1366 S182 protein in Alzheimer’s disease neuritic plaques SIR-Most early-onset familial Alzheimer’s disease has linkage to a recently identified gene on chromosome 14, called S182 (see Harrison’s Aug 12 commentary).’ Already, 15 different mutations have been reported in this gene associated with early-onset familial Alzheimer’s disease in various kindreds, and another two mutations have been reported in a closely related gene (known as STM2, presenilin 2, or E5-1) found on chromosome 1.1-4 Do S182 gene products have a role in the pathogenesis of only chromosome-14-linked familial Alzheimer’s disease, or do they have a more general function in the disease? The primary neuropathological lesions are neurofibrillary tangles and senile plaques. The main protein associated with senile plaques is amyloid-&bgr;, whereas abnormally phosphorylated tau is related to neurofibrillary tangles. To help clarify whether the S182 protein is implicated in the pathogenesis of either of these lesions, we raised a polyclonal antibody to the carboxyl end of S 182 corresponding to residues 448-467. We used this antibody to immunostain brain sections from patients with amyloid-&bgr;-related cerebral amyloidoses: two with chromosome-14-linked Alzheimer’s disease, five with sporadic Alzheimer’s disease, four with hereditary cerebral haemorrhage with amyloidosis-Dutch type (HCHWA-D), and five with Down’s syndrome, as well as from four healthy elderly controls. In addition we used this antibody on sections from patients with other biochemical forms of cerebral amyloidosis including one patient each with: Gerstmann-Straussler syndrome, HCHWA-Icelandic type, British amyloidosis, and Hungarian amyloidosis. Our anti- S182 antibody immunolabelled senile plaques (figure, A), matching the immunoreactivity with monoclonal amyloid-&bgr; antibodies (figure, B) in all amyloid-&bgr;-related amyloidoses, whether they were linked to chromosome 14 or not, under the conditions used. This immunoreactivity was specific since it could be absorbed with the S 182-448 peptide and was unaffected by absorption with unrelated peptides. No immunoreactivity was found in the amyloid deposits of the four patients with non-amyloid-&bgr;-related diseases. In addition, the anti-S 182 antibody immunolabelled faintly some normal neurons and cerebral vessels. These results indicate that the S 182 protein has a general role in the pathogenesis of Alzheimer’s disease and not only in chromosome-14-linked cases. Fragments of all the gene products, which have been linked to early-onset familial and sporadic Alzheimer’s disease, including the carboxyl end of apolipoprotein E,’ amyloid-&bgr; (a degradation product of the amyloid-&bgr; precursor protein), and a carboxyl fragment of S 182 are now known to be constituents of the senile plaque. Figure: Sections of brain from patient with sporadic Alzheimer’s disease A, immunolabelling with polyclonal anti-S182 antibody; B, section sequential to A, immunolabelled with monoclonal anti-amyloid-&bgr; antibody (4G8, Senetek). Although each of these proteins is produced within the central nervous system, how they are inter-related is not known. The participation of several proteins in senile plaque formation suggests that the pathogenesis of Alzheimer’s disease involves a more complicated process than just an alteration of amyloid-&bgr; precursor protein processing. The accumulation of these proteins within the senile plaque may serve as a tombstone to the neuronal death that occurs as a final common pathway in Alzheimer’s disease. This study is supported by grants AG08721, AG05891, NS30455, and AG00542 from the National Institutes of Health. We thank Dr F Perini for assistance. *Thomas Wisniewski, Joana A Palha, Jorge Ghiso, Blas Frangione Departments of Pathology and *Neurology, New York University Medical Center, New York, NY 10016, USA 1 Sherrington R, Rogaev EI, Liang Y, et al. Cloning of a gene bearing a missense mutation in early-onset familial Alzheimer’s disease. Nature 1995; 375: 754-60. 2 Rovaev EI, Sherrington R, Rogaeva EA, et al. Familial Alzheimer’s disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer’s disease type 3 gene. Nature 1995; 376: 775-78. 3 Levy-Lahad E, Wasco W, Poorhaj P, et al. Candidate gene for the chromosome 1 familial Alzheimer’s disease locus. Science 1995; 269: 973-77. 4 Alzheimer’s Disease Collaborative Group. The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families. Nat Genet 1995; 11: 219-22. 5 Wisniewski T, Lalowski M, Golabek A, Vogel T, Frangione B. Is Alzheimer’s disease an apolipoprotein E amyloidosis? Lancet 1995; 345: 956-58. Blood pressure rise and ischaemic stroke SIR-Ischaemic strokes tend to occur in the morning,’ in association with a rise in blood pressure.2,3 Such rises in pressure may stress a vulnerable plaque causing its rupture and thrombus formation, although this causal link has not been documented. a-sympathetic vasoconstrictor activity’ and platelet aggregability5 increase during early morning. We report an acute ischaemic stroke preceded by an abrupt morning blood pressure rise. A 60-year-old white man with mild hypertension for 7 years and non-insulin-dependent diabetes mellitus treated with metformin (850 mg twice daily) was admitted to hospital because of two episodes of transient (duration 15 min) left upper-arm numbness during the previous week. He was in sinus rhythm and receiving no antihypertensive medications. Blood pressure was 166/90 mm Hg; clinical examination was normal. Enteric-coated aspirin 325 mg daily was started. On the second day of admission, the patient had 24-hour ambulatory blood pressure monitoring (SpaceLabs 90202, Redmond, Washington, USA; one reading every 15 min, starting at 10 h). The patient woke up and got out of bed at 0610 h; left hemiparesis, left-side sensory loss and loss of left visual field appeared gradually from 0650 to 0700 h (timing of events was witnessed and registered by ward nurses). Computed tomography, performed immediately afterwards, was negative. Over the next few days, his neurological condition slightly improved, but he had repeated transient episodes of dysarthria and left-side face weakness. A carotid duplex doppler scan showed a 99% stenosis of his right carotid bifurcation extending into the internal carotid artery. Transoesophageal echocardiography excluded sources of cardiac emboli. On the eighth day, the patient underwent successful right carotid endarterectomy, with only mild and non-disabling residual neurological signs. 24-hour blood pressure monitoring showed a sharp morning rise in blood pressure and heart rate in association with the onset of stroke (figure).