JAGS 38:475-482, 1990

GERIATRIC

BIOSCIENCE

The Aging - Disease Dichotomy

Cerebral Amyloid Angiopathy -An Independent Entity Associated with Dementia

Herman T. Blumenthal, PhD, MD,*f and Bhartur N. Premachandra, PhD, DScf#

xcept for multiinfarct dementia attributable to arterio- or atherosclerosis, the role of other vascular lesions of the brain in the genesis of de‘mentia appears not to have been sufficiently evaluated. It is the purpose of thisreview to direct attention to the premise that cerebral amyloid angiopathy (CAA) may be considered to be a disease of intrinsic origin whose etiology may be derived from the normal aging process. In addition, the possible role of CAA in the genesis of dementia is discussed. There are many causes of dementia in old people,’ but vascular disease appears to have at least some role in the genesis of the most common dementias of the aged. Nevertheless, Adamsz has emphasized the complexity of the problem when he states “there is no pathological or physiological evidence to support the idea that widespread degeneration of nerve cells and tracts found in association with dementia is simply the result of ischemia caused by cerebrovasculardisease. . . .Pathological as well as clinical distinctions can be drawn between a primav neuronal, or senile, form of dementia and other varieties attributable to vascular disease, but the two may be mixed, and differentiation between them clinically or pathologically may be difficult” (p 11). Now, some 15 years later, the issues Adams addressed remain relevant. The most common dementia of the aged, Alzheimer’s disease/senile dementia of the Alzheimer type (AD/SDAT), is associated with neuritic plaques, consistingof degenerated neurites and a core of amyloid, and neurofibrillarytangles (NlTs).As many as 92% of these cases also show CAA.B4 However, CAA also occurs as an independent entity with few or no

E

From the *Department of Community Medicine, St. Louis University School of Medicine, tThe Aging and Development Program, Department of Psychology, Washington Univmity, and the $Veterans Administration Medical Center, JeffersonBarracks, St. Louis, Missouri.

This investigation was supported, in part, by Veterans Affairs and The Narveen Medical Research Foundation, St. Louis, Missouri. Address correspondence and reprint requests to Herman T. Blumenthal, PhD, MD,Washington University, Aging & Development Program, Box 1125, St. Louis, MO 63130.

0 1990 by the American Geriatrics Society

associated neuritic plaques, and about 40% of patients with this finding also exhibit dementia.’ We shall refer here to the latter as cases with independent CAA (ICAA). Cerebral amyloid angiopathy may thus be a more common associate of dementia than arterio- or atherosclerosis. The second most common lesion associated with dementia of the aged, multiinfarct dementia (MID), is characterized by small cerebral infarcts, usually measuring 2 - 10 mm in diameter, with cystic (lacunar) degeneration. MID cases typically have a history of hypertension and manifest severe cerebral arteriosclerosis with vascular stenosis. A much less common vascular lesion associated with dementia of the aged is Binswanger’s disease (subcortical arteriosclerotic encephalopathy) associated with diffuse severe arteriosclerosis affecting the subcortical white matter. Dementia is also associated with some rare v d t i d e s ; some of these show intimal thickening and a perivascular infiltrate of small cerebral arteries, while others show a granulomatous arteritiswith necrosis of the vessel wall and thrombosis of the lumen. In an autopsy study of dementia of the aged, Tomlinson et a1found that about half the cases showed changes exclusively of AD, 20% exclusively of MID, and 12% of a c~mbmation.~ Katzman estimates that if the entire population lived to age 90, one-third would remain intact intellectually, about one-third would develop AD, and about one-third would have a mixture of benign forgetfulness and a variety of other dementing diseases, the most common of which would be MID.6 The term “association” has been generally applied to the relationship between a particular lesion and the clinical manifestations of dementia. However, some patients with the pathological changes of AD have retained normal cognitive function during life. The same holds true for MID.Whatever singlemarker one chooses for AD there is at least some overlap between normal older people and persons with AD. For correlationwith clinical status, a combination of lesions may be necessary.’ Furthermore, both AD and MID lesions can be found in the same patient, thus leading Roth to express 0002-8614/90/$350

