Understanding the cause of sporadic Alzheimer’s disease

Abstract

The increasing prevalence of Alzheimer’s disease (AD) and a lack of effective prevention or disease-modifying therapies are global challenges with devastating personal, social and economic consequences. The amyloid β (Aβ) hypothesis posits that cerebral β-amyloidosis is a critical early event in AD pathogenesis. However, failed clinical trials of Aβ-centric drug candidates have called this hypothesis into question. Whereas we acknowledge that the Aβ hypothesis is far from disproven, we here re-visit the links between Aβ, tau and neurodegeneration. We review the genetics, epidemiology and pathology of sporadic AD and give an updated account of what is currently known about the molecular pathogenesis of the disease.

Keywords::

• aging
• Alzheimer’s disease
• amyloid
• apolipoprotein E
• neurodegeneration
• pathogenesis
• tau

Acknowledgements

We gratefully acknowledge the support of the Leonard Wolfson Experimental Neurology Centre, the Swedish Research Council, the Knut and Alice Wallenberg Foundation, the JPND BIOMARKAPD project, EMIF-AD, the Göteborg Medical Society, Swedish Brain Power, Stiftelsen Gamla Tjänarinnor, Alzheimerfonden, The Swedish Medical Society, Klinisk Biokemi i Norden, and Carl-Bertil Laurells foundation. We wish to thank colleagues and patients and their families for generating the extensive literature that was reviewed here.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• There is not just one, but several causes of clinical Alzheimer’s disease (AD); this is a highly heterogenic condition, especially in the elderly.

• Likewise, there is not just one, but several causes of AD neuropathology.

• There is nothing mystic about the heterogeneity; it is explained by molecular pathologies affecting the brain at different locations in different manners in different individuals who are more or less vulnerable to particular pathologies because of their genetic make-up and life history.

• We need better biomarkers for a broader range of molecular pathways that may cause cognitive dysfunction and dementia.

• We need new forms of epidemiological studies, in which biomarkers for molecular pathologies are taken into account.

• To assess the amyloid β (Aβ) cascade hypothesis, we have to perform trials of the most promising Aβ-targeting drug candidates in asymptomatic, Aβ-positive individuals with no or few other risk factors for dementia.