Neurology -- Correspondence for Regan et al., 67 (8) 1357-1362

Correspondence published:

Relationship of vascular risk to the progression of Alzheimer disease: Barbara Borroni, Silvana Archetti, Maria Ferrari, Bruno M. Cesana, and Alessandro Padovani (12 December 2006)

Reply from the authors: Ciaran E Regan, Cornelius Katona, Zuzana Walker, and G. Livingston. (12 December 2006)

Relationship of vascular risk to the progression of Alzheimer disease 12 December 2006

Barbara Borroni,
Department of Neurology, University of Brescia
P.za Spedali Civili 1, 25125 Brescia, Italy,
Silvana Archetti, Maria Ferrari, Bruno M. Cesana, and Alessandro Padovani
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Re: Relationship of vascular risk to the progression of Alzheimer disease

bborroni{at}inwind.it Barbara Borroni, et al.

We read with interest the manuscript by Regan et al in which the authors discuss the role of vascular risk factors on disease progression in Alzheimer Disease (AD). [1] There was no difference in rate of deterioration between people with and without vascular risk factors except in those who had a cerebrovascular accident. Thus, vascular risk factors may contribute to the expression of AD initially but are not part of the underlying etiologic process. [1]
These findings correspond with our ongoing study carried out on a consecutive series of AD patients [2] aimed at evaluating the genotype-phenotype effect of well -known vascular risk factors and their possible interactions. Among 230 AD patients, 90 had been followed periodically through a 1-year follow-up. Each patient underwent a clinical and standardized neuropsychological assessment, including Mini-Mental State Examination (MMSE). Comorbidities (i.e., hypertension, history of cardiovascular events, and diabetes mellitus) were noted according to current clinical criteria.
Venous blood was collected for laboratory analyses and genotyping. Each patient was genotyped for Apolipoprotein E (APOE) isoforms [3], and Methylenetetrahydrofolate Reductase (MTHFR) C677T and A1298C polymorphisms. [4] In particular, the relationship between APOE genotype- cholesterol levels and MTHFR polymorphisms-homocysteine levels were considered.
AD patients were classified into two subgroups as presenting progressive cognitive decline through 1-year follow-up (pAD, MMSE 1-year minus MMSE baseline less than 0) or stable cognitive functions (sAD, MMSE 1-year minus MMSE baseline greater than or equal to 0). pAD was present in 60% of patients (n=54), while sAD in 40% (n=36). The two groups differed neither for APOE genotype distribution (APOE epsilon 4; pAD vs. sAD, 46.3% vs. 50.0%) nor for cholesterol levels (213.5�45.8 vs. 224.2�40.0). In pAD and sAD, MTHFR C677T (TT, 25.9% vs. 22.2%) and A1298C (AA, 48.1% vs. 52.8%) polymorphism distributions as well as homocysteine levels (18.2�12.5 vs. 18.0� 7.5) were comparable.
Finally, no significant differences in comorbidities were present. We did not include patients with cerebrovascular accidents during the 1-year follow- up.
In agreement with the observation by Regan et al these results show that vascular risk factors may play a different role in modulating disease onset or affecting progression. Further studies are needed on larger samples to establish genotype-phenotype effect of the different vascular risk factors on AD course.
References
1. Regan C, Katona C, Walker Z, Hooper J, Donovan J, Livingston G. Relationship of vascular risk to the progression of Alzheimer disease. Neurology 2006;67:1357-1362.
2. McKhann G, Drachman D, Folstein M, et al. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 1984;34:939-944.
3. Borroni B, Grassi M, Costanzi C, et al. APOE genotype and cholesterol levels in Lewy Body Dementia and Alzheimer Disease: investigating genotype-phenotype effect on disease risk. Am J Ger Psychiatry (in press).
4. Wakutani Y, Kowa H, Kusumi M, et al. A haplotype of the methylenetetrahydrofolate reductase gene is protective against late-onset Alzheimer's disease. Neurobiol Aging 2004;25:291-294.
Disclosure: The authors report no conflicts of interest.

Reply from the authors 12 December 2006

Ciaran E Regan,
University College London
Dept of Mental Health Sciences, Holborn Union Building, Archway Campus, London, N19 5NL, UK,
Cornelius Katona, Zuzana Walker, and G. Livingston.
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Re: Reply from the authors

rejucr0{at}ucl.ac.uk Ciaran E Regan, et al.

We thank Borroni et al for their interest and comments on our paper. [1] We also read their findings that genotypes, which certainly in the case of apolipoprotein E (APOE), appear to have a significant effect on disease development [5] and do not emerge as contributors to the course of the illness. This has been investigated before and certainly evidence does show the complex relationship between APOE and cognitive decline. [6]
It appears similar to our findings that vascular risk factors do not contribute to disease advancement in AD. [1] Vascular risk factors appear to augment the risk for the initiation of the disease, incontrovertibly amplifying it. [7] This process could be secondary to the change in climate within the brain so as to allow the development of AD.
With the growing body of evidence that this is not due to atherosclerotic disease [8], these changes increasingly appear to be caused by an inflammatory response or oxidative stress, triggering the production of �amyloid. External factors such as dietary supplements are now being examined and found to be beneficial. [9].
In the particular case of the Mediterranean diet, lack of deterioration was not associated with improved vascular markers [10]: there was a conferred benefit independent of the vascular protection of the diet which may have been due to the antioxidant effect of the foods involved. Further research aimed at changing the internal environment of the brain to reduce the risk of AD is urgently needed.
References
5. Blair CK, Folsom AR, Knopman DS, et al. Apolipoprotein E genotype and cognitive decline in a middle-aged cohort. Neurology 2005;64:268�276.
6. Martins CAR, Oulhaj A, de Jager CA, Williams JH. APOE alleles predict the rate of cognitive decline in Alzheimer disease. Neurology 2005;65:1888-1893.
7. Dik MG, Deeg DJH, Bouter LM, Corder EH, Kok A, Jonker C.Stroke and Apolipoprotein E {epsilon}4 Are Independent Risk Factors for Cognitive Decline : A Population-Based Study. Stroke 2000;31:2431-2436.
8. Slooter AJ, Cruts M, Ott A, et al. The effect of APOE on dementia is not through atherosclerosis: the Rotterdam Study. Neurology 2000;54:2356�2358.
9. Schaefer EJ, Bongard V, Beiser AS, et al. Plasma Phosphatidylcholine Docosahexaenoic acid content and risk of dementia and Alzheimer disease. Arch Neurol 2006;63:1545-1550.
10. Scarmeas N, Stern Y, Mayeux, Luchsinger JA. Mediterranean diet, Alzheimer disease, and vascular mediation. Arch Neurol. 2006;63(doi:10.1001/archneur.63.12.noc60109).
Disclosure: The authors report no conflicts of interest.