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the opinion that but for the added brain damage caused trinsic," "irreversible," "progressive," "universal," and by infarctions, some individuals would have avoided "genetically programmed."12 In plots used to express dementia.8He has, therefore, proposed the concept of a rates of biological aging or the incidence of aging-related threshold phenomenon in which the volume of infarcts, diseases, the starting point has traditionally been about or the number of plaques may determine whether or not age 30. Thus Brody and Schneider have defined agedementia will be present. On the other hand, Glatt and dependent diseases (as distinguished from those that Katzman believe that the question of whether the de- are age-associated) as diseases that show a progressive mentias are a function of quantity of tissue or the in- rise in incidence after about age 30, without a decline in volvement of specific structures remains unres~lved.~advanced old age.l3 They propose that diseases that exMore recently Katzman has attributed the absence of hibit such an age-specific incidence may be derived dementia in some patients with AD lesions to the con- from an extension or intensification of a biological aging tinued survival of large nerve cells in the association phenomenon. Their proposal is, therefore, not in accord cortex.6 with the dichotomy doctrine, although they do not diIn the several publications that have addressed these rectly address this issue. variables, a possible direct role for CAA in the genesis of In a previous essay in which the age distribution of a dementia has not been taken into account.6-9 Since CAA composite of all amyloid types was analyzed, we noted is present as part of the AD lesions, but occurs as well in that important additional information relevant to an the absence of neuritic plaques and NFTs, it may be aging-disease connection may be gained if the age dispossible to evaluate its contribution to the dementia. tribution is plotted from birth." In such a plot (Figure 1) Since the lesions associated with AD are also considered there may be a juvenile-onset minor peak of a disease by some to be a normal aging phenomenon, intensified followed by an ascending curve representing the disease or accelerated in AD,lOJl we also examine CAA from of adult or senescent onset. The juvenile-onset peak reflects, for the most part, disease of congenital or inherthis perspective in this essay. ited derivation with minimal or no input from extrinsic THE DICHOTOMY AND THE BIMODAL risk factors. The advantage of such a bimodal lifespan LIFESPAN CURVE plot, therefore, is that information regarding the juveThe doctrine that separates disease from biological nile-onset disease might provide clues as to intrinsic aging, and thus creates a dichotomy between the two, phenomena relevant to the adult-senescent counterpart characterizes biological aging with such terms as "in- of the disease. It should be noted, however, that there

FIGURE 1. The bimodal Lifespan Curve. This illustrates the minor mortality peak between ages 20- 30, followed by a progressive increase comparable to the Gompertz plot.61

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may not be clearly delineated age-onset periods, and that overlaps may be present between different age categories. Such a lifespan plot with respect to the lesions associated with AD, including neuritic plaques, NFTs and CAA reveals a juvenile-onset segment represented by Down's syndrome (DS),' an adult-onset segment represented by familial and sporadic AD, and a senescentonset segment represented by SDAT. As a consequence of the association of DS with abnormalities of chromosome 21, counterpart abnormalities of the genes of this chromosome have been sought and found for AD and SDAT.15 Katzman has noted that the age distribution of MID also conforms to the Brody - Schneider plot.6 Although there are several syndromesof premature aging, including DS, some of which exhibit premature arteriosclerosis, there is evidently no juvenile-onset counterpart of MID.~~J~ Viters provides an account of the age distribution of ICAA.4There is an extremely rare inherited form of this lesion in both the United States (in families of German origin)and in Japan, with widespread vascular lesions in multiple organs, including the leptomeninges and the brain parenchyma. The more common forms of inherited ICAA are, however, limited to the brain and meninges. There are Icelandic and Dutch varieties of the latter, inherited as an autosomal dominant trait with high penetrance, in which clinical manifestations typically occur in the third and fourth decades. With respect to age-related ICAA, while there are many reports dealing with a small number of cases14J8 several studies have also been carried out in which 50 or more brains have been examined. At mean ages of 70 80 years, the incidence of sporadic ICAA is approximately 45%. Two studies19,20 contain a more specific age distribution as shown in Table 1. The age-specific incidence of this lesion clearly conforms to the BrodySchneider model for an age-dependent disease. THE PATHOLOGY OF ICAA

