New therapeutic targets for Alzheimer’s disease

Epigenetics and neuroinflammation are two of the multiple processes contributing to neurodegeneration in Alzheimer’s disease. The molecules involved in these processes are therefore potential therapeutic targets for alleviating the symptoms, comorbidities, and progression of Alzheimer’s disease, explained experts at ADPD2022.

The therapeutic armamentarium for managing the diverse array of symptoms and comorbidities experienced by patients with Alzheimer’s disease (AD) contains many gaps, said Professor Marwan Sabbagh, Phoenix, AZ. These gaps not only impact patients but also their families and caregivers.

75 drugs are being investigated to treat specific aspects or stages of AD

As a result, 75 drugs are in phase 1, 2, and 3 trials to treat specific aspects or stages of AD, added Professor Sabbagh.

Furthermore, promising new therapeutic targets are being revealed by ongoing research into epigenetic and neuroinflammatory processes in the pathophysiology of AD.


Targeting epigenetic molecules

Histone deacetylation makes DNA inaccessible for activation

Professor Pedro Rosa-Neto, Montreal, Canada, highlighted the importance of the downstream effects of amyloid beta (Aβ) and tau as potential therapeutic targets in AD.

These downstream effects include epigenetic modifications in which gene expression is modulated by for example developmental, environmental, aging, and dietary effects without changing the genetic sequence,1 explained Professor Rosa-Neto.

The two basic epigenetic mechanisms are:

  • DNA methylation to activate or repress gene expression
  • Histone modification — either histone acetylation (HATs), which causes DNA to unwind and become active; or histone deacetylation (HDACs), which makes DNA inaccessible for activation1

A decrease in HDAC1 in AD-related areas of the brain with high Aβ and tau loads is an epigenetic signature of AD

Professor Rosa-Neto and his colleagues have found decreased HDAC1 in mild cognitive impairment and AD in AD-related areas,2 with:

  • A negative association between HDAC1 availability and Aβ and tau loads in the brain
  • A positive association between HDAC1 availability and cognitive decline

They also found that HDAC1 availability predicts 2-year hippocampal atrophy and cognitive decline.2

A conceptual model for AD therefore emerges in which HDAC1 mediates the effects of Aβ and tau on cognition,2 said Professor Rosa-Neto. This is in contrast to the National Institute on Aging and Alzheimer’s Association (NIA-AA) sequential model in which the downstream effects of toxic Aβ and tau aggregates drive the neurodegeneration.3

HDAC1 is a potential therapeutic target for AD

Professor Pedro Rosa-Neto concluded that the decrease in HDAC1 in AD-related areas of the brain with high Aβ and tau loads is an epigenetic signature of AD and a potential therapeutic target for AD. So, interventions targeting epigenetics might mitigate neurodegeneration.


Targeting neuroinflammatory molecules

Microglia — the brain’s resident innate immune cells — are the brains’ first line of defence against infection, said Professor Michael Henneka, University of Luxembourg, Luxembourg, and are evolutionarily primed to respond to amyloid on the surface of some bacteria.4

Microglial activation by Aβ can lead to chronic neuroinflammation and neuronal degeneration

As a result, Aβ deposits in AD also activate microglia and this can lead to chronic microglial activation,5 and in turn chronic neuroinflammation and neuronal degeneration.6

Neuroinflammation is therefore being targeted in a number of completed and ongoing AD clinical trials, while ongoing research promises to reveal new potential therapeutic targets, concluded Professor Henneka.

This industry symposium was funded by Novo Nordisk.

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.

  1. Lindgren A. Stroke genetics: a review and update. J Stroke 2014;16:114–23.
  2. Rosa-Neto P, et al. Nature Comm 2022. In press.
  3. Jack R, et al. NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease. Alzheimers Dement 2018;14(4):535–62.
  4. Chapman MR, et al. Role of Escherichia coli curli operons in directing amyloid fiber formation. Science 2002;295(5556):851–55.
  5. Heneka MT, et al. Innate immunity in Alzheimer's disease. Nat Immunol 2015;16:229–36.
  6. Heneka MT, et al. Neuroinflammation in Alzheimer's disease. Lancet Neurol 2015; 14:388–405.
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