ALZHEIMER'S DISEASE Vh Esltogen Therapy 197 A number of studies examining gender as a risk factor for AD find an increased risk in women, especially older women, even after controlling for education level and other factors, such as differential survival rates. This led to the hypothesis that hormonal factors may play a role in determin- ing susceptibility to AD. This suggestion is supported by the finding that postmenopausal women receiving hormone replacement therapy have a re- duced risk of AD (Paganini-Hill and Henderson, 1994, 1996). A reduced risk of AD was also identified in the Baltimore Longitudinal Study of Aging, a prospective study of the effect of estrogen replacement therapy on incident AD (Kawas et al., 1997). The mechanism by which estrogen protects from AD is unclear. It was suggested the mode of action is through estrogen-sensitive neurons in the hippocampus and cortex (Maki and Resnick, 2000), although evidence from transgenic mice showed that estrogen treatment increased the amount of the neuroprotective sAPP fragment, but did not reduce the production of Aft (Vincent and Smith, 2000). Estrogen has also been shown to have antiox- idant activity (Niki and Nakano, 1990) that may contribute to its protective role. Treatment of women with mild to moderate AD with estrogen for 1 year has not been found to improve cognitive function or slow the progression of the disease (Mulnard et al., 2000). Interestingly, however, nondemented subjects treated with estrogen have better cognitive performance and in- creased regional CBF than nontreated subjects (Maki and Resnick, 2000). This, together with the epidemiological evidence of reduced risk of AD in subjects treated with estrogen, suggests the benefits of estrogen are lost after the onset of AD. This is not surprising as the regions found to be sensitive to estrogen (i.e., hippocampus, parahippocampus, and temporal cortex; Maki and Resnick, 2000) are the areas of the brain that are damaged ear- liest and to the greatest degree in AD (Braak and Braak, 1991; Gomez-Isla et al., 1996). Vlh Vascular Pathology in AD There is mounting evidence for an etiological link between AD and vas- cular pathology. Although both AD and cerebrovascular disease are com- mon in the elderly and their importance as independent causes of brain pathology is acknowledged (Kokmen et al., 1996; Snowdon et al., 1997; 198 JILLIAN J. KRIL AND GLENDA M. HALLIDAY Shi et al., 2000), it is their possible synergy that provides exciting oppor- tunities for the investigation of the pathogenesis of AD. Evidence exists to suggest that cerebrovascular disease may contribute to AD pathology by promoting non-NFT mediated neuronal loss (Grammas et al., 1999) and exacerbating Aft plaque formation (Lin et al., 1999; Bennett et al., 2000). The relationship between AD and vascular disease is far from clear; how- ever, we know that both infarction and microvascular pathology can be in- volved (Fig. 4). Abnormalities in cerebral white matter have been identified at autopsy in more than half the patients with AD (Englund, 1998). These include reduced vessel density, white matter pallor (rarefaction), and glio- sis and thickening of the vessel wall. Such changes are believed to be the pathological correlate of the leukoaraiosis, which is frequently seen on neu- roimaging in elderly subjects with and without dementia (Smith et al., 2000). In addition, numerous studies showed altered architecture of the cerebral microvasculature including atrophic vessels, glomerular loops, and tortu- osities in AD (Ravens, 1978; Kalaria and Hedera, 1995; Buee et al., 1999). These were also shown to occur in normal aging, although they are more frequently encountered in AD. One of the main theories for how abnormal arterioles and capillaries can affect brain function is the disturbance of the normal laminar flow that exists in blood vessels (de la Torre, 1997; Fig. 4). Briefly, in situations of normal flow, red blood cells travel in the center of a vessel where flow is greatest. At the periphery, there is a cell-free zone with virtually no flow, which allows for the transfer of nutrients and other molecules across the vessel wall. Alterations