Amyloid is defined as one of a variety of hyalinoid substances often deposited in diseased and aging tissues, replacing normal parenchyma. It is a generic term applied to a spectrum of abnormal proteins,21many of which are glycosylated,22 and which exhibit congophilia, birefringence, a characteristicfibrillar structure, and a beta-pleated configuration "not normally found in

this almost pure conformational state in mammalian tissues."21 Amyloid contains all of the common amino acids, with the possible exceptions of hydroxyproline, hydroxylysine, desmosine, and isodesmosine found in collagen or elastin.23There is also a spectrum of atypical or para-amyloids that exhibit some, but not all, of the characteristics of true amyl~id.~' There are six major types of amyloid (AL, AA, AF, AH, AE and ASc), as well as heterogeneities within types. As discussed in the section that follows, these amyloids may derive from a variety of pathogenic pathways and differ in their molecular characteristics, but morphologically, ultrastructurally, and with respect to the beta-pleated configuration, they are all identical. In this regard, Katzman notes a resemblance to some of the childhood lipoidoses in which the final pathological lesion may be produced by many genotypes with different biochemical pathways.6 Blood vessels generally appear to have a particular affinity for several types of amyloid,24 perhaps because they contain a glycoprotein component designated amyloid P (AP)in their basement membrane and elastic fibrils.26 Intracerebral vessels contain Ap, but the amyloid core of the neuritic plaque does not.2'. The affinity of vessels for amyloid is particularly evident in aged subjects. A distinctive subtype of age-related amyloid has been observed in the aorta,?8 and amyloid has been identified in a variety of angiodysplasiasin several anatomic sites, including the central nervous system. However, in subjects of a wide spectrum of age, an age-related type has been found in the angiodysplasias of only those over age 30.29n30In one case with a sderosing angioma of the frontal cortex, NFTs were encountered adjacent to the vascular lesion, but not elsewhere in the brain, and no mention is made of amyloid in the angioma.31 CAA and ICAA are by definition vascular lesions confined to the brain and meninges, with CAA being associated with neuritic plaques, and ICAA occurring as an independent entity. In the inherited Dutch variant, cerebral infarcts are common much as in MID, although areas of hemorrhage may also be present. In the inherited Icelandic variant, structures such as the brain stem and cerebellum are involved, structures usually spared in age-dependent ICAA;rupture of vessels with intracerebral and subarachnoid hemorrhage are common, and microinfarctsrare. In both inherited variants, the lesions are almost always hemispheric and located in the sub-

TABLE 1. AGE-SPECIFIC INCIDENCE OF SPORADIC ICAA Percent by Age Group (Years)

Source Tomonaga (1981)19 Vinters and Gilbert (1983)20

477

60-69

70-79

80-89

90+

8

23

37

5

43

46

58 57

478 BLUMENTHAL AND PREMACHANDRA

cortical white matter, the same areas that are involved in Binswanger‘s disease. The two inherited variants are, however, indistinguishablemorphologically,ultrastructurally, and with respect to the beta-pleated configuration; and they are also indistinguishable from the agedependent ICAA with respect to these characteristics. Vinters provides a detailed description of the morphological characteristics of cerebral vascular amyloidosis (CAA).‘ The walls of small- and medium-sized vessels, as well as of arterioles, show a characteristic acellular hyaline thickening that complies with all of the characteristics of amyloid, including the nonbranching, nonparallel fibrils common to all types of amyloid. These deposits replace smooth muscle and produce a splitting of the internal elastic membrane. The amyloid infiltrates the media and adventitia, and spills over into the adjacent brain parenchyma. Sometimes the vessel wall is infiltrated with amyloid to such a degree that it is not possible to determine whether the vessel is an artery or a vein. Affected vessels may exhibit a “double barrel” appearance because of a distinctive layering of the amyloid deposits. Areas of necrosis may be present and microaneurysms may form. “Glomerular” formations and obliterative fibrosis have also been described. While some of the obliterative changes may represent superimposed effects of hypertension in some patients, there is also evidence that they may be induced by pathological processes secondary to the CAA.32 The physiological effects of these structural changes have also been considered. One experimental study on systemic vascular a m y l o i d ~ s i sconcludes ~~ that despite fairly extensive structural changes “the vessels remain a functional part of the local microcirculation.” Another study that deals specifically with cerebral vessels in AD describes a loss of the perivascular neural network, and the discussion of this finding cames an implication of a reduction in cerebral blood flow (CBF).N However, this neural deficit might also have a direct role in the genesis of dementia. This study makes no mention of amyloid in vessels with the perivascular neural lesion. Cerebral blood flow in dementia has also been discussed by Glatt and K a t ~ m a nThey . ~ note reports of a reduction in CBF with age in the absence of dementia, usually associated with some degree of cerebral arteriosclerosis, and they conclude that, in dementia, a reduction in CBF “is due to reduced demand secondary to either degenerative or vascular disease of the brain.” Several reports have dealt with a possible breakdown of the blood-brain bamer (BBB) attributable to amyloid deposits in vessel^,^,^,^^ or to normal alterations with age in neurochemical systems whose neurotransmitters may affect vascular permeability.36 Those who attribute a possible breakdown in the BBB to deposits of amyloid in vessels propose that an amyloid precursor in the peripheral circulation is converted to amyloid by a unique system present only in cerebral vessels and that these deposits in turn cause the vessels to become leaky and

