Why does the cellular response to amyloid determine whether an individual develops Alzheimer’s disease?

What happens in the three decades between amyloid-beta (Aβ) deposition in the brain and the development of full-blown Alzheimer’s disease (AD)? At a fascinating plenary at AAIC 2019, evidence was presented to suggest that the response of the brain’s immune defence cells — the microglia — to the Aβ deposits determines whether an individual with Aβ deposits will or will not develop AD.

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

Our correspondent’s highlights from the symposium are meant as a fair representation of the scientific content presented. The views and opinions expressed on this page do not necessarily reflect those of Lundbeck.

References
  1. De Strooper B and Karran E. Cell 2016;164:603–15.
  2. Gatz M, et al. Arch Gen Psychiatry 2006;63:168-74.
  3. Escott-Price V, et al. Ann Neurol 2017;82: 311–14.
  4. Frigerio C, et al. Cell Reports 2019:27:1293–1306.
Country selection
We are registering that you are located in Brazil - if that's correct then please continue to Progress in Mind Brazil
You are leaving Progress in Mind
Hello
Please confirm your email
We have just sent you an email, with a confirmation link.
Before you can gain full access - you need to confirm your email.
The information on this site is exclusively intented for health care professionals.
All the information included in the Website is related to products of the local market and, therefore, directed to health professionals legally authorized to prescribe or dispense medications with professional practice. The technical information of the drugs is provided merely informative, being the responsibility of the professionals authorized to prescribe drugs and decide, in each concrete case, the most appropriate treatment to the needs of the patient.
Congress
Register for access to Progress in Mind in your country