LETTER TO THE EDITOR No country for old men: a polypill strategy to prevent dementia? F. Pistoia a,b , G. Desideri a , M. Sara` b and C. Ferri a a Department of Internal Medicine and Public Health, University of LÕAquila, LÕAquila, Italy; and b Istituto San Raffaele, Post-Coma Intensive and Rehabilitation Care Unit, Cassino, Italy Correspondence: Francesca Pistoia, Istituto San Raffaele, Via Gaetano di Biasio 1, 03043 Cassino (FR), Italy (tel.: +39 0776 394880; fax: +39 0776 394403; e-mail: pistoiafrancesca@ hotmail.com). Keywords: brain aging, CADASIL, vascular risk factors Received 15 October 2008 Accepted 20 October 2008 We would like to comment on the paper by Formichi et al. on the usefulness of cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoence- phalopathy (CADASIL) as a model of pure subcortical vascular dementia (SVD) [1]. Young CADASIL patients represent a suitable model to clarify the pathogenesis of subcortical vascular lesions as they present cerebrospinal proteins profiles similar to those detectable in subjects with sporadic SVD, without degenerative and age-related confounding factors. This is an interesting suggestion, espe- cially with respect to recent observations raising questions about the traditional distinction between Alzheimer disease (AD) and SVD, the boundaries of which are controversial [2]. Several evidence suggest a pathogenetic overlap between AD and SVD probably depending on shared vascular risk factors: signs of endothelial dysfunction may be recog- nized in the cerebral microvessels of AD patients, whereas neurofibrillary tangles may be detected in the brain of SVD patients [2]. In this respect, it is reasonable to assume that vascular processes in both AD and SVD may mutually induce each other. Moreover, vascular and degenera- tive changes may act in an additive way, thus contributing to the development of mixed dementias. In this regard, we have recently proposed a pathogenetic role in AD for circulating soluble CD40 ligand, a proatherogenic molecule deeply involved in vascular damage induced by different risk factors, including diabetes [3]. Shared vascular risk factors probably responsible for the reported pathogenetic overlap include hypertension, diabetes, metabolic syndrome, hypercholesterol- emia and insulin resistance. All the above factors contribute to cognitive deteriora- tion through either degenerative or vas- cular mechanisms or both, in all cases by promoting oxidative stress and therefore altering lipid or glucose metabolisms. In this respect, the interest about the patho- genetic overlap has obvious practical rea- sons as cardiovascular drugs might help to prevent or, at least, delay, the develop- ment of a cognitive impairment regardless of its nature: for this aim statins, antihy- pertensive, antioxidant and antiaggregant agents have been recently recognized as useful preventive tools, although the specific mechanism by which these drugs exert their protective effect is not clear [4–6]. In conclusion, the pathogenetic overlap between dementias, along a broad spec- trum ranging from purely vascular to mixed to purely degenerative, require further attention with a view to recognize commonalities in risk factors. As patients with CADASIL show vascular lesions that are independent from an age and AD- related pathology, they may help to better understand the causal mechanisms linking vascular risk factors to overall dementia and to plan concerted preventive strate- gies. This might allow us to control all risk factors that, if unknown or untreated, may favor an accelerated brain aging. A multitargeted interventional strategy with a view to control vascular risk factors that are amenable to interventions might war- rant a successful aging in middle-aged people. References 1. Formichi P, Parnetti L, Radi E, Cevenini G, Dotti MT, Federico A. CSF levels of beta- amyloid 1-42, tau and phosphorylated tau protein in CADASIL. European Journal of Neurology 2008; 15: 1252–1255. 2. Kalaria RN, Ballard C. Overlap between pathology of Alzheimer disease and vascular dementia. Alzheimer Disease and Associated Disorders 1999; 13: S115–S123. 3. Desideri G, Cipollone F, Necozione S, et al. Enhanced soluble CD40 ligand and AlzheimerÕs disease: evidence of a possible pathogenetic role. Neurobiology of Aging 2008; 29: 348–356. 4. Forette F, Seux ML, Staessen JA, et al. Prevention of dementia in randomised dou- ble-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial. Lancet 1998; 352: 1347–1351. 5. Dufouil C, Richard F, Fie´vet N, et al. APOE genotype, cholesterol level, lipid- lowering treatment, and dementia: the Three-City Study. Neurology 2005; 64: 1531–1538. 6. Luchsinger JA, Tang MX, Miller J, Green R, Mayeux R. Relation of higher folate in- take to lower risk of Alzheimer disease in the elderly. Archives of Neurology 2007; 64: 86– 92. Ó 2008 The Author(s) Journal compilation Ó 2008 EFNS e11 European Journal of Neurology 2009, 16: e11 doi:10.1111/j.1468-1331.2008.02393.x