Assessing Astrocytes in Alzheimer's Disease

Abstract

Alzheimer's DiseaseDemen�a is among the top five causes of death worldwide. Alzheimer's disease (AD) is the number one cause of demen�a, accoun�ng for 60-70% of all cases. Worldwide each year almost 10 million people develop AD, which leads to a large socio-economic burden World Health Organiza�on, 2021). The main neuropathological hallmarks of AD are the extracellular deposits of amyloid-β (Aβ) (i.e. the plaques), the intraneuronal accumula�on of hyperphosphorylated tau protein (i.e. the neurofibrillary tangles), and neuroinflamma�on (i.e. ac�vated microglia and reac�ve astrocytes) (Figure 1) . Clinically, AD is characterised by a con�nuous decline in various cogni�ve abili�es, of which especially memory loss is a well-known aspect (Querfurth & LaFerla, 2010).When discussing memory loss in AD, it is important to keep in mind that there are many different types of memory. In humans, we dis�nguish working memory, short-term memory, long-term memory, explicit memory such as episodic and seman�c memory, and implicit memory such as priming, skill learning, and condi�oning (Purves et al., 2013). Generally, in AD pa�ents, seman�c memory is the first type of memory that is impaired, leading to difficul�es with fluency in speech and naming persons and objects. At this stage, disease pathology in the brain is mainly observed in the entorhinal cortex (Kazim & Iqbal, 2016). Other early signs of AD are problems with visual orienta�on and episodic memory. With disease progression, as disease pathology spreads to the hippocampus, and medial temporal lobe, pa�ents are increasingly sensi�ve to distrac�on. Their working memory decays, which leads to problems with following verbal instruc�ons, mental arithme�c, and remembering direc�ons. In later stages of AD, when disease pathology has spread further throughout the neocor�cal areas, impairments in planning, problem-solving, cogni�ve flexibility and goal-directed behaviour are o�en observed (Jahn, 2013). The last brain areas to be affected are the cerebellum, striatum, thalamus, and hypothalamus (Braak & Braak, 1991;. At this final stage, a pa�ent with AD can lose the ability to produce recognizable speech, can have trouble walking, and normal body func�ons start to hamper un�l finally succumbing to death.The biggest risk factor for AD is ageing, and the majority of people with AD are 65 years or older (h�ps://www.alz.org/alzheimers-demen�a/facts-figures, visited 23-04-2022). Only 4-6% of all cases of AD start before the age of 65 years, and are called earlyonset AD. Besides ageing there are several other non-gene�c risk factors: head injury, hypertension, depression, diabetes, and smoking, all increase the risk of developing AD (Hersi et al., 2017;Silva et al., 2019). Gene�cs also play an important role in the likelihood of developing AD, and studies have shown that the heritability for AD is between 60 and 80% (Gatz et al., 2006). Amyloid precursor protein (APP) and Presenilin (PSEN) are proteins involved in the forma�on of amyloid-beta (Aβ) plaques and will be discussed in mor...