Early intervention is crucial, but anti-Aβ drugs do not work
The cellular response to Aβ deposition
Aβ and tau are the early biochemical phases of AD, the presenter explained, and are followed by a cellular phase over many decades before the clinical phases of AD become evident.1 This cellular phase determines whether an individual will or will not develop AD.
To understand AD, it is therefore necessary to integrate Aβ and tau biochemistry into the complex cellular context of the brain.
The genetic basis of AD
Three genes are responsible for familial AD, the presenter explained. And the resulting enzyme and substrate mutations invariably affect Aβ generation and lead to AD with plaques, tangles, and neurodegeneration.
Genes also play a role in sporadic AD. A Swedish registry investigation of nearly 12,000 twin pairs aged over 65 years estimated heritability for AD to be 58% and found that the same genetic factors are influential for both men and women. However, nongenetic risk factors are also important.2
Over 1000 genetic loci have been associated with sporadic AD, and a polygenic risk score analysis for the prediction of AD shows a predictive area under the curve of 84%.3
What links the genetics and cellular response?
APOE regulates plaque formation and microglia reactivity to plaques
Most of the sporadic AD genes associated with loci identified by genome-wide association analysis or by rare variant sequencing studies are expressed in glial cells, for example:
- APOE (apolipoprotein E), which is the major genetic risk factor for AD
- TREM2 (triggering receptors expressed on myeloid cells)
The expression of genetic risk genes in sporadic AD changes when exposed to Aβ plaques. Activated microglia accelerate progressive Aβ accumulation and upregulate APOE, which in turn regulates plaque formation and the activated microglia. Lack of APOE impairs the microglial response to plaques.4
What does the future look like for AD?
Genetic risk of AD is largely determined by the microglia response
Knowledge about AD is rapidly increasing, but despite its huge health and societal impact, AD research lags way behind that carried out for other major diseases such as human immunodeficiency virus infection and cancer.
The presenter highlighted that over the past 20 years over 7000 cancer clinical trials have been carried out, resulting in the approval of 180 new drugs (a 2.7% success rate), compared with just 234 AD clinical trials, resulting in the approval of four new drugs (a 1.7% success rate).
New technologies and multicellular models, however, promise to reveal a much clearer understanding of the cellular and molecular response to Aβ in the future. For example, further investigations of plaque-induced genes (PIGS) expression will:
- clarify the role of this gene regulatory network for microglia, astroglia, and oligodendrocytes in the microglial response to Aβ plaques
- might provide clues for further targets for preventing or delaying the development of AD