8 Chapter 1 Alzheimer’s disease as cause of dementia Worldwide, more than 55 million people are affected by dementia (1). Dementia refers to a clinical syndrome characterized by the progressive deterioration of cognitive functions with interference in daily functioning (2). It can be caused by several different diseases, and Alzheimer’s disease (AD) is its most common cause (1). According to the amyloid cascade hypothesis, accumulation of the protein amyloid-beta is the primary event in the pathogenesis of AD (3). It is thought to initiate a series of events including the formation of neurofibrillary tangles, inflammation and synaptic dysfunction, which ultimately leads to neuronal injury, neurodegeneration and cognitive decline (4, 5). The progression of cognitive symptoms is gradual, and therefore several predementia stages can be identified. Dementia is preceded by the stage of mild cognitive impairment (MCI), in which there are deficits in one cognitive domain but no significant interference in daily living yet (6). Subjective cognitive decline (SCD) might be an even earlier manifestation of neurodegenerative disease than MCI, since it refers to the stage in which there are no objective cognitive disorders yet, while individuals experience a self-perceived decline in cognition (Figure 1). However, not all individuals with MCI or SCD suffer from a neurodegenerative disease, since there is a myriad of other causes for both syndromes, nor will all individuals with SCD progress to MCI and dementia. Research interest is shifting increasingly to these early stages, in which pathology is beginning to accumulate, while there are no cognitive deficits yet, because these stages potentially provide a window of opportunity to halt the progression of the disease. However, how to accurately identify SCD patients with a neurodegenerative disease who are at risk at risk of future cognitive decline remains largely unknown. Figure 1. Course of cognitive decline. SCD = subjective cognitive decline, MCI = mild cognitive impairment. Adapted from Jessen et al. (2014) (7).