunction which in turn may advance the onset, severity, and transmissibility of the prion which is evident in the clinical findings of the numerous prion strains within a single species.

Such alterations could result in every mammalian species developing a prion disease specific to itself with maximized effect. The ability for different etiological agents to produce histopathological signs within the central nervous system having similar features amongst numerous mammalian species may indicate a predisposition which encourages genetic incorporation.

Sourcing of bovine material for any purpose, including consumption, manufacturing, research etc. should be from a country where CWD, scrapie and BSE are not present. In this way a level of confidence can be achieved which cannot be obtained presently with products from certain countries. The summons to take the prion situation seriously of almost a decade ago could never be more prophetic than on this threshold that we currently find ourselves upon.

Human prion gene deletions in atypical Alzheimer's disease

Perry RT; Go RC; Harrell LE; Acton RT
Am J Med Genet 60: 12-8 (1995)

Alzheimer's disease (AD) is a progressive, degenerative neurological disorder of the central nervous system. AD is the fourth leading cause of death in elderly persons 65 years or older in Western industrialized societies. The etiology of AD is unknown, but clinical, pathological, epidemiological, and molecular investigations suggest it is etiologically heterogeneous.

Mutations in the amyloid protein are rare and segregate with the disease in a few early-onset familial AD (FAD) families. Similarities between AD and the unconventional viral (UCV) diseases, and between the amyloid and prion proteins, implicate the human prion protein gene (PRNP) as another candidate gene.

Single strand conformation polymorphism (SSCP) analysis was used to screen for mutations at this locus in 82 AD patients from 54 families (30 FAD), vs. 39 age-matched controls. A 24-bp deletion around codon 68 of the prion gene that codes for one of five Gly-Pro rich octarepeats was identified in two affected sibs and one offspring of one late-onset FAD family. Two other affected sibs, three unaffected sibs, and three offspring from this family, in addition to one sporadic AD patient and three age-matched controls, were heterozygous for another octarepeat deletion located around codon 82.

Two of the four affected sibs had features of Parkinson's Disease (PD), including one who was autopsy-verified AD and PD. Although these deletions were found infrequently in other AD patients and controls, they appear to be a rare polymorphism that is segregating in this FAD family. It does not appear that mutations at the PRNP locus are frequently associated with AD in this population.

Familial Alzheimer's disease--analysis of prion protein mutations

Nagano K; Miki T; Yoshioka K; Katsumi D; Katsuya T; Takeda M; Ikeda M; Tanabe H; Nishimura T; Sakai Y; et al
Nippon Ronen Igakkai Zasshi 29: 509-14 (1992)

Numerous Caucasian familial Alzheimer's disease (FAD) pedigrees have been described in the literature, while only 21 Japanese FAD families have been reported to date. Here we report the clinical findings and the result of molecular genetic analysis of 4 patients from two FAD kindreds, OS-2 and OS-3.

The proband in OS-2 family has developed loss of recent memory and place disorientation age at 43. A brain CT showed severe diffuse cortical atrophy. Her younger brother had dementia at 42 years and her mother and other 3 siblings had also dementia symptoms suspected to be Alzheimer's disease.

The proband in OS-3 family showed declining recent memory at 49 years and developed dysphagia, gait disturbance and emotional incontinent with cerebral atrophy at 52 years. His father and elder brother demonstrated dementia signs at 60 and 54 years old, respectively.

Recently it was reported that affected members from 2 Caucasian kindreds with FAD had missense mutation in exon 17 of the gene for amyloid precursor protein (APP). Patients from three different Japanese kindreds with FAD also showed the same mutation on the APP gene. Amino acid substitution (Val-Ile) at codon 717 by this mutation is responsible for FAD in at least some kindreds.

We used genomic DNA from 4 affected members of 2 families to determine whether the disease in these families is associated with a APP717 mutation and the mutated codons, 102, 117, 129, 178 and 200, on the gene for protease-resistance prion protein (PrP) which cause transmissible dementia, Creutzfelt-Jacob disease (CJD) and Gerstmann-Strausler syndrome (GSS). [[abstract terminated, journal not available -- webmaster]]

Alzheimer's disease and CJD: overlap of pathogenic mechanisms.

