Alzheimer’s disease could be a blessing in disguise

To the Editor

It is accepted that Aβ plays a key role in Alzheimer’s disease (AD), the most common neurodegenerative subtype in the elderly. Aβ plaques can be found in normal individuals as well as in individuals who have a predominant non-AD neurodegenerative process in vivo. While soluble Aβ oligomers (sABO) and their accumulation into extracellular Aβ plaques is not specific to AD, having dense (not sparse) Aβ plaque deposits results in AD dementia.

The amyloid cascade hypothesis is the most developed hypothesis of the neuropathological cause of AD dementia (Hardy and Higgins, 1992). It asserts that a characteristic pathway involving the slow accumulation of sABO into dense deposits of Aβ plaques is the key antecedent event which leads to the formation of neurofibrillary tangles, typically in AD signature cerebral regions. This triggers other neuropathological processes, eventually resulting in neuronal death and the development of cognitive symptoms seen in AD. This hypothesis is supported by the fact that no other neuropathologies seen in AD have been demonstrated to trigger Aβ plaque accumulation. Also, this characteristic pathway is consistent across any cohort of individuals whether they have early onset AD (i.e. before 65 years of age, so other neuropathologies have not yet accumulated), or whether they have late onset AD (so other neuropathologies had a lifetime to accumulate, to some extent). In general, Aβ plaque accumulation plateaus when one with mild cognitive impairment due to AD progresses to AD dementia.

Insoluble Aβ deposits are relatively inert however, unlike sABO which are more neurotoxic (Espraza et al., 2018). Also, removal of Aβ plaques has not been shown to enable individuals supposedly destined to develop AD dementia to revert back to a normal cognitive ageing trajectory. Further-more, development of typical AD dementia symptoms does not always accurately predict having dense deposits in vivo. These points motivate the proposal of other hypotheses of the causes of AD. Interestingly, one point not considered by all hypotheses is that AD sufferers generally follow a less malignant clinical course compared to those with non-AD neurogenerative subtypes (Robertson et al., 2005). Incorporating this point into the bigger picture, perhaps the accumulation of Aβ plaques is simply a natural means to buffer the neurotoxic effects of cerebral β-amyloidosis, until its accumulation plateaus (Espraza et al., 2018).

Accumulation of Aβ plaques may be the cause of AD. Yet, accumulation of Aβ plaques could also be a natural means to buffer the neurotoxic effects of cerebral β-amyloidosis. So has AD actually been a blessing in disguise all along (Figure 1)?

Figure 1.

The Ong–Woodward hypothesis.