Alzheimer's disease (AD) is a progressive neurodegenerative disease and in its familial form is associated with mutations in the amyloid precursor protein (APP) and the presenilins (PSs). Much data regarding the interactions of APP, its proteolytic fragments and PS have been generated, expanding our understanding of the roles of these proteins in mechanisms underlying cognitive function and revealing many complex relationships with wide ranging cellular systems. In this review, we examine the multiple interactions of APP and its proteolytic fragments with other neuronal systems in terms of feedback loops and use these relationships to build a map. We highlight the complexity involved in the APP proteolytic system and discuss alternative perspectives on the roles of APP and its proteolytic fragments in dynamic processes associated with disease progression in AD. We highlight areas where data are missing and suggest potential confounding factors. We suggest that a systems biology approach enhances representations of the data and may be more useful in modelling both normal cognition and disease processes.

Introduction

Behavioural and psychological symptoms of dementia (BPS) include depressive symptoms, anxiety, apathy, sleep problems, irritability, psychosis, wandering, elation and agitation, and are common in the non-demented and demented population.

Methods

We have undertaken a systematic review of reviews to give a broad overview of the prevalence, course, biological and psychosocial associations, care and outcomes of BPS in the older or demented population, and highlight limitations and gaps in existing research. Embase and Medline were searched for systematic reviews using search terms for BPS, dementia and ageing.

Results

Thirty-six reviews were identified. Most investigated the prevalence or course of symptoms, while few reviewed the effects of BPS on outcomes and care. BPS were found to occur in non-demented, cognitively impaired and demented people, but reported estimates vary widely. Biological factors associated with BPS in dementia include genetic factors, homocysteine levels and vascular changes. Psychosocial factors increase risk of BPS; however, across studies and between symptoms findings are inconsistent. BPS have been associated with burden of care, caregiver's general health and caregiver depression scores, but findings are limited regarding institutionalisation, quality of life and disease outcome.

Conclusions

Limitations of reviews include a lack of high quality reviews, particularly of BPS other than depression. Limitations of original studies include heterogeneity in study design particularly related to measurement of BPS, level of cognitive impairment, population characteristics and participant recruitment. It is our recommendation that more high quality reviews, including all BPS, and longitudinal studies with larger sample sizes that use frequently cited instruments to measure BPS are undertaken. A better understanding of the risk factors and course of BPS will inform prevention, treatment and management and possibly improve quality of life for the patients and their carers.

Identifying the causes of dementia is important in the search for effective preventative and treatment strategies. The concept of mild cognitive impairment (MCI), as prodromal dementia, has been useful but remains controversial since in population-based studies it appears to be a limited predictor of progression to dementia. Recognising the relative contribution of neurodegenerative and vascular causes, as well as their interrelationship, may enhance predictive accuracy. The concept of vascular cognitive impairment (VCI) has been introduced to describe the spectrum of cognitive change related to vascular causes from early cognitive decline to dementia. A recent review of this concept highlighted the need for diagnostic criteria that encompass the full range of the VCI construct. However, very little is known regarding the mildest stage of VCI, generally termed 'vascular cognitive impairment, no dementia' (VCIND). Whether mild cognitive change in the context of neurodegenerative pathologies is distinct from that in the context of cerebrovascular diseases is not known. This is key to the definition of VCIND and whether it is possible to identify this state. Distinguishing between vascular (that is, VCIND) and non-vascular (that is, MCI) cognitive disorders and determining how well each might predict dementia may not be possible due to the overlap in pathologies observed in the older population. Here, we review the concept of VCIND in an effort to identify recent developments and areas of controversy in nosology and the application of VCIND for screening individuals at increased risk of dementia secondary to vascular disease and its risk factors.