ANEXO TABLAS

In 1991, Braak and Braak mapped the distribution and spread of both amyloid-β and

hyper-phosphorylated tau in the brain during the progression of AD [27]. For amyloid-β Braak

determined that deposits are mainly found in the isocortex of the cerebral cortex of the brain. That

the amyloid-β plaques are not uniform in shape or size and early stage accumulation is inconsistent,

suffering from inter-individual variation. Amyloid-β deposition also develops before the onset of tau,

however, the presence of amyloid-β does not necessarily mean tau pathology will develop [27]. Braak

and Braak developed a three-stage progression of amyloid-β in AD. During stage A, amyloid-β is found

in the base layer of the frontal, temporal and occipital lobes. In stage B, amyloid-β progresses to almost

all isocortex areas and in stage C, amyloid-β is densely packed in the isocortex [27]. Figure 2: Microtubule destabilisation due to

10 Other researchers developed pathological scales for amyloid-β including: the 5 phases by Thal et al

[41] in 2002 using post-mortem brain tissue and 4 phases by Grothe et al [42] in 2017 using

neuroimaging. The amyloid-β phases developed by Thal et al [41] are shown in Figure 3. showing initial

amyloid accumulation starts in the neocortex then spreads to other parts of the brain, a more

extensive distribution of amyloid when compared to the three Braak stages. Grothe et al supports the

Thal phases, especially phases 1-3, when they used neuroimaging to determine the spread of

amyloid-β. They conclude that the amyloid-β deposition follows a predictable pattern, however their

research does not indicate whether the participants in the study will inevitably progress through the

stages or the time in which this progression would occur [42].

Figure 3: Schematic diagram showing the staging of amyloid-β deposition developed by Thal et al.

The Braak stages (Figure 4) correspond to the distribution and spread of tau through the brain during

AD progression. Braak stages I and II are centred on the transentorhenial region, with stage II being

more densely packed than stage I with tau pathology. When progressing to stage III, pathology moves

into the entorhinal region with low levels of tau seen in CA1 of the hippocampus and mild or negligible

changes present in the isocortex [27]. Due to the hippocampus being responsible for episodic memory,

damage here leads to a loss of memory connected to autobiographical events [43] and corresponds

with early symptoms seen in AD. At stage IV there is increased pathology in the entorhenial region

11 for neuropathologic diagnosis of AD. At stage V, tau is found in almost all areas of the hippocampus

and the isocortex, with all areas mentioned severely affected by stage VI. Involvement of the isocortex

corresponds to late AD and clinical diagnosis [27]. It is estimated that it can take 48 years to develop

from Braak stage I to Braak stage V in which AD symptoms are apparent [9]. A large proportion of that

time is when the disease is non-symptomatic because it can take 30 years to progress from stage I to

stage III [9]. There are limitations to staging disease progression, for example it is difficult to get a

representative sample of the population which includes all socio-economic groups and races, and in

the assumption that all patients with AD will follow one pattern of pathology, so don’t allow for

patients that may follow another distinct pattern, or for patients with mixed dementia pathology [44].

12

2.2.1.1 Amyloid and Tau in Normal Aging

Evidence suggests that 30% to 50% of people between 57 and 102 who are non-symptomatic at

autopsy show AD pathology in the brain [45, 46]. The AD pathology could be due to normal aging [47,

48] or the patients have pre-clinical AD [46, 49, 50]. Large studies conducted on the presence of AD

pathology found that Braak stage correlates with dementia progression and those who are cognitively

normal with severe dementia accounted for between 8% -12% of participants [51-53]. It has been

suggested that these individuals with AD pathology and no cognitive symptoms have a cognitive

reserve. This reserve allows them to withstand the effects of AD pathology [54, 55]. However, it has

also been found that an individual with AD pathology at autopsy can be classed as clinically normal

during testing, but they do show significant differences in some aspects of cognition when compared

to individuals with no AD pathology [55, 56]. This could support the hypothesis that the AD pathology

in non-demented patients is due to normal aging. Another aspect that could support this is that

20%-30% of cognitively normal adults have amyloid-β deposition in the brain [57-59] and abnormal

amyloid-β can be found without the presence of tau pathology [60]. However, contradictory to this,

Tsartsalis et al has shown that low levels of tau can be present without amyloid-β deposition [61].