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5EJVT BY!Xerox Telecopier 7021 ;11-29-94 ; 17:43 The Danr Ail4ance for Brain Initistives -- PHILIP MORRIS;# 4 TA BASE Jsne 11Tevins, Editor in Chief of Publieationl 11 Nov. 1994 Topica: Alzheinter's Disease/Genetics Contact; Allen D. Roeas, M.D. (919) 684-6274 +Dr: W.R.Waltoa, Editor (202) 737-9200 Alzieei®etr's Disease & Inheritance "we would all be at risk of Alzheimer's disease if we were to live to age 130 years," says Allea Ro:es, a member of the Dana Alliance for Brain Initiatives who heads the Neurology division at Duke University Medical Center in Durham, NC. Dr. Roses and colleagues discovmrd a yoal'snd a hslfago the first lilxk between inheritance - a gene on chromosome 3 9- and the rate at which Alzheimer's disease progresses. Winking, one senior calls it "Old Times" diseese. But belying the wink. Alzbeimer's is perhaps the cruelest disease afflicting the aged - some four million Atneric.ans, gerhaps a third of 85-year-olds. Their aumberwill inarease in the years ahead, and according to his recent atutotu'-oement, will now include former President Ronald Reagan -'who, friends reportedly say, is adjustmg to the fature with optimistri. Dr. Roses explaine why optiusism is warranted, how the discovery of a genetic risk factor for Alzheimer's disease is li'1ce1y to prove useful in furthering resesroh efforts to understand and rixat the disease: ,+Alzheinier's disease is not simply aging speeded up. Everybne inherits two vcrsions, called alleles, of a gene known as APOE, one version from each parent, in much the same way one inherits a gene that codes for eye-color: from one parent maybe an allele for blue eyes, brown from the other. The APOTs puv aomes in three varieties labeled APOE2, 3, and 4. As these occur together in combinations, so a perBOn+s "genotype" might be 3/3. 3/4, 414, 2/4 or 2/3. (1be sixtb combination, Apt3F.2i2, Is very rare.) "What we have found, is that the APOE4 allele fiequency is increased in Alzheimas's d18n$Se. This has been collfittried in more than 40 laboratories. Depending on the combination of APOE alleles inherited, the average age of onset of Abbei[3ler's disease varies by As much as two decades. For gerrsc+ns certy'fn$ the APOE2!3 combination, the average age of onset is more th+sn 90 years old; but for persons carrying APOE414, the average age is leas then 70 yesrs. "It is important to recognize that a person nood not inherit an APOE4 allele to develop - Alzt-eimer's disease, nor Is it a given that the one to two percent ofpersons carrying the AP'OE4/4 combination will necessarily contract the disease during their lives. Some forma Of David Mahoney, Chairman, W. Maxwe1I Cr,wan, M.D., Ph.D. and Jamea D. Watson, Ph.D., Vice Chairmea 74.t" FiEth Avepp", Suite 700. New York. iVY 10151 1001 G 8trrr.i. lvW. Sutte 1025, Ws.hiuWon. DC 201++1

QL.171 J 1 AOI V^ 1{i 1 VbV+JiV1 i VL 1 1 1 I LV VW 9 1 i~ WW i ' I'111LLh" MUh(K1.7i4 ."For exemple, if a divg sho e. some Alzheimeis disease patier. ~~~ ,~~~ ~`I others, we can now exat»ine that G, comparing seleat populations. ~' predict, prredict, based on a pergons o-°'-- whot6er or when that indivic Alzheimer's. But we can use as a diagnostic tool for persoi developed syniptoams, in teslk familial Alr3,taimee's disease, for example„ have been liniced to other genes (on chromosomes 14 and 21), and other risk factors have yet to be identified. "Alziheimor's disease is a process, unfolding over time, and several factors appear to contribute to its development, so we cannot on APOE genotypes. When test an determine whether the diaease an individwai, combining those tea genotyping may be useful in selocte, uerapiss for patients. "We know from reports coai•irming our findibgs that, in Japan where the APQF.4 allele occurs less ftiequently, the aversge age of onset OfAlzheimer's diseasa is six to eight years older. Even a delay in the disease's onset by a coraparable six to eight years would benefit millions who would otherwise auffer. By deteYmiaag what difFerences in biologica,i processes are specific to each allele, it may be