A necessary shift of focus to the earlier stages of Alzheimer’s

Prof. Bart de Strooper (Katholieke Universiteit Leuven, Belgium) delivered an inspiring plenary lecture on the prodromal, cellular phase of Alzheimer’s disease (AD) [1]. He noted that the success rate of AD trials is not exceptionally low, but that we must continue to invest heavily in innovative research. Attention should be shifted towards the prodromal phase of AD, in which the window of opportunity for treatments to succeed will be much larger than in the final, symptomatic stages of AD.

“Most interventions are deployed in the advanced, clinical phase, when it is very hard to alter the course of the disease. “It is like treating cancer only in the late stages, when it has already metastasised”, Prof. De Strooper said. “We have to further increase our understanding of the cellular processes leading up to AD, which have generally started some 30 years earlier, before the formation of plaques.”

According to Prof. De Strooper, the best entrance for understanding AD is genetics. There are 3 causal genes: amyloid precursor protein (APP) and presenilin 1 and 2 (PSEN1 and PSEN2). “Destabilisation of PSEN and release of longer amyloid-beta peptides is at the core of the pathological mechanism.” He pointed out the main reasons why trials targeting these pathways have failed so far: flaws in the trials' design; intervening at a late stage of the disease; and the brain being too diffuse a target. An example is the failed trial of the small-molecule gamma-secretase inhibitor semagacestat [2]. “The idea was not wrong”, Prof. De Strooper said, “but in an attempt to minimise side-effects, the dose may well have been sub-therapeutic”.

He also argued that understanding how risk genes drive dementia is of paramount importance in developing new drug targets. Twins studies have shown that two thirds of the risk for sporadic disease is genetic. So far, over 1,000 loci have been identified that may predict an elevated risk of developing AD. Prof. De Strooper foresees a future in which individual polygenic risk score analysis may identify persons at high risk [3], thus enabling early and effective interventions.

1. De Strooper B, et al. EAN 2019, PLEN02_1.
2. Doody RS, et al. N Engl J Med 2013;369:341-50.
3. Escott-Price V, et al. Neurobiol Aging. 2017;49:214.e7-214.e11.

Posted on 27 August 201917 March 2021