in vessel architecture result in turbulence with im- paired flow and, ultimately, impaired delivery of nutrients. Such turbulence would result in ischemic neuronal loss as a consequence of the failure of de- livery of sustaining nutrients and may differentially affect those areas of the brain with higher metabolic demand, such as the hippocampus. Alternative mechanisms were also proposed for the link between AD and microvas- cular pathology. It has been demonstrated that microvessels isolated from patients with AD can result in neuronal death when cocultured with pri- mary rat neurons (Grammas et al., 1999). The effect was also demonstrated when neurons were cultured with media conditioned by AD microvessels, suggesting a soluble substance is responsible for the neurodegeneration. The nature of the soluble toxin is not known at present, but a number of candidates such as nitric oxide, reactive oxygen species, and cytokines were suggested (Grammas et al., 1999). Several studies have reported an association between cognitive function in AD and the presence of brain infarction (Nagy et al., 1997a; Snowdon et al., 1997). In the Nun study, patients with AD and infarcts showed poorer cogni- tive performance than AD patients without infarction (Snowdon et al., 1997). ALZHEIMER'S DISEASE 199 Similarly, for an equivalent level of cognitive impairment, the density of plaques is less in AD patients with cerebrovascular disease than those with- out such disease (Nagy et al., 1997a). In addition, lacunar infarction with or without leukoencephalopathy was found in 20 of 25 cases with clinically probable AD and the majority of these had a lower Braak neuritic stage than demented patients without cerebrovascular disease (Goulding et al., 1999). Furthermore, it was demonstrated that impaired circulation can result in in- creased Aft deposition. In experimental animals, chronic hypoperfusion can trigger the cleavage of APP and the formation of Aft (Bennett et al., 2000), whereas in humans, soluble A/31-42/43 levels are similar in patients with multi-infarct dementia and AD (Kalaria, 2000). Overall, these studies show that AD pathology may be less severe when there is coexisting cerebrovas- cular disease and that cerebrovascular disease may contribute to AD-type pathology. The association between vascular disease and AD is further supported by the finding that subjects dying of cardiovascular disease show more AD-type pathology than those dying of noncardiac causes (Sparks et al., 1990; Sparks, 1997). In nondemented individuals dying of cardiac causes, the density of senile plaques is half that seen in AD (Sparks et al., 1990). The effect of ApoE e4 in this population was not examined and a study by Irina and colleagues (1999), which was unable to confirm the finding, suggested the association is due to ApoE e4 and not cardiovascular disease per se. In addition to AD, an association between cardiovascular disease and ApoE genotype is well established (see Katzman, 1994), which further strengthens the link between vascular disease and AD. A. VASCULAR RISK FACTORS Epidemiological evidence links cardio- and cerebrovascular factors with AD. In a longitudinal study, subjects who developed dementia had higher systolic blood pressure measured 15 years earlier than their nondemented counterparts (Skoog et al., 1996). Interestingly, at the time of diagnosis of AD, these same subjects had blood pressure similar to or lower than the nondemented subjects. This latter point may underlie the cross-sectional association described between higher blood pressure and better cognitive function in later life (Farmer et al., 1987). These studies suggest early and midlife events significantly affect late-life neurodegenerative diseases. Diabetes mellitus, which is known to be associated with an increased risk of stroke, was also shown to be associated with an increased risk of AD (Kuusisto et al., 1997; Ott et al., 1999). A relative risk of 1.9 was found for both AD and dementia of any type (Ott et al., 1999). The risk is higher 200 JILLIAN J. KRIL AND GLENDA M. HALLIDAY (RR 4.3, CI 1.7-10.5) in those treated with insulin, suggesting there is an in- creasing