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permit the precursor to enter the brain parenchyma freely and give rise to plaque amyloid. However, there are several observations that do not support this theory:

1. A negative correlation has been found between vascular and plaque amyloid including cases with a large number of congophilic plaques and few congophilic vessel^;^' the conclusion is drawn that the findings are “most compatible with the hypothesis that amyloid is first produced in the parenchyma and somehow cleared by the vessels.” 2. In old monkeys plaque amyloid is common, but vascular amyloid is absent.38.39 3. CAA exists in the absence of parenchymal cerebral amyloid. 4. Integrity of the BBB appears not to be impaired as a simple function of aging;35and in a direct study of the competency of the BBB in AD40 the results did not support the hypothesized role of the BBB in the pathogenesis of AD.

THE MOLECULAR GENETICS OF THE SENILE AMYLOIDOSES The designation “senile amyloidosis” was introduced by Virchow“ and by S ~ y k a ‘because ~ they frequently encountered deposits of amyloid in the heart of old subjects. It was later extended by D i ~ r y 4to~include deposits in the brain, particularly in neuritic (senile) plaques. Later reports described frequent amyloid deposits in the genitourinary tract, pancreas, and spleen of old subjects.2‘ From studies in more recent years it has become evident that the molecular composition of these deposits in old subjects are not all identical, nor do they all derive from the same precursor molecules. As previously noted,“ no single mechanism has been proposed that would explain the genesis of all types of amyloid. Among the mechanisms proposed are the following: 1. An inherited or acquired mutation that specifies an abnormal protein. 2. A duplication or imbalance of genes resulting in the overproduction of a unique protein. 3. A posttranslational defect. 4. Loss of control of normal infolding of a protein, perhaps due to abnormal glycosylation. 5. Direct aggregation or polymerization of a precursor molecule. 6. Enzymatic cleavage of a variant (mutated) precursor molecule. 7. Unique enzymatic cleavage of a normal precursor molecule. 8. Loss of enzymatic activity to degrade an abnormal protein.

Amyloidogenesis may or may not be unique, in that a variety of pathogenic pathways and a comparable van-

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ety of molecules in the final product can result in an essentiallyidenticalend-stagepathologicallesion. However, if it can be shown that at least some of these processesare intrinsicallygenerated, and if similarphenomena can be identified in other so-called age-dependent diseases, then we may have a better understanding of the aging-disease connection. We now compare the molecular biology of inherited and senile amyloidosis, including ICAA, for the purpose of evaluating the intrinsic nature of the senile amyloidoses. Excluding cases in which the amyloidosis is secondary to some other disease process or associated with dialysis, there are three categories that are encountered in the period of senescence: (1) There are deposits in endocrine glands such as the anterior hypophysis and the islets of Langerhans that are of AE type and not generally included in the senile amyloidoses. Islet amyloid is a derivative of the polypeptide amylin secreted by the beta cell along with insulin. It increases with age and is the lesion most often associated with adult-onset non-insulin-dependent diabetes mellitus. AE is also seen in the thyroid in medullary carcinoma where it is a derivative of calatonin. It is of interest that amylin and calatonin contain common amino acid sequences. (2) The focal deposits of amyloid in the heart, genitourinary tract, extracerebral blood vessels, and a few other organs, as well as senile systemic amyloidosis are derived either from prealbumin or the precursor of beta protein. (3) There are the amyloid deposits restricted to the parenchyma and blood vessels of the brain that also are derived from the precursor of beta protein. Prealbumin (transthyretin)is the precursor of most of the focal-organ deposits and of senile systemic amyloidosis, although some contain unrelated proteins, as for example, the atrial deposits in the heart in which the fibrils contain atrial natriuretic peptide.u Prealbumin has a molecular weight of about 55,000 daltons and consists of four monomers. It has been identified as the precursor in the autosomal dominant (AF)neuropathic syndromes, hereditary cardiomyopathies, and senile systemic amyloidosis. A spea6c mutation of prealbumin has been identified in the hereditary syndromes in which methionine is substituted for valine at position 30 and glycine for threonine at position 49.45 While this appears to be the most common mutated form of prealbumin, several other polymorphic forms have also been identified.= In senile systemic amyloidosis a mutant prealbumin has been identi6ed in which isoleucine is substituted for valine at position 122.46AF cases exhibit a mixture of normal and variant prealbumin, but in senile systemic amyloidosis, all of the prealbumin is of the variant form. The focal deposits of amyloid deriving from prealbumin are not all identical, indicating that the prealbumin may be processed in different ways in different foci.

