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Early-Onset Familial Alzheimer Disease With Coexisting -Amyloid and Prion Pathology

To the Editor: Familial Alzheimer disease (AD) with early onset has been linked to 3 different genes with an autosomal dominant mode of inheritance: -amyloid, protein precursor, and the presenilins 1 and 2, representing not more than 50% of all cases of early-onset AD cases.¹ Thus, the genetic defect remains unexplained in at least half of the families with histories of early onset of AD. We have recently described such a Swiss family whose members presented with a standard clinical and neuropathologic profile of AD.² In particular, severe neurofibrillary tangle degeneration was present in the hippocampus and in several cortical areas, together with a large amount of -amyloid deposits and senile plaques (SPs). However, known mutations have not been found, either in the -amyloid precursor protein or in the presenilin 1 and 2 genes.² We now report that the brains of 5 deceased members of this family, from 2 generations, present a coexisting -amyloid and prion protein (PrP) pathology.

Methods
Five available cases with clinical AD were diagnosed using the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition, criteria. The age at onset of disease ranged from 43 to 64 years (mean, 55.8 years) and age at death ranged from 55 to 81 years (mean, 67.4 years). In addition, 4 of the 5 cases had epileptic features. Serial frozen sections (50 µm thick) through the temporal and frontal cortex of the 5 formalin-treated brains were pretreated with formic acid. They were then processed using monoclonal antibodies against amyloid-₄₀ peptide (1:100; ) and against PrP_106-126 (1:200; produced by one of us).³ The latter antibody specifically marks the pathological isoform of the PrP and does not cross-react with -amyloid deposits. In addition, double immunostaining using successive anti–-amyloid and anti-PrP_106-126 antibodies was performed.

Results
In all 5 cases, the cerebral cortex revealed spongiform changes, mainly in superficial layers, and some degree of gliosis. Neurofibrillary tangle and neuritic plaques revealed by Gallyas were numerous in all cortical regions including the primary visual area. In addition, frequent -amyloid–positive SPs were observed, together with SP stained by the monoclonal antibody against PrP_106-126. Successive sections alternately stained with the 2 antibodies showed that both -amyloid and PrP_106-126 positive SP are deposited in all layers of the frontal and temporal cortex. A population of SP, marked on 2 serial sections with both antibodies, was positive for both -amyloid and PrP_106-126. Double-stained sections with -amyloid and PrP_106-126 antibodies further demonstrate that 3 populations of plaques exist: only -amyloid, only PrP_106-126 positive, or positive for both antibodies (Figure 1) and a majority of SPs (>50%) are immunopositive for both -amyloid and PrP_106-126 antibodies. Comparatively, the relative proportion of SPs marked for each antibody alone is smaller. In particular, SPs marked for PrP_106-126 represent approximately 5% to 10% of the whole population.

View larger version (47K): [in this window] [in a new window] Figure. Double Immunostaining for -Amyloid and Prion Protein (PrP) in the Frontal Cortex Senile plaques immunopositive for -amyloid40 (arrowheads in panels A and C), PrP106-126 (arrowheads in B), and for -amyloid40 plus PrP106-126 (double arrowheads in C) are shown. Two different chromogens were used, first diaminobenzidine dihydrochloride to reveal the -amyloid peptide (reddish-brown) and second, benzidine dihydrochloride to reveal the PrP106-126 (blue). When both signals are superposed, the blue signal appears dark and is localized in the center of the plaque. Scale bar is 50 µm for panels A and B, and 75 µm for panel C.

Comment
Coexistence of Creutzfeldt-Jakob disease (CJD) and AD in some patients has been described but appears mainly related to age in patients proven to have CJD.⁴ However, since the individuals in the Swiss family died over a long interval and were all similarly affected, it is unlikely that CJD is purely coincidental. On the other hand, familial Gerstmann-Straüssler-Scheinker disease can present a variant with concomitant neurofibrillary tangle and prion-positive plaques, but not -amyloid–positive plaques. Within this variant, 2 mutations in the gene for the PrP have been identified in 2 different families, and the clinical profile with cerebellar ataxia and extrapyramidal signs⁵ differs from our findings.² Base pair deletion in the prion gene segregating as an uncommon polymorphism has been described in a family with a history of late-onset AD, but there is no neuropathological confirmation and the genetic association is uncertain.⁶

Thus, the data presented herein support the existence of a possible new subtype of familial early-onset AD with a concomitant -amyloid and prion brain pathology, together with a massive neurofibrillary tangle degeneration. Although all known mutations have been excluded in the coding regions of the AD genes, numerous candidate chromosome sites, either in the AD genes outside the coding regions or in other genes including PrP, must be considered.

AUTHOR INFORMATION
Funding/Support: This study was supported by grants 3100-045960.95 and 3100-043573.95 from the Swiss National Science Foundation.

G. Leuba, PhD, PD; K. Saini, PhD
University Psychogeriatrics Hospital
Lausanne-Prilly, Switzerland

A. Savioz, PhD; Y. Charnay, PhD
University of Geneva School of Medicine
Geneva, Switzerland

1. Cruts M, Van Broekhoven C. Molecular genetics of Alzheimer's diease. Ann Med. 1998;6:560-565. 2. Savioz A, Leuba G, Forsell C, et al. No detected mutations in the genes for the amyloid precursor protein and presenilins 1 and 2 in a Swiss early-onset Alzheimer's disease family with a dominant mode of inheritance. Dement Geriatr Cogn Disord. 1999;10:431-436. FULL TEXT | ISI | PUBMED 3. Boris N, Mestre-Frances N, Charnay Y, Tagliavini F. Spontaneous spongiform encephalopathy in a young adult rhesus monkey. Lancet. 1996;348:55. FULL TEXT | ISI | PUBMED 4. Hainfellner JA, Wanschitz J, Jellinger K, Liberski PP, Gullotta F, Budka H. Coexistence of Alzheimer-type neuropathology in Creutzfeldt-Jakob disease. Acta Neuropathol (Berl). 1998;96:116-122. FULL TEXT | PUBMED 5. Ghetti B, Tagliavini F, Giaccone G, et al. Familial Gerstmann-Straüssler-Scheinker disease with neurofibrillary tangles. Mol Neurobiol. 1994;8:41-48. PUBMED 6. Perry RT, Go RCP, Harrell LE, Acton RT. SSCP analysis and sequencing of the human prion protein gene (PRNP) detects two different 24 bp deletions in an atypical Alzheimer's disease family. Am J Med Genet. 1995;60:12-18. FULL TEXT | PUBMED

Letters Section Editors: Phil B. Fontanarosa, MD, Deputy Editor; Stephen J. Lurie, MD, PhD, Fishbein Fellow.

JAMA. 2000;283:1689-1691.