risk with increasing severity of diabetes. Patients with diabetes mel- litus have a high incidence of vascular complications (West, 1978), and the reported association with AD may reflect increased cerebrovascular disease in these patients. A postmortem study comparing cerebrovascular pathology in diabetic and nondiabetic AD patients has not been performed. However, AD-type pathology was studied in diabetic subjects and is not increased (Heitner and Dickson, 1997). The associated risk is therefore likely to be due to non-AD pathology, most likely, vascular disease. Genetic predisposition may also play a role in the relationship between vascular disease and AD. In addition to the association with ApoE, polymor- phisms of the angiotensin-converting enzyme (ACE) have been associated with an increased risk of AD (Hu et al., 1999; Kehoe et al., 1999). Despite associations between ACE and cardiovascular risk factors, the association is independent ofApoE (Hu et al., 1999). Thus, it appears there is a complex relationship between vascular disease and its risk factors and an increased risk of AD. B. SUMMARY A hypothesis has been presented that links many of the identified and pu- tative risk factors forAD and suggests a mechanism for their action. Crawford (1996, 1998) proposes an association between AD and cerebral blood flow (CBF) by citing evidence that many of the factors that are linked with an increased risk of AD also decrease CBF (e.g., old age, depression, under- activity, head trauma). Similarly, it is suggested factors that increase CBF are associated with a decreased risk of AD (e.g., education, exercise, smok- ing, NSAIDs). Although the authors acknowledge that reduced CBF is not sufficient to cause AD, the reported positive and negative associations pro- vide tantalizing evidence for a common mode of action for many of the equivocal risk factors reported to date. This hypothesis is also consistent with other data that links microvascular damage and impaired blood flow (de la Torre, 1997, 2000) and low education with increased cerebrovascular disease (Del Ser et al., 1999). Gaining a better understanding of the interaction between AD and vas- cular disease is of great importance. Not only will it provide insights into the pathogenesis of AD, but it may also provide us with a rare opportunity for the treatment and possible prevention ofAD. A great many risk factors for vascular disease have been identified and intervention programs have suc- cessfully reduced the incidence of heart disease and stroke. The potential exists to provide the same level of success with AD. ALZHEIMER'S DISEASE Acknowledgments 201 The authors are grateful to Heidi Cartwright for the preparation of the illustrations, Francoise Png and Smita Patel for bibliographic assistance, and Dr. Claire Shepherd for help- ful discussions. Studies described in this article were conducted with financial assistance from the Medical Foundation of The University of Sydney and the National Health and Medical Research Council (NHMRC) of Australia.J.J.K. is a Medical Foundation Fellow and G.M.H. is a Principal Research Fellow of the NHMRC. References Akiyama, H., Meyer, J. S., Mortel, K. E, Terayama, Y., Thornby, J. I., and Konno, S. (1997). Normal human aging: Factors contributing to cerebral atrophy. J. Neurol. Sci. 152, 39-49. Aletrino, M. A., Vogels, O.J., Van Domburg, P. H., and Ten Donkelaar, H.J. (1992). Cell loss in the nucleus raphes dorsalis in Alzheimer's disease. Neurobiol. Aging 13, 461-468. American College of Medical Genetics/American Society of Human Genetics Working Group on ApoE and Alzbemer's disease. (1995). Statement on the use ofapolipoprotein E testing for Alzheimer's disease. J.A.M.A. 274, 1627-1629. Anderson,J. M., Hubbard, B. M., Coghill, G. R., and Slidders, W. (1983). The effect of advanced old age on the neurone content of the cerebral cortex. J. Neurol. Sci. 58, 233-244. Arnold, S. E., Hyman, B. T., Flory, J., Damasio, A. R., and Van Hoesen, G. W. (1991). The topographical and neuroanatomical distrubution of neurofibrillary tangles and neuritic plaques in the cerebral cortex of patients with Alzheimer's disease. Cereb. Cortex 1, 103-116. Arriagada, E V., Growdon,J. H., Hedley-Whyte, T., and Hyman, B. T. (1992). Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease. Neu- rolog 3 42, 631-639. Auld, D. S., Kar, S., and Quirion, R. (1998)./3-amyloid peptides as direct cholinergic neuro- modulators: A missing link? Trends Neurosci. 21, 43-49. Ball, M.J. (1977). Neuronal loss, neurofibrillary tangles and granulovacuolar degeneration in the hippocampus with aging and dementia: A quantitative study. Acta Neuropathol. 37, 111-118. Ballerini, C., Nacmias, B., Rombola, G., Marcon, G., Massacesi, L., and Sorbi, S. (1999). HLA A2 allele is associated with age at onset of Alzheimer's disease. Ann. Neurol. 45, 397-400. Bancher, C., Braak, H., Fischer, E, and Jellinger, K. A. (1993). Neuropathological staging of Alzheimer lesions and intellectual status in Alzheimer's and Parkinson's disease patients. Neurosci. Lett. 162, 179-182. Bancher, C., Brunner, C., Lassmann, H., Budka, H., Jellinger, K., Wiche, G., Seitelberger, E, Grundke-lqbal, I., Iqbal, K., and Wisniewski, H. M. (1989). Accumulation of abnormally phosphorylated tau precedes tile formation of neurofibrillary tangles in Alzheimer's dis- ease. Brain Res. 477, 90-99. Bancher, C., Lassmann, H., Breitschopf, H., andJellinger, K. A. (1997). Mechanisms of cell death in Alzheimer's disease.J. Neural. Transm. 50(Suppl), 141-152. Barber, R., Gholkar, A., Scheltens, P., Ballard, C., McKeith, I. G., Morris, C. M., and O'Brien, J. T. (1999). Apolipoprotein E e4 Allele, temporal lobe atrophy, and white matter lesions in late-life dementias. Arch. Neurol. 56, 961-965. 202 JILLIAN J. KRIL AND GLENDA M. HALLIDAY Bartus, R. T., Dean, R. L., Beer, B., and Lippa, A. S. (1982). The cholinergic hypothesis of geriatric memory dysfunction. Science 217, 408-417. Baskin, D. S., Browning, J. L., Pirozzolo, E J., Korporaal, S., Baskin, J. A., and Appel, S. H. (1999). Brain choline acetyltransferase and mental function in Alzheimer's disease. Arch. Neurol. 56, 1121-1123. Beach, T. G., Kuo, Y. M., Spielgel, K., Emmerling, M. R., Sue, L. I., Kokjohn, I~, and Roher, A. E. (2000). The cholinergic deficit coincides with Abeta deposition at the earliest histopatho- logic stages of Alzheimer disease.J. Neuropathol. Exp. NeuroL 59, 308-313. Beard, M., Kokman, E., Offord, I~, and Kurland, L. T. (1992). Lack of association between Alzheimer's disease and education, occupation, marital status or living arrangement. Neurology 42, 2063-2068. Bennett, S. A. L., Pappas, B. A., Stevens, W. D., Davidson, C. M., Fortin, T., and Chen, J. (2000). Cleavage of amyloid precursor protein elicited by chronic cerebral hypoper fusion. Neurobiol. Aging 21,207-214. Berg, L., McKeel, D. W., Miller,J. E, Storandt, M., Rubin, E. H., Morris,J. C., Baty,J., Coats, M., Norton,J., Goate, A. M., Price,J. L., Gearing, M., Mirra, S. S., and Saunders, A. M. (1998). Clinicopathologic studies in cognitively healthy aging and Alzheimer's disease: Relation of histologic markers to dementia severity, age, sex, and apolipoprotein E genotype. Arch. NeuroL 55, 326-335. Blacker, D., Albert, M. S., Bassett, S. S., Go, R. C. E, Harrell, L. E., and Folstein, M. E (1994). Reliability and validity of NINCDS-ADRDA criteria for Alzheimer's disease. Arch. Neurol. 51, 1198-1204. Bobinski, M., de Leon, M. J., Wegiel, J., Desanti, S., Convit, A., Saint Louis, L. A., Rusinek, H., and Wisniewski, H. M. (2000). The histological validation of post mortem magnetic resonance imaging-determined hippocampal volume in Alzheimer's disease. Neuroscience 95, 721-725. Bobinski, M., Wegiel,J., Tarnawski, M., Bobinski, M., De Leon, M.J., Reisberg, B., Miller, D. C., and Wisniewski, H. M. (1998). Duration of neurofibrillary changes in the hippocampal pyramidal neurons. Brain Res. 799, 156-158. Bobinski, M., Wegiel, J., Wisniewski, H. M., Tarnawski, M., Reisberg, B., Mlodzik, B., de Leon, M.J., and Miller, D. C. (1995). Atrophy of hippocampal formation subdivisions with stage and duration of Alzheimer's disease. Dementia 6, 205-210. Bondareff, W., Harrington, C., Wischik, C. M., Hauser, D. L., and Roth, M. (1994). Immunohis- tochemical staging of neurofibrillary degeneration in Alzheimer's disease. J. Neuropathol. Exp. Neurol. 