doi: 10.1161/01.STR.0000028987.97497.22
(Stroke. 2002;33:2147.)
© 2002 American Heart Association, Inc.
Letters to the Editor |
Alzheimer Disease as a Vascular Disorder: Nosological Evidence
Departments of Psychiatry, Medicine, and Pharmacology, Audie L. Murphy VA Geriatric Research Education Clinical Center and the University of Texas Health Science Center at San Antonio, San Antonio, Texas
To the Editor:
The recent review by de la Torre1 on the apparent overlap between Alzheimer’s disease (AD) and vascular dementia (VaD) neglects a fundamental difference between these disorders. AD pathology progresses in a well-described and hierarchically arranged spatial sequence, which begins in the mesiotemporal cortex and moves out, over decades, to affect the frontal, temporal, and parietal lobes.2 Any attempt to explain AD on the basis of vascular disorder must be capable of explaining its consistent onset in very select regions of interest and both its temporal and spatial progression afterward.
Growing literature suggests that the dementia syndrome associated with AD is merely its final stages. Six progressively widespread pathological stages have been described by Braak and Braak.2,3 The age-specific prevalence of stages V and VI almost exactly matches the expected prevalence of clinical AD.3–5 Thus, the entire familiar clinical course of mild, moderate, and severe AD may represent only its terminal stages. Many more elderly persons have lesser levels of AD pathology. There is essentially complete penetrance of low-grade AD pathology after 70 years of age, and as many as 40% of 40 year olds may be affected.3
Moreover, the mere presence of AD pathology is not indicative of either dementia or imminent risk of conversion to dementia.6 AD lesions must reach the frontal lobes before clinicians recognize the disorder.7 Yet most elderly persons do not express that level of pathology.3 Such individuals’ risk of future progression to clinical AD is unknown. Even very elderly persons with AD pathology at autopsy can escape dementia.8
I believe that the apparent overlap in these disorders arises from the failure of clinicians to critically document a pattern of clinical features consistent with the Braak and Braak2,3 progression. For example, AD must involve the hippocampus, whereas VaD may not. The memory impairments associated with hippocampal disease can be psychometrically distinguished from those related to frontal systems lesions (which may dominate VaD), yet this distinction is seldom used in AD case definitions.9 The Braak and Braak sequence also indicates that olfaction should be affected before memory. In fact, anosmia is specifically associated with a hippocampal pattern of memory impairments and faster progression of cognitive impairments,10 yet this too is seldom documented.
It seems more likely that frontal system VaD converts nondemented persons with early AD pathology to "dementia" by affecting frontal system function.11 This has been observed in the Nun Study12 and elsewhere.7 Because VaD-related executive impairments are likely to be superimposed on common but unrelated mesiotemporal AD pathology, a cross-sectional examination might fail to distinguish such cases from clinical AD (eg, Braak and Braak stage V or higher). However, it is essential to appreciate that dementia in these patients would reflect VaD only, because hippocampal AD pathology does not contribute significantly to clinicians’ impressions of dementia independently of frontal systems disease either in AD7 or when comorbidly associated with frontal system vasculopathy.13 Longitudinal follow-up is needed to discriminate an AD-related dementia syndrome from VaD superimposed on subclinical AD pathology.
References
1. de la Torre JC. Alzheimer disease as a vascular disorder: nosological evidence. Stroke. 2002; 33: 1152–1162.
2. Braak H, Braak E. Staging of Alzheimer disease related neurofibrillary changes. Neurobiol Aging. 1995; 16: 271–278.[CrossRef][Medline] [Order article via Infotrieve]
3. Braak H, Braak E. Evolution of neuronal changes in the course of Alzheimer’s disease. J Neural Transm Suppl. 1998; 53: 127–140.[Medline] [Order article via Infotrieve]
4. Katzman R, Aronson M, Fuld P, Kavas C, Brown T, Mogenstern H, Frishman W, Gidy L, Eder H, Or WL. Development of dementing illnesses in an 80-year-old volunteer cohort. Ann Neurol. 1989; 25: 317–324.[CrossRef][Medline] [Order article via Infotrieve]
5. Bachman DL, Wolfe PA, Linn RT, Knoefel JE, Cobb JL, Belanger AJ, White LR, D’Agostino RB, White LR. Prevalence of dementia and probable senile dementia of the Alzheimer type in the Framingham study. Neurology. 1992; 42: 115–119.
