10 Chapter 1 INTRODUCTION Dementia and Alzheimer’s disease Dementia represents a worldwide public health problem, with more than 55 million people living with dementia (World Health Organization, March 2023; Dementia (who.int)). This number is expected to increase up to 131 million people living with dementia by 2050 [1]. The most common cause of dementia (~70% of all cases) is Alzheimer’s disease (AD). The development of symptoms in AD takes decades and can be characterized by several stages describing progression of impairment [Figure 1]. The preclinical AD stage refers to presence of AD pathology in the absence of objectively measurable impairment. This stage also includes subjective cognitive decline (SCD), which refers to the subjective experience of cognitive decline, without objective impairment on cognitive assessment. Compared to cognitively normal individuals who do not experience complaints, individuals with SCD have an increased risk of subsequent objective cognitive decline, especially in a memory clinic setting [2-4]. As such, SCD can be a possible first expression of AD, albeit SCD can have many causes and most individuals with SCD do not harbour AD pathology. The next stage, in which cognitive decline is formally objectified (by e.g. neuropsychological assessment), is called mild cognitive impairment (MCI) due to AD [5]. In individuals with MCI due to AD, there is impairment, but cognitive decline does not yet interfere substantially with everyday activities. The stage in which the presence of progressive loss of cognition in multiple cognitive domains co-occurs with interference in daily functioning (eg, social, occupational, self-care) is called AD dementia. Depending on the degree of interference with daily life activities, the AD dementia stage can be subdivided into mild, moderate, and severe AD dementia [Figure 1]. While AD dementia most often affects individuals of older age, a minority of individuals develop symptoms at a younger age (usually defined as below the age of 65), referred to as early onset AD (EOAD). From a clinical perspective, AD dementia is typically characterized by amnestic symptoms (memory impairment), with often co-occurrence of non-amnestic symptoms (e.g. language or executive functioning impairment or behavioral changes), especially in later stages of the disease. When non-amnestic symptoms characterize the clinical phenotype early in the disease, it can be referred to as an atypical variant AD [6]. Atypical variants of AD affect young people (EOAD) disproportionally often. The presence of non-amnestic symptoms leads to diagnostic challenges, as they can closely resemble symptoms related to other causes of dementia. For an accurate diagnosis, prognosis and health care management plan it therefore is essential to gain insight into the underlying pathophysiology of the disease.
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