Alzheimer disease (AD) is an incurable, progressive neurodegenerative disorder with a long presymptomatic period that is clinically characterized by cognitive and behavioural impairment, social and occupational dysfunction and, ultimately, death. In the USA, AD was the sixth most common cause of death in 2015 and showed the largest age-adjusted increase (16%) relative to 2014 (ref. 1). According to current estimates, 17% of people aged 75-84 years in the USA have AD, and the disease costs the country US$236 billion per year. The prevalence is projected to triple by 2050 to >15 million, with annual costs of >$700 billion 2. Diagnosis of AD is usually based on medical history and clinical findings, sometimes corroborated by brain imaging. Therapies are symptomatic and do not affect disease progression; currently, cholinesterase inhibitors and the N-methyl-d-aspartate receptor antagonist memantine are the only available options. Despite extensive research into the pathophysiology of AD, the large number of drugs entering clinical development and the enormous expenditure on large and complex trials, no new drug has been approved since memantine in 2003. Many reasons have been proposed to explain this failure, including inappropriate patient selection, variable rates of progression, suboptimal dosing, drug exposure and/or target engagement, inappropriate time of intervention, inappropriate outcome measures and low sensitivity of clinical scales. In addition, an incomplete understanding of AD pathophysiology might have led to selection of the wrong targets. Most of the drugs tested for AD in the past 20 years have targeted the accumulation of the amyloid-β (Aβ) peptide. In this article, we consider the current anti-Aβ drugs and the possible reasons for their failure to provide meaningful clinical benefits. Anti-Aβ therapies have been extensively tested in sporadic late-onset forms of AD, which will be the main focus of our discussion; no therapeutic studies have yet been conducted in individuals with the less common familial forms. The amyloid cascade hypothesis The Aβ peptide is generated by metabolism of amyloid precursor protein (APP), a type I transmembrane glycoprotein of 695-770 amino acids. APP is cleaved close to the membrane by an extracellular protease known as α-secretase. This cleavage liberates a soluble extracellular fragment, sAPPα. APP is also cleaved by an aspartyl protease known as β-secretase 1 (BACE1),

Frailty, a critical intermediate status of the aging process that is at increased risk for negative health-related events, includes physical, cognitive, and psychosocial domains or phenotypes. Cognitive frailty is a condition recently defined by operationalized criteria describing coexisting physical frailty and mild cognitive impairment (MCI), with two proposed subtypes: potentially reversible cognitive frailty (physical frailty/MCI) and reversible cognitive frailty (physical frailty/pre-MCI subjective cognitive decline). In the present article, we reviewed the framework for the definition, different models, and the current epidemiology of cognitive frailty, also describing neurobiological mechanisms, and exploring the possible prevention of the cognitive frailty progression. Several studies suggested a relevant heterogeneity with prevalence estimates ranging 1.0–22.0% (10.7–22.0% in clinical-based settings and 1.0–4.4% in population-based settings). Cross-sectional and longitudinal population-based studies showed that different cognitive frailty models may be associated with increased risk of functional disability, worsened quality of life, hospitalization, mortality, incidence of dementia, vascular dementia, and neurocognitive disorders. The operationalization of clinical constructs based on cognitive impairment related to physical causes (physical frailty, motor function decline, or other physical factors) appears to be interesting for dementia secondary prevention given the increased risk for progression to dementia of these clinical entities. Multidomain interventions have the potential to be effective in preventing cognitive frailty. In the near future, we need to establish more reliable clinical and research criteria, using different operational definitions for frailty and cognitive impairment, and useful clinical, biological, and imaging markers to implement intervention programs targeted to improve frailty, so preventing also late-life cognitive disorders.

In the last decade, the association between diet and cognitive function or dementia has been largely investigated. In the present article, we systematically reviewed observational studies published in the last three years (2014-2016) on the relationship among dietary factors and late-life cognitive disorders at different levels of investigation (i.e., dietary patterns, foods and food-groups, and dietary micro- and macronutrients), and possible underlying mechanisms of the proposed associations. From the reviewed evidence, the National Institute on Aging-Alzheimer's Association guidelines for Alzheimer's disease (AD) and cognitive decline due to AD pathology introduced some evidence suggesting a direct relation between diet and changes in the brain structure and activity. There was also accumulating evidence that combinations of foods and nutrients into certain patterns may act synergistically to provide stronger health effects than those conferred by their individual dietary components. In particular, higher adherence to a Mediterranean-type diet was associated with decreased cognitive decline. Moreover, also other emerging healthy dietary patterns such as the Dietary Approach to Stop Hypertension (DASH) and the Mediterranean-DASH diet Intervention for Neurodegenerative Delay (MIND) diets were associated with slower rates of cognitive decline and significant reduction of AD rate. Furthermore, some foods or food groups traditionally considered harmful such as eggs and red meat have been partially rehabilitated, while there is still a negative correlation of cognitive functions with saturated fatty acids and a protective effect against cognitive decline of elevated fish consumption, high intake of monounsaturated fatty acids and polyunsaturated fatty acids (PUFA), particularly n-3 PUFA.

No abstract

View this article online at wileyonlinelibrary.com.