DeArmond SJ
Curr Opin Neurol 6: 872-81 (1993)

This article compares beta-amyloid precursor protein (beta-APP) disorders exemplified by Alzheimer's disease (AD), with prion protein (PrP) disorders, exemplified by Creutzfeldt-Jakob disease (CJD) in humans and scrapie in animals. Although there are obvious differences in the etiology and pathogenesis of both sets of disorders, a remarkable number of similarities exist.

Both sets of disorders are characterized clinically by age-related sporadic and familial diseases. In both, an abnormal form of a neuronal membrane protein appears to play a key role in the pathogenesis: beta-A4 peptide in AD and PrPCJD in CJD. Both beta-A4 and PrPCJD are amyloidogenic. Neuritic plaques characteristic of AD were once thought to be exclusively associated with beta-A4 amyloid; however, some pedigrees with familial prion disease produced neuritic plaques with PrP amyloid cores.

Finally, beta-APP accumulation in skeletal muscle has been implicated in the age-related muscle disorder, inclusion body myositis. A similar myopathy has recently been discovered in transgenic mice expressing high levels of normal PrP. These similarities suggest that what is learned about one set of disorders may be applicable to the other.

Dementia associated with a 216 base pair insertion in the prion protein gene

Duchen LW; Poulter M; Harding AE
Brain 116 ( Pt 3): 555-67 (1993)

We report the clinical and neuropathological findings in a patient with a 216 base pair insertion in the prion protein (PrP) gene. She died aged 57 years after a 2.5-year illness characterized by falls, axial rigidity, myoclonic jerks and progressive dementia. There was no history of affected relatives. The pathological changes consisted of the deposition in cerebellum, basal ganglia and cortex of small plaques composed of variable amounts of amyloid and degenerative material which was associated with a marked macrophage reaction. The amyloid deposits in the cerebellum and basal ganglia gave a positive immunoperoxidase staining reaction for PrP.

In some places plaques bore a resemblance to senile neuritic plaques and in the hippocampus there were abundant typical neuritic plaques giving positive staining reactions for beta-amyloid protein and tau protein, but not PrP. There were few neurons bearing neurofibrillary tangles.

This is the first report of the neuropathological changes associated with this particular abnormality of the PrP gene and it seems to demonstrate a transition between the pathology of prion disease and that of Alzheimer's disease. The importance of PrP gene analysis to the understanding of neurodegenerative diseases is stressed.

Relation to other amyloidoses

Diringer H
Exp Clin Immunogenet 9: 212-29 (1992)

The pathogenesis as well as the genetic disposition to develop clinical symptoms in transmissible spongiform encephalopathies (e.g. Creutzfeldt-Jakob disease, scrapie, bovine spongiform encephalopathy) relate these diseases to classical noninfectious amyloidoses (familial amyloidotic polyneuropathy as an example) and to Alzheimer's disease. This is not obvious to the nonexpert at first glance. This communication tries to elucidate this association, to reveal which immunochemical techniques have contributed their share.

Background on apo E and Alzheimer risk

Charlotte News and Observer 31 May 1996

The APOE test shows which of the three APOE gene types -- E2, E3 or E4 -- a person is born with. Since everyone inherits two copies of a gene, there are six possible combinations. The gene's job is to transport cholesterol in the bloodstream. Thousands of people have had APOE testing since the late 1980s as part of a heart disease work-up.

But recent studies by Roses and colleagues showed that people with at least one copy of the E4 type have an increased risk of Alzheimer's:

  • 20% of people with Alzheimer's have two E4's.
  • A person with dementia and E4/E4 has a 95% chance of having Alzheimer's, usually in their early 60s.
  • 60% of people with Alzheimer's have E3/E4.
  • People with symptoms and an E3/E4 have a better than 85% chance of having the diseaseby age 80.
  • E3 is the most common type and is considered normal.
  • E2 is rarer and conveys a lower than average risk.

