Background and aims: Recently, the Italian Ministry of Health started a national project (CRONOS project), aiming at assessing how a multi-level therapeutic approach - including 2-year free-of-charge treatment with cholinesterase inhibitors (ChE-I), pharmacologic and non-pharmacologic management of behavioral disorders, periodic multi-dimensional assessment, and informal caregivers' counseling - performs in subjects with mild-to-moderate Alzheimer's disease (AD). Five hundred and three Alzheimer Evaluation Units (AEUs) were instituted for this purpose all over Italy. In this paper we present the results of this approach in a large population of AD subjects followed for 36 weeks by 14 AEUs in Eastern Lombardy, Italy. Methods: The project lasted for two years (September 2000-September 2002). Subjects eligible for the CRONOS project had a diagnosis of probable AD, a Mini Mental State Examination (MMSE) score at baseline ranging from 10 to 26, and onset of cognitive disorders between 40 and 90 years of age. Periodic clinical and multi-dimensional assessments, including MMSE, Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL) were made at 12 and 36 weeks; ChE-I doses, psychotropic and antidepressant drugs were also re-assessed at all clinical examinations. Caregivers were instructed about dementia and drug-related problems. Results: Of the 808 subjects who completed the 36-week follow-up, 441 were naives (i.e., never previously treated with ChE-I drugs) and 367 non-naives. At 12 weeks, both naives (mean variation from baseline= 0.8 points) and non-naives (mean variation from baseline= 0.5 points) improved their MMSE scores, while at 36 weeks only naives improved (mean variation from baseline= 0.1) and non-naives decreased (mean variation from baseline= -1.2). The IADL and ADL scores progressively and mildly declined from baseline to the 36(th) week (ADL, mean variation from baseline= -0.5 for naives, -0.3 for non-naives; IADL= -0.7 for naives, mean variation from baseline = -0.4). However, when the MMSE, ADL and IADL variations were controlled for age, sex and education, no significant time effect was found (MMSE, Wilks' lambda p=0.34; ADL, Wilks' lambda p=0.25; IADL, Wilks' lambda p=0.3, respectively). These patterns were apparently unrelated to ChE-I doses. Neuroleptic use doubled in naives and antidepressants increased in both groups. Conclusions: This multi-level therapeutic approach seems to slow down progression in cognitive and functional performance.. in both naive and non-naive subjects. The possibility of recurrent examinations by specialized physicians, accurate, close management of psychotropic drugs, and informal counseling to caregivers probably aid in achieving such results in a "real world" population of AD elderly subjects living at home. Future studies are needed to assess whether a multi-level therapeutic approach including higher ChE-I dose may perform better in these subjects.