6. Goldman WP, Price JL, Storandt M, Grant EA, McKeel DW, Rubin EH, Morris JC. Absence of cognitive impairment or decline in preclinical Alzheimer’s disease. Ann Neurol. 2001; 49: 53–66.[CrossRef][Medline] [Order article via Infotrieve]
7. Royall DR, Palmer R, Mulroy A, Polk, MJ, Román GC, David J-P, Delacourte A. Pathological determinants of clinical dementia in Alzheimer’s disease. Exp Aging Res. 2002; 28: 143–162.[CrossRef][Medline] [Order article via Infotrieve]
8. Rebeck GW, Perls TT, West HL, Sodhi P, Lipsitz LA, Hyman BT. Reduced apolipoprotein 
4 allele frequency in the oldest old Alzheimer’s patients and cognitively normal individuals. Neurology. 1994; 44: 1513–1516.
9. Reed BR, Eberling JL, Mungas D, Weiner MW, Jagust WJN. Memory failure has different mechanisms in subcortical stroke and Alzheimer’s disease. Ann Neurol. 2000; 48: 275–284.[CrossRef][Medline] [Order article via Infotrieve]
10. Royall DR, Chiodo LK, Polk MJ, Jaramillo CJ. Severe dysosmia is specifically associated with Alzheimer-like memory deficits in non-demented elderly retirees. Neuroepidemiology. 2002; 21: 68–73.[CrossRef][Medline] [Order article via Infotrieve]
11. Román GC, Royall DR. Executive control function: a rational basis for the diagnosis of vascular dementia. Alzheimer Dis Assoc Disord. 1999; 13: S69–S80.[CrossRef][Medline] [Order article via Infotrieve]
12. Snowdon DA, Grenier LH, Mortimer JA, Riley KP, Markesbery WR. Brain infarction and the clinical expression of Alzheimer disease: the Nun Study. JAMA. 1997; 277: 813–817.
13. Natté R, Maat-Schieman MLC, Haan J, Bornebroek M, Roos RAC, van Duinen SG. Dementia in hereditary cerebral hemorrhage with amyloidosis-Dutch type is associated with cerebral amyloid angiopathy but is independent of plaques and neurofibrillary tangles. Ann Neurol. 2001; 50: 765–772.[CrossRef][Medline] [Order article via Infotrieve]
Response
Neuropathology Section, University of California, San Diego
I want to thank Dr Royall for his comments. I agree with most of the issues he raises. In my judgment, what is most interesting about vascular dementia (VaD) and Alzheimer’s disease (AD), which I outline in my review, is both their confluence and contrasting clinicopathological features. In the recent Kyoto conference Vascular Factors in Alzheimer’s Disease1 (Kyoto, Japan, April 7–10, 2002), it was reported that mixed dementia (AD plus VaD) now appears as the most common of all dementias, surpassing either AD or VaD.2 What that finding implies is that a common pathological mechanism may be responsible for the origin of both conditions. This concept is supported by reports showing the many risk factors shared by both dementias,3 as well as identical pathological changes observed in the brains of AD/VaD patients such as the formation of senile plaques, neurofibrillary tangles, and vasculopathic lesions.4
For these reasons, it is important to open the door to the possibility that AD has been and continues to be erroneously classified. If this is true, the implications for patient treatment and management are vast. Dr. Royall’s letter of concern is a good step in airing and questioning this and other paradoxes involving AD.
References
1. de la Torre JC, Kalaria RN, Nakajima K, Nagata K, eds. Alzheimer’s Disease: Vascular Epidemiology and Pathology. Ann NY Acad Sci. In press.
2. Korkcyn AD. Mixed dementia: the most common cause of dementia. Ann N Y Acad Sci. In press.
3. Breteler MM. Vascular risk factors for Alzheimer’s disease: an epidemiological study. Neurobiol Aging. 2000; 21: 153–160.[Medline] [Order article via Infotrieve]
4. Teahan O, Slade J, Perry R, Ballard C, Kalaria R. White matter pathology in Alzheimer’s disease and vascular dementia: quantification by amyloid-beta precursor protein immunocytochemistry. Neuropathol Appl Neurobiol. 2002; 28: 168.
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