  • Allelic variations in apo E and prion protein in sporadic CJD

    Pickering-Brown SM; Mann DM; Owen F; Ironside JW; de Silva R; Roberts DA; Balderson DJ; Cooper PN
    Neurosci Lett 187: 127-9 (1995)

    Prion gene sequence is thought to affect the phenotypic expression of prion disease and the E2 variant of apolipoprotein E (Apo E) can be neuroprotective in dementia. We determined codon 129 of the prion gene and the Apo E variants in Creutzfeldt-Jakob disease (CJD) using PCR and restriction digest. We found a significant correlation between valine at codon 129 of the prion protein gene and the presence of plaque in CJD and a later age of onset in CJD cases possessing the Apo E2 allele. This study provides further evidence that sequence variations in the prion gene can modify disease pathology and the neuroprotection afforded by Apo E2 is not confined to Alzheimer's disease.

    Apolipoprotein E alleles and susceptibility to CJD

    Amouyel P; Vidal O; Launay JM; Laplanche JL
    Lancet 344: 1315-8 (1994)

    Creutzfeldt-Jakob disease (CJD) is a rapid progressive mental and neurological disorder characterised by dementia and is both infectious and genetic. Pathogenic mutations and a predisposing polymorphism have been described in the prion protein gene and an abnormal prion product accumulates in the brain of affected patients.

    Apolipoprotein E (APOE), a protein of lipid metabolism, has been detected in some prion protein deposits. This ApoE exists as three common isoforms, coded by specific allele (epsilon 2, epsilon 3, epsilon 4). The presence of at least one epsilon 4 allele was described as a major risk factor for Alzheimer's disease, another neurodegenerative disorder.

    From a series of 61 patients with CJD we found that epsilon 4 allele of the APOE gene was a risk factor for the disease (p < 0.01). This association was observed in both definite and probable cases, and for patients with and without prion protein gene mutations. Moreover, in affected subjects, epsilon 2 allele of the APOE gene delayed occurrence of death (p < 0.01) independently of other known mutations influencing the phenotype of the disease. These effects on neurodegenerative disease associated with APOE alleles suggest a strong involvement of the APOE locus in brain metabolism.

    Alzheimer's and CJD

    Michael Greger
    16 June 1996

    If indeed a form of Bovine Spongiform Encephalopathy (BSE) exists in the United States, one might expect to see a rise in the number of cases of Creutzfeldt-Jakob disease (CJD). CJD, however, is not a reportable illness in this country (Holman, 1995). Because the Centers for Disease Control (CDC) does not actively monitor the disease (Altman, 1996d) a rise similar to the one in Britain could be missed (Altman, 1996d).

    Already, a number of U. S. CJD clusters have been found. In the largest known U. S. outbreak of sporadic cases to date(Flannery, 1996) a five-fold expected rate was found to be associated with cheese consumption in Pennsylvania's Lehigh Valley (Little, 1993) A striking increase in CJD was also reported in Florida (Berger, 1994) and there is an anecdotal report of an cluster in Oregon (Boule, 1996). An analysis of death certificates in a number of states, though, showed an overall stable and typical CJD incidence rate from 1979 to 1993 (World, 1996). To track the disease, the CDC has just initiated a four-state study of death certificates (Altman, 1996a), but since it is considered well known that death-certificate diagnoses are not always accurate (Davanpour, 1993) the survey may not provide an accurate assessment.

    The true prevalence of prion diseases in this or any other country remains a mystery (Harrison, 1991). Compounding the uncertainty, autopsies are rarely performed on atypical dementias (Harrison, 1991), because medical professionals fear infection (Altman, 1996a). The officially reported rate in this country is less than 1 case in a million people per year (World, 1996). An informal survey of neuropathologists, however, registered a theoretical range of 2-12% of all dementias as actually CJD (Harrison, 1991). And hundreds of thousands of Americans suffer from severe dementias every year (Brayne, 1994; United, 1995). Two other studies average about a 3% CJD rate among dementia patients (Mahendra, 1987; Wade, 1987). A preliminary 1989 University of Pennsylvania study showed that 5% of patients diagnosed with dementia were actually dying from Creutzfeldt-Jakob disease (Boller, 1989). It would seem CJD is seriously underdiagnosed at present (Harrison, 1991).