53, 158 164. Bowler,J. V., Munoz, D. G., Merskey, H., and Hachinski, V. (1998). Fallicies in the pathological confirmation of the diagnosis of Alzheimer's disease, jr. Neurol. Neurosurg. Psychiatry 64, 18-24. Braak, E., Braak, H., and Mandelkow, E M. (1994). A sequence of cytoskeleton changes related to the formation of neurofibrillary tangles and neuropil threads. Acta Neuropathol. 87, 554- 567. Braak, H., and Braak, E. (1991). Neuropathological staging of Alzheimer-related changes. Acta Neuropathol. 82, 239-259. Braak, H., and Braak, E. (1997). Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol. Aging 18, 351-357. Breimer, J. C. S. (1996). Inflammatory processes and anti-inflammatory drugs in Alzheimer's disease: A current appraisal. Neurobiol. Aging 17, 789-794. Breteler, M. M. B. (2000). Vascular risk factors for Alzheimer's disease: An epidemiologic perspective. Neurobiol. Aging21, 153-160. Brion,J P. (1998). Neurofibrillary tangles and Alzheimer's disease. Eur. Neurol. 40, 130-140. ALZHEIMER'S DISEASE 203 Brody, H. (1955). Organisation of the cerebral cortex III. A study of aging in the human cerebral cortex.J. Comp. Neurol. 102, 511-556. Broe, G. A., Grayson, D. A., Creasey, H. M., Waite, L., Casey, B.J., Bennett, H. E, Brook, W. S., and Halliday, G. M. (2000). Anti-inflammatory drugs protect against Alzheimer's disease at low doses. Arch. Neurol. 57, 1586-1591. Broe, G. A., Henderson, A. S., Creasey, H., McCusker, E., Korton, A. E.,Jorm, A. E, Longley, W., and Anthony, J. L. (1990). A case control study of Alzheimer's disease in Australia. Neurology 40, 1698-1707. Buee, L., Hof, E R., and Delacourte, A. (1999). Brain microvascular changes in Alzheimer's disease and other dementias. Ann. N.Y. Acad. Sci. 826, 7-24. Buldyrev, S. V., Cruz, L., Gomez-Isla, T., Gomez-Tortosa, E., Havlin, S., Le, R., Stanley, H. E., Urbane, B., and Hyman, B. T. (2000). Description of microcolumnar ensembles in associ- ation cortex and their disruption in Alzheimer and Lewy body dementias. Proc. Natl. Acad. Sci. USA 97, 5039-5043. Burns, A., Luthert, E, Levy, R., Jacoby, R., and Lantos, P. (1990). Accuracy of clinical diagnosis of Alzheimer's disease. Br. Med.J. 301, 1201. Busch, C., Bohl,J., and Ohm, T. G. (1997). Spatial, temporal and numeric analysis of Alzheimer changes in the locus coeruleus. Neurobiol. Aging 18, 401-406. The Canadian Study of Health and Aging Study Center. (1994). The Canadian study of health and aging: Risk factors for Alzheimer's disease in Canada. Neurology 44, 2073-2080. Checler, F. (1999). Presenilins: Multifunctional proteins involved in Alzheimer's disease pathol- ogy. IUBMB Life48, 33-39. Cobb, J. B., Wolf, P. A., White, R., and D'Agostino, R. B. (1995). The effect of education on the incidence of dementia and Alzheimer's disease in the Framingham study. Neurology 45, 1707-1712. Coffey, C. E., Lucke, J. E, Saxton, J. A., Ratcliff, G., Unitas, L.J., Billig, B., and Bryan, R. N. (1998). Sex differences in brain aging: A quantitative magnetic resonance imaging study. Arch. Neurol. 55, 169-179. Colon, E.J. (1973). The cerebral cortex in presenile dementia A quantitative analysis. Acta Neuropathol. 23, 281-290. Combarros, O., Escribano, J., Sanchez-Velasco, P., Leyva-Cobian, E, Oterino, A., Leno, C., and Berciano,J. (1998). Association of the HLA-A2 allele with an earlier age of onset of Alzheimer's disease. Acta Neurol. Scand. 98, 140-141. Convit, A., de Asis, J., de Leon, M.J, Tarshish, C., De Santi, S., and Rusinek, H. (2000). Atro- phy of the medial occipitotemporal, inferior, and middle temporal gyri in non-demented elderly predict decline to Alzheimer's disease. Neurobiol. Aging21, 19-26. Convit, A., de Leon, M., Hoptman, M.J., Tarshish, C., De Santi, S., and Rusinek, H. (1995). Age-related changes in brain: I. Magnetic resonance imaging measures of temporal lobe volumes in normal subjects. Psych. Quart. 66, 343-455. Convit, A., De Leon, M. J., Tarshish, C., De Santi, S., Tsui, W., Rusinek, H., and George, A. (1997). Specific hippocampal volume reductions in individuals at risk tor Alzheimer's disease. Neurobiol. Aging 18, 131-138. Corder, E. H., Saunders, A. M., Strittmatter, W.J., Schmechel, D. E., Gaskell, E C., Small, G. W., Roses, A. D., and Pericak-Vance, M. A. (1993). Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261, 921-923. Coughlan, C. M., and Breen, IC C. (2000). Factors influencing the processing and function of the amyloid/3 precursor protein A potential therapeutic target in Alzheimer's disease? Phavmacol. Th~ 86, 111-144. Crawford,J. G. (1996). Alzheimer's disease risk tactors as related to cerebral blood flow. Med. Hypotheses 46, 367-377. 204 JILLIAN J. KRIL AND GLENDA M. HALLIDAY Crawford,J. G. (1998). Alzheimer's disease risk factors as related to cerebral blood flow: Addi- tional evidence. Med. Hypotheses 50, 25-36. Creasey, H.,Jorm, A., Longley, W., Broe, G. A., and Henderson, A. S. (1989). Monozygotic twins discordant for Alzheimer's disease. Neurology 39, 1474-1476. Crook, R., Verkkoniemi, A., Perez-Tur,J., Mehta, N., Baker, M., Houlden, H., Farrer, M., Hutton, M., Lincoln, S., Hardy, J., Gwinn, K., Somer, M., Paetau, A., Kalimo, H, Ylikoski, R., Poyhonen, M., Kucera, S., and Haltia, M. (1998). A variant of Alzheimer's disease with spastic paraparesis and unusual plaques due to deletion of exon 9 of presenilin 1. Nat. Med. 4, 452-455. Cullen, IC M., and Halliday, G. M. (1998). Neurofibrillary degeneration and cell loss in the nucleus basalis in comparison to cortical Alzheimer pathology. Neurobiol. Aging 19, 297- 306. Cullen, K. M., Halliday, G. M., Double, IC L., Brooks, W. S., Creasey, H., and Broe, G. A. (1997). Cell loss in the nucleus basalis is related to regional cortical atrophy in Alzheimer's disease. Neuroscience 78, 641-652. Culpin, D., MacGowan, S., Laundy, G.J., and Wilcock, G. K. (1999). HLA-DR3 and DQAI* 0401: possible risk factors in Alzheimer's disease. Alz. Rep. 2, 93-97. Curran, M Middleton, D., Edwardson, J., Perry, R., McKeith, I., Morris, C., and Neill, D. (1997). HLA-DR antigens associated with major genetic risk for late-onset Alzheimer's disease. Neuroreport 8, 1467-1469. Czech, C., Tremp, G., and Pradier, L. (2000). Presenilins and Alzheimer's disease: Biological functions and pathogenic mechanisms. Prog. Neurobiol. 60, 363-384. de la Torre, J. C. (1997). Hemodynamic consequences of deformed microvessels in the brain in Alzheimer's disease. Ann. N. E Acad. Sci. 826, 75-91. de la Torre,J. C. (2000). Critically attained threshold of cerebral hypoperfusion: The CATCH hypothesis ofAlzheimer's pathogenesis. NeurobioL Aging21, 331-342. Dekaban, A. S. (1978). Changes in brain weights during the span of human life: Relation of brain weights to body heights and body weights. Ann. Neurol. 4, 345-356. Del Ser, T., Hachinski, V., Merskey, H., and Munoz, D. G. (1999). An autopsy-verified study of the effect of education on degenerative dementia. Brain 122, 2309-2319. Detoledo-Morrell, L, Sullivan, M. E, Morrell, E, Wilson, R. S., Bennett, D. A., and Spencer, S. (1997). Alzheimer's disease: In vivo detection of differential vulnerability of brain regions. Neurobiol. Aging 18, 463-468. Di lorio, A., Zito, M., Lupinetti, M., and Abate, G. (1999). Are vascular factors involved in Alzheimer's disease? Facts and theories. Aging (Milano) 11,345-352. Dickson, D. W. (1997). The pathogenesis of senile plaques. J. Neuropathol. Exp. Neurol. 56, 321-339. Double, IC L., Halliday, G. M., Kril,J.J., Harasty,J. A., Cullen, K., Brooks, W. S., Creasey, H., and Broe, G. A. (1996). Topography of brain atrophy during normal aging and Alzheimer's disease. Neurobiol. Aging 17, 513-521. Druganow, M., Faull, R. L., Lawlor, E, Beilharz, E.J., Singleton, K., Walker, E. B., and Mee, E. (1995). In situ evidence for DNA fragmentation in Huntington's disease striatum and Alzheimer's disease temporal lobes. Neuroreport 6, 1053-1057. Duyckaerts, C., Colle, M. A., Dessi, E, Piette, E, and Hauw,J.J. (1998). Progression of Alzheimer histopathological change. Acta Neurol. Belg. 98, 180-185. Duyckaerts, C., and Hauw, J.J. (1997). Prevalence, incidence and duration of Braak's stages in the general population: Can we know? NeurobioL Aging 18, 362-369. Elias, M. E, Beiser, A., Wolf, E A., Au, R., White, R. E, and D'Agosdno, R. B. (2000). The preclinical phase of Alzheimer disease: A 22-year prospective study of the Framingham Cohort. Arch. NeuroL 57, 808-813. ALZHEIMER'S DISEASE 205 Englund, E. (1998). Neuropathology of white matter changes in Alzheimer's disease and vas- cular dementia. Dement. Geriatr. Cogn. Disord. 