Towards a novel understanding of Alzheimer’s disease

The future of Alzheimer’s disease (AD) involves intervention at a much earlier stage than the onset of dementia, predicted the presenter of the 2019 Brain Prize Lecture at EAN 2019. He envisaged a tailored approach to AD in individual patients starting with genetic profiling at birth to determine AD risk, cognitive tests throughout life to detect early symptoms and signs of AD, and a multi-therapeutic approach following disease onset.

Genetic profiling, early intervention and a multi-therapeutic approach may combine to offer the best management strategy for AD in future

Genetic predisposition to AD

In the last 20 years, studies of rare familial AD have identified 3 causal genes. More than 20 mutations in amyloid precursor protein (APP), the precursor for amyloid β (Aβ), are found along with >200 mutations in the enzymes presenilin 1 or 2 (PSEN1/2). These mutations invariably affect Aβ peptide generation, which causes full blown AD with plaques, tangles and neurodegeneration.
PSEN belongs to the γ-secretase family that generates Aβ peptides of different lengths from APP, and destabilising PSEN mutations shift Aβ profiles toward longer peptides, which are at the core of AD pathogenesis.¹

What is the cause of sporadic AD?

Over two-thirds of the risk of sporadic AD is genetic with the remaining risk due to environmental factors.² There are >1000 genetic mutations associated with an increased risk for AD, and polygenic risk score analysis enables prediction of age-specific lifetime risk of AD.^3,4

Polygenic risk score analysis enables prediction of age-specific lifetime risk of AD

How and under which conditions genetic risk manifests as AD development is of research interest. Genome‐wide association studies point to the involvement of microglia. The genetic risk of AD is largely determined by the microglia response to Aβ.

The  microglia’s response:

• is enriched for AD risk genes,
• is abolished by apolipoprotein E deletion,
• develops faster in females,
• and is also part of normal aging.⁵

Thus, major AD risk factors converge on the microglia. Plaque induced genes act as a gene regulatory network over the microglia, astroglia and oligodendrocytes to coordinate the reaction towards Aβ.

The cellular phase of AD

Anti-amyloid drugs should offer an ideal targeted therapy. Why trials have failed so far to show benefit may be due in part to the timing of treatment. Early intervention is crucial as treating dementia may be too late in the disease process.

Early intervention in AD is crucial as treating dementia may be too late in the disease process

Evidence supports a long, complex cellular phase of AD consisting of feedback and feed-forward responses of astrocytes, microglia, and vasculature. The cellular phase identifies a time delay of around 30 years between the accumulation of Aβ plaques and brain changes that lead to the clinical phase.⁶ Thus, drugs that target the biochemical processes of disease must be employed at an earlier stage for success.

In conclusion, the presenter of the 2019 Brain Prize Lecture considered that research using multicellular models will show further insights into the cellular phase of AD and answer remaining questions such as: whether amyloid plaque is a trigger not the driver of disease, whether the response of the microglia determines if you get AD or if you are protected, whether neurodegeneration occurs downstream of inflammation, and where tau fits in this model.