    The most common misdiagnosis of CJD is Alzheimer's disease (Harrison, 1991). CJD was even described by our government's top CJD researcher (Wlazelek, 1990a) as "Alzheimer's in fast forward (Wlazelek, 1990b)." The symptoms and pathology of both diseases overlap (Brown, 1989). There can be spongy changes in Alzheimer's, for example, and senile plaques in CJD (Brown, 1989). The causes may overlap as well; epidemiological evidence suggests that people eating meat more than four times a week for a prolonged period have a three times higher chance of suffering a dementia than long-time vegetarians (Giem, 1993), although this result may be confounded by vascular factors (Van Duijn, 1996).

    Paul Brown, medical director for the U.S. Public Health Service (Gruzen, 1996), said that the brains of the young people who died from the new CJD variant in Britain even look like Alzheimer's brains (Hager, 1996). Stanley Prusinger, the scientist who coined the term prion, speculates Alzheimer's may in fact turn out to be a prion disease (Prusiner, 1984). In younger victims the disease could look like multiple sclerosis or a severe viral infection, according to Alzheimer's expert Gareth Roberts (Brain, 1996).

    An estimated two to three million Americans are afflicted by Alzheimer's (Scully, 1993); it is the fourth leading cause of death among the elderly in the U.S (Perry, 1995). Twenty percent or more of people clinically diagnosed with Alzheimer's disease are found at autopsy to not have had Alzheimer's at all (McKhann, 1984). At Yale, out of 46 patients clinically diagnosed with Alzheimer's, 6 were proven to be CJD at autopsy (Manuelidis, 1989). In another post-mortem study 3 out of 12 "Alzheimer" patients actually died from a spongiform encephalopathy (Teixeira, 1995).

    Carleton Gajdusek, who was awarded a Nobel Prize for his work with prion diseases (Manuelidis, 1985), estimates that 1% of people showing up in Alzheimer clinics actually have CJD (Folstein, 1983). That means that hundreds of people (Hoyert, 1996; United, 1995) may already be dying from mad cow disease each year in the United States.

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         Times_ 9 April 1996a.
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         Has Not Occured Here."  _New York Times_ 27 March 1996d: 12A.
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          (1996): 1-8
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         Experience."  _Neurology_ 44  (1994): A260.
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         38 (1989): 76-79.
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    Compensated Frequency of CJD

    Listserve Item:
    8 July 96
    Stephen J. Seligman, M.D.
    Professor of Medicine
    SUNY Health Science Center

    A few weeks ago, mention was made of a memorandum submitted by Gareth Roberts to the Agricultural Committee, House of Commons, June 1990. For those of us who are not habitues of the House, very similar arguments were made in a Lancet editorial (1). The editorial writer calculates that if 2% of patients with diagnosed dementias have CJD (1500 cases per annum) and that if 10% of patients with undiagnosed dementias also have CJD (7500/year), the actual incidence would be some 250 times that reported.

    That these estimates are markedly high is shown by another reference previously made in the list, the report of the very same Gareth Roberts and his colleagues studying 1000 cases of dementia (2) . They found that on review of the histopathology of autopsied dementia cases and doing immunochemical stains, the diagnosis of CJD could be increased a relatively modest 1.7 fold. Only one of the patients was under 45 and that patient had a "strong" family history, an observation suggesting either familial CJD or Gerstmann-Straussler-Scheinker syndrome (GSS). Accordingly none of the patients would fit the criteria for variant CJD.

         1. Prion disease - Spongiform encephalopathies unveiled. Lancet 1990; 336:
         2. Bruton CJ, Bruton RK, Gentleman SM, and Roberts GW: Diagnosis and
         incidence of prion (Creutzfeldt-Jakob) Disease: A retrospective
         archival survey with implications for future research.
         Neurodegeneration 1995; 4: 357-368.