9(suppl 1), 6-12. Farmer, M. E., White, L. R., Abbott, R. D., Kitmer, S.J., Kaplan, E., Wolz, M. M., Brody, J. A., and Wolf, P. A. (1987). Blood pressure and cognitive performance: The Framingham study. Am. J. Epidemiol. 126, 1103 1114. Folstein, M. E, Folstein, S. E., and McHugh, P. R. (1975). "Mini-mental state": A practical method for grading the cognitive state of patients for the clinician. J. Psychiatry Res. 12, 189-198. Forstl, H., and Kurz, A. (1999). Clinical features of Alzheimer's disease. Eur. Arch. Psychiatry Clin. Neurosci. 249, 288-290. Fox, N. C., Cousens, S., Scahill, R., Harvey, R.J., and Rossor, M. N. (2000). Using serial registered brain magnetic resonance imaging to measure disease progression in Alzheimer disease: Power calculations and estimates of sample size to detect treatment effects. Arch. Neurol. 57, 339-344. Fox, N. C., Warrington, E. K., Freeborough, E A., Hartikainen, E, Kennedy, A. M., Stevens,J. M., and Rossor, M. N. (1996). Presymptomatic hippocampal atrophy in Alzheimer's disease. A longitudinal MRI study. Brain 119, 2001-2007. Francis, E T., Palmer, A. M., Snape, M., and Wilcock, G. K. (1999). The cholinergic hypothesis of Alzheimer's disease: A review of progress. J. Neurol. Neurosurg. Psychiatry 66, 137-147. Frisoni, G. B., Laasko, M. E, Beltramello, A., Geroldi, C., Bianchetti, A., Soininen, H., and Trabucchi, M. (1999). Hippocampal and entorhinal cortex atrophy in frontotemporal dementia and Alzheimer's disease. Neurolog 3 52, 91-100. Fukumoto, H., Asami-Odaka, A., Suzuki, N., Shimada, H., Ihara, Y., and Iwatsubo, T. (1996). Amyloid /3-protein deposition in normal aging has the same characteristics as that in Alzheimer's disease. Predominance of A/3 and association of Aft40 with cored plaques. Am.J. Pathol. 148, 259-265. Gahtan, E., and Overmier, J. B. (1999). Inflammatory pathogenesis in Alzheimer's disease: Biological mechanisms and cognitive sequeli. Neurosci. Biobehav. Rev. 23, 615-633. Gandy, S., and Petanceska, S. (2000). Regulation of Alzheimer/3-amyloid precursor trafficking and metabolism. Biochim. Biophys. Acta 1502, 44-52. Gertz, H J., Xuereb, J., Huppert, E, Brayne, C., McGee, M. A., Paykel, E., Harrington, C., Mukaetova-Ladinska, E., Arendt, T., and Wischik, C. M. (1998). Examination of the validity of the hierarchical model of neuropathological staging in normal aging and Alzheimer's disease. Acta Neuropathol. 95, 154-158. Gervais, E G., Xu, D., Robertson, G. S., Vaillancourt, J. E, Zhu, Y., Huang, J. Q., LeBlanc, A., Smith, D., Rigby, M., Shearman, M. S., Clarke, E. E., Zheng, H., Van Der Ploeg, L. H. T., Ruffolo, S. C., Thornberry, N. A., Xanthoudakis, S., Zamboni, R.J., Roy, S., and Nicholson, D. W. (1999). Involvement of caspases in proteolytic cleavage of Alzheimer's amyloid-/3 precursor protein and amyloidogenic A/3 peptide tormation. Cell 97, 395-406. Goedert, M., Spillantini, M. G., and Crowther, R. A. (1991). Tau proteins and neurofibrillary degeneration. Brain Pathol. 1,279-286. Gomez-Isla, T., Hollister, R., West, H., Mui, S., Growdon,J. H., Petersen, R. C., Parisi,J. E., and Hyman, B. T. (1997). Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer's disease. Ann. Neurol. 41, 17-24. Gomez-Isla, T., Price, J. L., McKeel, Jr., D. W., Morris, J. C., Growdon,J. H., and Hyman, B. T. (1996). Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer's Disease.J. Neurosci. 16, 4491-4500. Goulding, J. M. R., Signorini, D. E, Chatterjee, S., Nicoll, J. A. R., Stewart, J., Morris, R., and Laramie, G. A. (1999). Inverse relation between Braak stage and cerebrovascular pathology in Alzheimer predominant dementia ]. Neurol. Neurosurg. Psychiatry 67, 654-657. 206 JILLIAN J. KRIL AND GLENDA M. HALLIDAY Grammas, E, Moore, E, and Weigel, P. H. (1999). Microvessels from Alzheimer's disease brains kill neurons in vitro. Am.J. Pathol. 