Rethinking dementias.

pathophysiology, while in the elderly population with dementia an important role is played by comorbidities that can interfere with, and significantly modify, the clinical picture. From an epidemiological point of view, dementias and cognitive disorders are a social and healthcare emergency; indeed, the coming decades are expected to bring an exponential increase in the number of new cases, and, as reported in the last two World Alzheimer Reports (2015 and 2016), national policies will need to be able to cope with this. Over the past 15 years our knowledge about dementias, and particularly Alzheimer’s disease (AD), which is by far the most common dementia in late life, has increased considerably. In 2008, Hachinski suggested a new way of thinking about dementia, moving away from the concept of thresholds to that of a continuum of cognitive impairment, and with the focus shifting from the late to the early stages of the disease. Accordingly, novel research criteria and a new lexicon were proposed (Dubois et al., 2007, 2010, 2014); in 2011, McKhann’s diagnostic criteria, first published in 1984, were revised for application in daily clinical practice. Now, some years on, we feel that there is a need to review this area once again; critical interpretation of recent literature seems to confirm this, and indicates a changing mindset towards dementia. This year’s World Alzheimer's Day (September 21, 2017) prompted us to elaborate some considerations in order to tackle the misinformation that surrounds a global problem requiring global action — a problem with numerous aspects upon which to reflect. First of all, the field of epidemiology has given us interesting, but also complex and even controversial, data. The expected increase in new cases of dementia in the near future will mainly involve lowand middle-income countries; by contrast, data from high-income countries seem to point to a decrease in dementia incidence over the past three decades, even though these observations require further confirmation (Schrijvers et al., 2012; Satizabal et al., 2016; Scheltens et al., 2016). These are data that should probably be interpreted in the light of the better control of cardiovascular and metabolic risk factors and, more generally, the adoption of healthier life-styles in high-income settings, which suggests that there exists a considerable potential margin of action for tackling the expected rise in dementia, and that public health interventions are needed (de Bruijn et al., 2015). The scenario is rendered even more complex by the fact that global development of dementia is determined not by one element alone, but by a number of concurrent factors. Moreover, since the different indicators of a phenomenon do not necessarily all move in the same direction, predictions can be difficult to make. One of the main objectives of successful dementia risk reduction could be that of delaying dementia onset to older age. This phenomenon, described by Langa et al. as “the compression of cognitive morbidity” (2008), is a desirable outcome from both the public health perspective and for individual quality of life, as it means dementia onset occurring closer to the ‘natural’ end of life. From a more strictly clinical point of view, growing attention is being paid to the distinction between earlyversus lateonset AD; in the past, both conditions were indeed included in the diagnosis of AD, as they were considered to be characterized by the same neuropathology. On the contrary, it is now reported that early-onset AD has well-defined clinical and neuroimaging characteristics, different risk factors and comorbidities, as well as a higher psycho-social impact (Mendez, 2017). This condition is particularly devastating because onset of the disease in middle age leads to the loss of many years of potentially productive life (Moschetti et al., 2015); therefore, its management also requires a different approach. With regard to the therapeutic management of AD, at present only symptomatic treatments with modest clinical effects are available. The focus of pharmacological research has therefore shifted from symptomatic drugs towards compounds with a disease-modifying effect, i.e. treatments able to interact with the pathological process underlying the disease. Consequently, alongside the concept of “timely” diagnosis, the new concept of “early” or even “preclinical” diagnosis has been developed, as it is widely known that the pathognomonic lesions of AD can be present many years before the onset of the clinical manifestations. Currently, the main target of treatments is amyloid, even though an increasing role for tau pathology is now being considered. The results of the most recent studies, however, have been negative, and although research is ongoing and new drugs are under development, these data have led us to question the correctness of our current pharmacological approach. Undoubtedly, the main difficulty is to identify when treatments should be administered, and at what dosage, but as suggested by Husain (2017), other aspects must also be considered: the brain’s anatomical and functional complexity, the inter-individual variability of AD clinical features, and the possibility that a drug may act on some specific functions rather than on others. Moreover, we can argue that patient evaluation using the current neuropsychological instruments may not be sensitive enough to capture even small cognitive changes, especially in the early stages. In short, outcomes need to be redefined and controlled pharmacological trials improved (Cummings et al., 2016).