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Shirahama et a14' have reported that prealbumin is a common constituentof neuritic plaques, NFTs, and cerebral vessels with amyloid deposits. Other studies reviewed by Vinters4have identified other serum components, including immunoglobulins; in virtually all of these studies, antibody-binding techniques have been used. Vinters attributes these results to the leakiness of amyloid-laden vessels and therefore regards them as nonspecific. However, immunoglobulins have also been observed in plaque amyloid39,48,49 in the absence of vascular amyloid. The vast majority of studies, however, have focused on the identification of beta (A4) protein and its precursor (preA4) in cerebral amyloid. The gene coding for beta protein has been identified and sequenced,w and the precursor protein coded by it has a molecular weight of 79,000 daltons. PreA4 resembles a normal surface protein within which is a 42 or 43 amino acid sequence of a beta protein. The beta protein of plaque and vascular amyloid has a molecular weight of 4,200 daltons and a unique amino-acid composition unrelated to any known sequenced protein.5' However, Whitson et a152 have demonstrated that a synthetic beta amyloid molecule enhances the survival of neurons in cultures, thus manifesting neurotrophic activity. They propose that it may be a naturally occurring neurotrophic substance produced in excess in diseased degeneratingbrains, and that aberrant processing of precursor molecules might result in the production of inactive, insoluble beta amyloid in plaques. PreA4 and/or A4 protein have been identified not only in plaque and vascular amyloid of the brain, but also in anterior horn cells, brain stem neurons, in neurons containing lipofuscin, and in adrenal and kidney cells that also contain lipofuscin.5324Because of such observations, Selkoe53 believes that the precursor is present in the systemic circulation much as in the case of other systemic amyloids, including those with a prealbumin precursor, although preA4 is not present in increased levels in the blood of patients with DS or AD/SDAT.55 All studies seem to agree that beta protein is the constituent fibril protein of plaque and vascular amyloid of DS and AD/SDAT, as well as the inherited Dutch variant and the age-dependent ICAA. The fibril protein of the Icelandic variant of ICAA, however, consists of a Glu 58 mutant of cystatin C-so-called gamma trace protein.' Plaque amyloid beta protein consists of 42 or 43 amino acid residues and it exhibits marked heterogeneity at the amino terminus. Vascular amyloid of both the inherited Dutch variant and of AD shows only minimal heterogeneity at the amino terminus, and only 39, rather than 42, aminoaadresidues, at the carboxyterminus.56 These differences between plaque and vascular amyloid have been attributed to different processing of the beta protein precursor in the vessel wall and brain parenchyma by tissue-specific endopeptidases. Vinters et a132 believe, however, that not all amyloid of age-