154, 337-342. Green, M. S., Kaye,J. A., and Ball, M.J. (2000). The Oregon brain aging study. Neuropathology accompanying healthy aging in the oldest old. Neurology 54, 105-113. Grober, E., Dickson, D., Sliwinski, M.J., Buschke, H., Katz, M., Crystal, H., and Lipton, R. B. (1999). Memory and mental status correlates of modified Braak staging. Neurobiol. Aging 20, 573-579. Haas, C. (1996). The molecular significance of amyloid fl-peptide for Alzheimer's disease. Eur. Arch. Psychiatry Clin. Neurosci. 246, 118-123. Hall, K. S., Gao, S., Unverzagt, E W., and Hendrie, H. C. (2000). Low education and childhood rural residence: Risk for Alzheimer's disease in African Americans. Neurology 54, 95-99. Halliday, G., Robinson, S., Shepherd, C., and Kril, J. (2000a). Alzheimer's disease and inflam- mation: A review of cellular and therapeutic mechanisms. Clin. Exp. Pharmacol. Physiol. 27, 1-8. Halliday, G. M., McCann, H. L., Pamphlett, R., Brooks, W. S., Creasey, H., McCusker, E., Cotton, R. G. H., Broe, G. A., and Harper, C. G. (1992). Brain stem serotonin-synthesizing neurons in Alzheimer's disease: A clinicopathological correlation. Acta Neuropathol. 84, 638-650. Halliday, G. M., Shepherd, C. E., McCann, H., Reid, W. G.J., Grayson, D. A., Broe, G. A., and Kril, J. J. (2000b). Anti-inflammatory medications do not decrease Alzheimer's disease neuropathology. Arch. Neurol. 57, 831-836. Harding, A.J., Halliday, G. M., and Kril,J.J. (1998). Variation in hippocampal neuron number with age and brain volume. Cereb. Cc~rtex 8, 710-718. Harding, A. J., Kril, J.J., and Halliday, G. M. (2000). Practical measures to simplify the Braak tangle staging method for routine pathological screening. Acta Neuropathol. 99, 199-208. Harkany, T., Penke, B., and Luiten, E G. (2000). Beta-amyloid excitotoxicity in rat magnocel- lular nucleus basalis. Effect of cortical deafferentation on cerebral blood flow regulation and implications for Alzheimer's disease. Ann. N.Y. Acad. Sci. 903, 374-386. Hartley, D. M., Walsh, D. M., Ye, C. E, Diehl, T., Vasquez, S., Vassilev, E M., Teplow, D. B., and Selkoe, D.J. (1999). Protofibrillar intermediates of anayloid fl protein induce acute electrophysiological changes and progressive neurotoxicity in cortical neurons, f Neurosci. 19, 8876-8884. Hartmann, T. (1999). Intracellular biology of Alzheimer's disease amyloid beta peptide. Eur. Arch. Psychiatry Clin. Neurosci. 249, 291-298. Haug, H., and Eggers, R. (1991). Morphometry of the human cortex cerebri and corpus striatum during aging. Neuro&'ol. Aging 12, 336-338. Heitner,J., and Dickson, D. (1997). Diabetics do not have increased Alzheimer-type pathology compared with age-matched control subjects. Neurology 49, 1306-1311. Henderson, A. s.,Jorm, A. E, Christensen, H.,Jacomb, E A., and Korten, A. E. (1997). Asprin, anti-inflammatory drugs and risk of dementia. Intl. J. Geriatric Psychiatry 12, 926-930. Henderson, G., Tomlinson, B. E., and Gibson, P. H. (1980). Cell counts in human cerebral cortex in normal adults throughout life using an image analysing computer.J. Neurol. Sci. 46, 113-136. Heyman, A., Wilkson, W. E., Stafford, J. A., Helms, M.J., Sigmon, A. H., and Weinberg, T. (1984). Alzheimer's disease: A study of epidemiological aspects. Ann. Neurol. 15, 335-341. Horsburgh, K., McCarron, M. O., White, E, and Nicoll,J. A. R. (2000). The role of apolipopro- tein E in Alzheimer's disease, acute brain injury and cerebrovascular disease: Evidence of common mechanisms and utility of animal models. Neurobiol. Aging21, 245-255. Howieson, D. B., Holm, L. A., Kaye, J. A., Oken, B. S., and Howieson, J. (1993). Neurologic function in the optimally healthy oldest old: Neuropsychological evaluation. Neur0/ogy 43, 1882-1886. . disease. Neu- rolog 3 42 , 63 1-6 39. Auld, D. S., Kar, S., and Quirion, R. (1998)./3-amyloid peptides as direct cholinergic neuro- modulators: A missing link? Trends Neurosci. 21, 4 3 -4 9. Ball,. and Hachinski, V. (1998). Fallicies in the pathological confirmation of the diagnosis of Alzheimer's disease, jr. Neurol. Neurosurg. Psychiatry 64, 1 8-2 4. Braak, E., Braak, H., and Mandelkow,. Phavmacol. Th~ 86, 11 1-1 44 . Crawford,J. G. (1996). Alzheimer's disease risk tactors as related to cerebral blood flow. Med. Hypotheses 46 , 36 7-3 77. 2 04 JILLIAN J. KRIL AND GLENDA M. HALLIDAY