Neurology -- Correspondence for Beeri et al., 66 (9) 1399-1404

Correspondence published:

Coronary artery disease is associated with Alzheimer disease neuropathology in APOE4 carriers: Christine M Hulette, Kathleen Welsh-Bohmer (13 July 2006)

Reply from the Authors: Michal Schnaider Beeri, Michael Rapp, Jeremy M. Silverman, James Schmeidler, Hillel T. Grossman, John T. Fallon, Dushyant P. Purohit, Daniel P. Perl, Aamir Siddiqui, Gerson Lesser, Clive Rosendorff, Vahram Haroutunian (13 July 2006)

Coronary artery disease is associated with Alzheimer disease neuropathology in APOE4 carriers 13 July 2006

Christine M Hulette,
Duke University Medical Center
Department of Pathology Box 3712 Durham, NC 27710,
Kathleen Welsh-Bohmer
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Re: Coronary artery disease is associated with Alzheimer disease neuropathology in APOE4 carriers

hulet001{at}mc.duke.edu Christine M Hulette, et al.

Beeri et al describe an interesting postmortem study of Alzheimer disease (AD) patients and controls. [1] We have also investigated coronary atherosclerosis, cardiovascular disease and cardiac valve pathology in AD subjects and controls. [2]
The number of autopsies examined in our study was similar to that reported by Beeri et al. We analyzed general systemic autopsy data from 84 neuropathologically confirmed AD patients and from 60 non- AD control patients using a grade of membership model. All cases of AD were Braak stage IV, V or VI. Consistent with reports from our center [3] and others, the late onset AD groups had elevated APOE e4 frequency. However, the late onset AD groups also had frequent mitral and aortic valve dilation, evidence of ventricular pathology, or both.
In contrast to the report by Beeri et al, we observed only modest systemic and coronary atherosclerosis in the late onset AD cases. Systemic or coronary atherosclerosis was more common in the control groups and was associated with younger age at death. [2] The finding of mitral and aortic valve damage, and evidence of ischemic injury to the left ventricular myocardium for the AD groups are consistent with the hypothesis that myocardial pathology may contribute to brain hypoperfusion, which may in turn contribute to dementia and possibly to AD pathogenesis.
We have also reported loss of cerebrovascular smooth muscle actin in subjects with AD. [4] This pathologic change is amplified in subjects with the APOE e4. [4] It is possible that physiologic factors associated with loss or deficient function of smooth muscle actin contributes directly to aortic and mitral valve injury and impaired myocardial contractility. Suboptimal myocardial contractility due to loss of smooth muscle actin or coronary atherosclerosis which causes impaired perfusion of the myocardium may have a negative impact on cardiac output which may also reduce healthy cognitive function. Thus, a constellation of related pathophysiologic events may come together to cause AD pathology and dementia. Further research is needed to address these issues in a prospective longitudinal study with complete and detailed neuropathology and systemic autopsy analysis.
References
1. Beeri MS, Rapp M, Silverman JM, et al. Coronary artery disease is associated with Alzheimer disease neuropathology in APOE4 carriers. Neurol 2006;66:1399-1404.
2. Corder EH, Lockhart E, Ervin JF, et al. Cardiovascular damage in Alzheimer disease: Autopsy findings from the Bryan ADRC. J Biomedicine Biotechnology 2005:2;189-197.
3. Saunders IS, Strittmatter WJ, Schmechel D, et al. Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer's disease. Neurology 1993;43:1467-1472
4. Ervin JF, Pannell C, Szymanski M, Welsh-Bohmer K, Schmechel DE, Hulette CM. A quantitative analysis of vascular smooth muscle actin in Alzheimer's disease. J Neuropathol Exp Neurol.2004; 63:735-41.
Disclosure: Supported by NIA P50 AG05128 & R01 AG07198 and Glaxo Smith-Kline.

Reply from the Authors 13 July 2006

Michal Schnaider Beeri,
Mount Sinai School of Medicine
One Gustave Levy Place, Box 1230, New York, NY 10029,
Michael Rapp, Jeremy M. Silverman, James Schmeidler, Hillel T. Grossman, John T. Fallon, Dushyant P. Purohit, Daniel P. Perl, Aamir Siddiqui, Gerson Lesser, Clive Rosendorff, Vahram Haroutunian
Send Correspondence to journal:
Re: Reply from the Authors

michal.beeri{at}mssm.edu Michal Schnaider Beeri, et al.

Drs. Hulette and Welsh-Bohmer cite a study by Corder et al [2] published after our study [1] was accepted. Corder et al showed more coronary artery atherosclerosis in a control group than in severe late-onset Alzheimer�s disease (AD). At face value, this apparently contradicts our findings of positive associations between coronary artery atherosclerosis and AD neuropathology. However, this discrepancy may represent differences in methodology and group assignment of study subjects.
In our study, we used the full spectrum of AD neuropathology (from none to severe) and corrected for confounding variables such as age at death and BMI. Not controlling for these variables reduced the observed associations between coronary artery atherosclerosis and AD neuropathology.
Corder et al used grade of membership analysis to define five prototypical sub-groups. Three groups had clinically diagnosed dementia (I - early onset, IV- late onset males, and V-late onset females) and two (II -mostly cancer and III-no cancer) did not. The clinically demented groups had neuropathologically confirmed late stage AD. However, 43% of group III had neuropathological "possible AD". The control groups were substantially younger and higher BMI than the AD groups, but these group differences were not factored into the statistical analyses. The apparent differences between study results may be attributed to the effects of age, BMI, and the inclusion of cases with enough neuropathology to warrant a diagnosis of possible AD in the control groups in Corder et al's study. [2]
The Ervin et al [4] results that report loss of cerebrovascular smooth muscle actin in subjects with AD complements our findings. These results, together with Corder�s finding of mitral and aortic valve damage in AD subjects, suggest that aging related cardiovascular pathology, irrespective of the specific cardiovascular lesion, might affect the severity of AD neuropathology. These processes may occur indirectly through hypoperfusion or more directly through brain and systemic vascular pathology. [5] Thus, AD-neuropathology and dementia may be associated with systemic cardiovascular deterioration. [6]
If these conclusions are supported by additional studies then approaches to improve cardiovascular health in the elderly may lead to additional neuropathological and cognitive benefits. [7]
References
5. Kalback W, Esh C, Castano EM et al. Atherosclerosis, vascular amyloidosis and brain hypoperfusion in the pathogenesis of sporadic Alzheimer's disease. Neurol Res 2004;26:525-539.
6. Newman AB, Fitzpatrick AL, Lopez O et al. Dementia and Alzheimer's disease incidence in relationship to cardiovascular disease in the Cardiovascular Health Study cohort. J Am Geriatr Soc 2005;53:1101-1107.
7. Roher AE, Kokjohn TA, Beach TG. An association with great implications: vascular pathology and Alzheimer disease. Alzheimer Dis Assoc Disord 2006;20:73-75.
Disclosure: The authors report no conflicts of interest.