Our results suggest that APOE and ACE genotypes may be independent risk factors for late-onset AD, but the ACE association needs to be confirmed in independent samples in which the time and extent of vascular cofactors can be assessed.

Alzheimer's disease, a fatal neurodegenerative disorder of unknown aetiology, is usually considered to be a single disorder because of the general uniformity of the disease phenotype. Two recent genetic linkage studies revealed co-segregation of familial Alzheimer disease with the D21S1/S11 and D21S16 loci on chromosome 21. But two other studies, one of predominantly multiplex kindreds with a late age-of-onset, the other of a cadre of kindreds with a unique Volga German ethnic origin, found absence of linkage at least to D21S1/S11. So far it has not been possible to discern whether these conflicting reports reflect aetiological heterogeneity, differences in methods of pedigree selection, effects of confounding variables in the analysis (for example, diagnostic errors, assortative matings), or true non-replication. To resolve this issue, we have now examined the inheritance of five polymorphic DNA markers from the proximal long arm of chromosome 21 in a large unselected series of pedigrees with familial Alzheimer's disease. Our data suggest that Alzheimer's disease is not a single entity, but rather results from genetic defects on chromosome 21 and from other genetic or nongenetic factors.

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Alzheimer's disease (AD) is the most common neurocognitive disorder and a global health problem. The prevalence of AD is growing dramatically, especially in low-and middle-income countries, and will reach 131.5 million cases worldwide by 2050. Therefore, developing a disease-modifying therapy capable of delaying or even preventing the onset and progression of AD has become a world priority, and is an unmet need. The pathogenesis of AD, considered as the result of an imbalance between resilience and risk factors, begins many years before the typical clinical picture develops and involves multiple pathophysiological mechanisms. Since the pathophysiology of AD is multifactorial, it is not surprising that all attempts done to modify the disease course with drugs directed towards a single therapeutic target have been unsuccessful. Thus, combined modality therapy, using multiple drugs with a single mechanism of action or multi-target drugs, appears as the most promising strategy for both effective AD therapy and prevention. Cerebrolysin, acting as a multitarget peptidergic drug with a neurotrophic mode of action, exerts long-lasting therapeutic effects on AD that could reflect its potential utility for disease modification. Clinical trials demonstrated that Cerebrolysin is safe and efficacious in the treatment of AD, and may enhance and prolong the efficacy of cholinergic drugs, particularly in moderate to advanced AD patients. In this review, we summarize advances of therapeutic relevance in the pathogenesis and the biomarkers of

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