p+sssible to mimic APOE213 biolog,y, or block the effect ofAP4E4/4. "'Ibe protein for which the APt7E gene codes (apolipoprutein B. a ch~t1~+---• has 1~-- r- 6Z46 ,~.YiLQQ - .a.mess ofneuronal cell dying results in fewer connections among nerve r.s31s, affecting memory, reason and emotion. Our findings enable investigatars to inquire further into the biology which normally confers a life span of a hundred yam on nerve celts, to ask what goes wrong in the Alzheimes disease presaess that might explain loss of synaptic connecliotts and essential cell dettth in perticular brain regions. and how APtJE is involved." See alsa, John Q. Tro)enov+slc,i, M.D., Ph.D. °Alzheimer's Disease & Metals" Data Base (24 OCt.1944). Ecl nott: We thought you might also be iat.erested in the enclosed Latter to the Lditor, ptated by The Lw N Ar;gelas 7Ynrssi by Dtevid Mahoney, Chtdrman ofthG Dana Alliaace for Brain xnitiai'ivm in response to former ~ President R~gan's recent ettnouncqment, made "to raise public awaitlne~SS." L.' Pgrmission ro reprint Aarsby $rcauad (Credit to the Dana.dlliamfor.s'rain Inttiatfvea will be Wrectaterl)

SENT BY:Xerox Telecopier 7021 ;11-29-84 ; 19:44 ; .4 PHILIP MORRIS;# 5 familist Atrheimet's diseese, for example, have been linked to other genes (on chromosomes 14 and 21), and other risk factors have ye;'t to be identified. "Alzheimor's disease is a process, unfolding over time, and several factors appear to contribute to its development, so we cannot predict, based on a perbton's genotype alone, whatf:er or when that individual might develop Alzheiiner's. But we can use APOE genotypes as a dir postic tool for persons who have developed syrnptoms, in testing drugs, and for comparing select populations. . "For example, if a drug should work in some Aizheiffier's disease patients but not others, we can now examine those groups, based on APOE $enotypes. When teats are fourYd that an determine whether the disease is active in an individwl, combining those tests with APOE genotyping may be useful in selecting therapies for patients. "We know from reports conficming our findings that, in Japan where the APOE4 allele occurs len frequently, the average age of onset of'Alzheimer's disease is six to eight years older. Even a delay in the diseese's onse, by a comparable six to eight years would Uenef'it millions who would otherwise suffer. By ' aetetmiaittg vfat differences in biological processes are specific to each allele, it may be possible to mimic AP'()E213 biology, or block the effect of A.POE4/4. "Tfte protein for which the APOE gene codes (apolipoprntein E. a cholesterol csrrier) has been found together in the brain with both oftwo features used to oh$racterize Alzheimer's disease: in senile plaques outside ncme cells and in nerve cells containing nearofcbrillaiy tangles. Our hypothesis is that both ofthese feafiues, found at autopsy as scara, or lesions, are the consequences in Alzheimer'9 disease of biological processes `altere+d specifiCa1Ly by APOE alleles. "Nerve cells having a life span of more than a hundred years die earlier in A.lztteimer's disease, and they die in part3GUlar are+as of the brain. This process of neuronal cell dying results in fewer connections among nerve =31s, aecting memory, reason and emotion. Our 1indings enable investigators to inquire fiuther into the biology which normally confers a life span of a hundred years on nerve cells, to ask what goes wrong in the Al-dieimer's disease prifCess that might e7cplai3i loss of SyqBptic connections and essential cell death in particular brain regions, and how APOE is involved." See also, John Q. Trojenowski, M.D., Ph.lp. °'Althoiatei's l7-iseese & Metals" Ddsa 8as$ (24OCt,1994). Ed note: We thought you might also be interested in the enclosed Letter to the Wtor, printed by The Lo ~ Angr1e,s TYmes, by David Mahoney, !Cbei:rnan of the Dsna Alliance for Brain initiadves, in response to former President Re~an's recant announcement, made to raise public 8watenese." 0 Ffrnelssion zo reprent harsby grunred (cwedit to the I3ana dttianaa for Brain Inittatfvas will bs appreelated) ",4