9 July 2023
Understanding and treatment of disease go hand in hand. Despite decades of research efforts in academia and the drug industry, and hundreds of clinical trial studies, we have no treatment, and no prevention for Alzheimer's disease (AD). Why is that? The short answer is that we do not understand AD, its origin and disease mechanisms.
AD is the most common form of aging-associated neurodegenerative brain disorder and the major cause of dementia. AD is characterized by progressive and irreversible impairment of learning and memory formation, followed by remarkable changes of behavior and personality, and in the end, loss of self. In the US, 6.7 million people live with AD at home, long-term care facilities and hospices, for $1 billion a day in healthcare cost. In addition, 18 billion hours a year of unpaid home care is estimated at $335 billion . In 2023, the National Institute of Aging (NIA) of NIH is funding AD research with $3.2 billion .
According to the amyloid hypothesis, Aβ protein amyloid formation in the brain causes AD. Thus, the hypothesis predicts that removal of brain amyloid provides a treatment for AD patients, and preventing brain amyloid formation prevents the development of AD [3,4]. Ever since its formulation in 1991-1992, the amyloid hypothesis has almost singularly misguided AD research, drug development, and clinical trial studies. While a hypothesis can never be proven right, it can be proven wrong, in theory or by experiment, even a single experiment will do .
In clinical trials of AD patients, reducing Aβ peptides production with drugs inhibiting β- or γ-secretase enzymes, or clearing amyloid from the brain with anti-Aβ antibodies, have not slowed dementia progression and reduced cognitive decline. Similarly, preventive trials in people at high risk of developing AD, due to carrying the major dementia-risk gene APOE4, or having elevated brain amyloid (as seen in PET pictures), have all failed to prevent the development of AD. Also, preventive anti-Aβ antibody therapies have not helped people destined to getting AD, caused by the APP, PS1, or PS2 gene mutations. Most alarmingly, however, often times the drugs only harmed the clinical trial participants, by causing significant health problems associated with edema (swelling) and hemorrhages (bleeding) in the brain, as well as enhanced cognitive decline and dementia progression [6-8].
This gives AD research a bad name. This is not evidence-based science. This is amyloid hypothesis driven theology. We can only imagine the people living with AD having volunteered for the clinical trials, their family members, friends. and other carers, their hopes and dreams all but dashed. How long do the people living with AD have to wait? There are no AD survivors .
It is fair to say the lack of treatment and prevention of AD today is due to the the amyloid hypothesis, which, it seems, cannot be proven wrong. It is also fair to say the amyloid hypothesis has generated significant research interest in the amyloid-β protein precursor (AβPP), β- and γ-secretase enzymes, and Aβ peptides, so much that they have become perhaps the most studied proteins in biology, comparable to the proteins and enzymes involved in the blood clotting cascade mechanism. However, AβPP is more than the precursor for Aβ peptides. For example, AβPP is a G-protein coupled cell surface receptor essential in learning and memory formation, and in synapse formation between neurons [9.10]. AβPP is an ‘old’ protein of 770 amino acids, conserved in evolution 400 million years, which means it is an ‘important’ protein , important because AβPP has multiple molecular interactions, thus its amino acid sequence must have remained the same. Aβ peptides do much more than form amyloid. For example, they are potent wide-spectrum antimicrobial peptides, an ancient arm of the innate immune system against infections by bacteria, fungi, and viruses . And γ-secretase (PS1 or PS2) has 149 substrates, including AβPP, and interacts with many proteins, such as glutamate transporter EAAT2 [13,14].
Inherited dominant mutations in the APP, PS1, or PS2 genes cause early-onset AD at age 19-55, at about the same age as their mother or father, and their mother or father got AD, the exact timing of onset dictated by the gene and the particular mutation . This is a fact as fact can be, but how the mutations do it we know absolutely nothing about. Why we don’t know why the APP mutation A673V (position 2 in the Aβ peptides) causes AD at age 55, while another mutation A673T of the same alanine protects against AD . If we don’t study that, what hope we have to understand AD, its origin and disease mechanisms?
In 2014, when Jack de la Torre was writing in The New England Journal of Medicine: “[...] when is a dead hypothesis really dead?”, he was commenting on the failed clinical trials in AD patients with the anti-Aβ antibodies solanezumab and bapineuzumab . However, the ‘die-hard’ amyloid hypothesis is not dead yet, as exemplified by the recent approval of aducanumab (June 7, 2021) and lecanemab (July 6, 2023) by the US Food and Drug Administration (FDA) for the treatment of AD patients [18,19]. By doing so, it is very clear the FDA does not “promote, protect, and ensure the full enjoyment of human rights by persons with disabilities” as articulated in the UN’s Convention on the Rights of Persons with Disabilities (CRPD), May 3, 2008, in force in 186 nations.
Markku Kurkinen, PhD
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