Our speculative but data-informed view: Alzheimer disease is a result of the cumulative combination of stresses on the brain in people who have increased neuronal plasticity, and reach a tipping point of neuronal fragility leading to apoptosis.
In this view, amyloid, as well as tau, are symptoms, not causes of the neuronal deterioration. In fact, they may slow down and try to mitigate neuronal apoptosis, so their therapeutic targeting is not indicated.
ApoE is involved in the increased neuronal plasticity, disconnection, remodeling and adaptation in response to stress, useful in young people with robust neurons, but detrimental in older people with fragile neurons. Free radical damage and decreased growth factor levels make neurons more fragile with age.
Evolutionarily, populations that have been subjected over the centuries to harsh and stressful environments (in Africa or other continents-genocides, pogroms, persecution) may be more susceptible to Alzheimer in old age- if they reach that age, as they do in more modern and safer societies. Individually, people with a history of exposure to major stress and who have PTSD may be at higher risk of Alzheimer in old age, even more so if accompanied by traumatic brain injury. This should become a major area or research and intervention in combat veterans, and contact-sport athletes.
How to treat Alzheimer? Target neuronal apoptosis, specifically enough that you do not increase the opposite elsewhere, which is cancer. GSK3beta and its connected biological pathways are worth exploring.
How to prevent Alzheimer? In a Mindscape fashion, addressing the three dimensions: anxiety, mood and cognition. Reduce cumulative exposure to stress (or use an anti-anxiety medication such as an SSRI), modulate neuronal plasticity through cognitive-behavioral therapy (or use a mood stabilizing medication such as lithium), decrease neuronal fragility through rich nutrients and a rich environment (or use a cognitive enhancing medication). Infection and inflammation are major stressors on the brain, so limiting them helps prevent Alzheimer. For a “primum non nocere” strategy: physical exercise, omega-3 fatty acids, antioxidants and a stimulating life. These may be our best bets- in combination.
Last but not least, in our view schizophrenia is just an accelerated early form of this whole process- indeed dementia praecox, as Emil Kraepelin has suggested. The stresses occurs earlier on, including in utero, and the neurons are more plastic and more fragile due to multiple genetic vulnerability factors. Prevention and treatment: the same, but a need to intervene very early on, in childhood, to prevent full blown illness from developing in young adults.
Alexander B. Niculescu, III, MD, PhD