480 BLUMENTHAL AND PREMACHANDRA

dependent ICAA or brain amyloid can be linked with beta protein, and they predict that new and biochemically unique forms of ICAA will be discovered. CONCLUSIONS In this brief review we have shown that ICAA conforms to the bimodal lifespan plot with the inherited Dutch variant representing the minor early-onset peak and the age-dependent (sporadic)form representing the ascending segment of the plot with no decline in advanced old age. Thus the plot for ICAA parallels that for neuritic plaques in which DS cases represent the minor early peak, and AD/SDAT (familial and sporadic)-as well as the nondemented aged -represent the ascending curve. As to possible clues provided by the inherited/ congenital counterparts of the disorders of later life, preA4 appears to be the precursor of plaque and vascular amyloid in DS and AD/SDAT, as well as in the Dutch variant and age-dependent ICAA.55,56While genes on chromosome 21 have been implicated in DS and AD/SDAT,55 they have not, as yet, been implicated in either the inherited Dutch form or the age-dependent form of ICAA. Moreover, there are noteworthy differences in the length of the molecules and the amino acid sequences between plaque and vascular amyloid regardless of whether the vascular amyloid is associated with neuritic plaques or is of the independent variety. Plaque amyloid fibrils are markedly heterogeneous near the amino terminus and consists of 42 or 43 amino acid residues while vascular amyloid is much less heterogeneous at the amino terminus and has only 39 amino acid residues.56 PreA4 is present in the systemic circulation and appears to be a normal protein with neurotrophic activity;52 however, it is not elevated in DS or AD/SDAT55 and presumably not in ICAA, although this has not been determined. While there has been much discussion about the possibility that the BBB becomes leaky and permits preA4 to enter the brain, there is as yet no evidence that the BBB weakens either with age or in DS or AD/SDAT, and probably not in ICAA. However, it has not been ruled out that the brain may have an independent capacity to produce preA4, in which case systemic preA4 levels may be irrelevant. Neuritic plaques alone or with associated CAA, NFTs, and ICAA, as well as multiple small infarcts, have each been linked with dementia. However, each of these lesions is present in nondemented subjects, and plaques appear to be present in everyone over age 65.57How one translates these observations into explanations of dementia remains unresolved. Quantity of lesions, location of lesions, or the sparing of particular neurons have all been considered. Although it is not clear how CAA might produce or exacerbate dementia, further investigations of this possibility are warranted.

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There has also been much discussion as to whether amyloid-containinglesions of the brain represent accelerated and intensified biological aging phenomena or disease.11In respect to the criteria that define biological aging, EvanslO has made the point that extrinsic influences can be identified by traditional epidemiological methods, while intrinsic aging “lies among what remains when extrinsic factors cannot be detected.” By this definition the vast majority of cases have an intrinsic origin. Moreover, an intrinsic nature is also supported by the existence of inherited/congenital counterparts. While, as already noted, universality appears to hold for neuritic plaques, ICAA is not universal after age 90, occurring in only about 60% of this age group. If by progressivity, we mean that with each succeeding decade an increasing proportion of individuals of a given cohort exhibit lesions, then both neuritic plaques and ICAA are in accord with this criterion. Furthermore, there is, as yet, no evidence that these lesions are reversible either spontaneously or by medical intervention. Thus the pathology of CAA/ICAA represents an abnormality at the molecular level that may be considered as a disease of intrinsic origin or as biological aging. As to genetic programming, Holliday5*contends that developmental processes and maintenance mechanisms are coded by genes, and that failure of the latter over time results in the gradual accumulation of random defects in macromolecules. Except for the inherited/ congenital counterparts, the amyloidoses discussed here would appear to fit with this concept. Also in accord with this concept is a recent statement that defines aging as the result of many independent molecular and physiological processes acting collectively.59Among such diverse phenomena is the accumulation of a variety of abnormal proteins.60 There are several aspects of the amyloid model for bridging the aging- disease dichotomy that merit particular emphasis. It demonstrates that the same end-stage pathological lesion can result from a diversity of pathogenic pathways. The latter may derive from an inherited/congenital disorder, exposure to an extrinsic agent as in some chronic infectious diseases, or directly from a biological aging phenomenon, as in the case of the abnormal cleavage of a normal precursor protein. Moreover, the proteins contained in this end-stage lesion can also exhibit extensive heterogeneity. Another consideration directly related to a correlation of pathological lesions with dementia is that the role of the amyloid angiopathy appears to have been inadequately evaluated. There are several features of this angiopathy that suggest that in AD/SDAT the vascular lesion may be an independent entity superimposed on the plaque lesion. As already noted the vascular amyloid contains AP while the plaque amyloid does not.*’ Furthermore, the protein structure of the vascular amyloid fibril is different from that of the plaque amyloid fibril,56

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and the cerebral amyloid angiopathy, as demonstrated by ICAA, can occur in the absence of neuritic plaques. A comOdY used ‘lich6 in gerontology that a@% is not a disease-meaning that aging per se cannot cause disease. If, as the foregoing seem to indicate, neuritic and ICAA with the criteria Of plaques, biological aging and are necessary, if not sufficient, Causes of dementia, then the concept that aging cannot cause disease may have to be changed. Or as Evans10 has remarked ”to draw a distinction between disease and normal aging is to attempt to separate the undefined from the undefineable.” REFERENCES

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