Alzheimer's dementia (AD)

see also:

• dementia

• Alzheimer's disease is a common progressive dementia
  • dementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging
• usually slow progression but may have a rapid progressive onset

• most often, it is diagnosed in people over 65 years of age, although the less-prevalent early-onset Alzheimer's can occur much earlier.
  • people with Down's syndrome are at higher risk of developing early onset AD and often have amyloid plaques by age 40
• predicted to affect 1 in 85 people globally by 2050

• genetic
  • homozygous for APOE4 variant gene is a high risk and increases risk of earlier onset
    • present in 2-3% of European population and in 15% of those with AD
    • by age 65yrs, 95% will have abnormal levels of CSF beta amyloid and 75% will have positive brain scans for amyloid ¹⁾

• in 1991, the amyloid hypothesis postulated that amyloid beta (Aβ) deposits are the fundamental cause of the disease.
  • support for this postulate comes from the location of the gene for the amyloid beta precursor protein (APP) on chromosome 21, together with the fact that people with trisomy 21 (Down Syndrome) who have an extra gene copy almost universally exhibit AD by 40 years of age.
    • also APOE4, the major genetic risk factor for AD, leads to excess amyloid buildup in the brain before AD symptoms arise. Thus, Aβ deposition precedes clinical AD.
• in 2009, this theory was updated, suggesting that a close relative of the beta-amyloid protein, and not necessarily the beta-amyloid itself, may be a major culprit in the disease. The theory holds that an amyloid-related mechanism that prunes neuronal connections in the brain in the fast-growth phase of early life may be triggered by aging-related processes in later life to cause the neuronal withering of Alzheimer's disease. N-APP, a fragment of APP from the peptide's N-terminus, is adjacent to beta-amyloid and is cleaved from APP by one of the same enzymes. N-APP triggers the self-destruct pathway by binding to a neuronal receptor called death receptor 6 (DR6, also known as TNFRSF21)
• it now appears that tau modifies itself in a futile attempt with p-38 gamma protein to combat beta amyloid and ends up forming fibrous knots that prevent nutrients getting to neurons. Tau propagation is related to a cellular process called the UFMylation cascade ²⁾

• early symptoms include:
  • inability in recalling recently observed events
  • subtle problems with the executive functions of attentiveness, planning, flexibility, and abstract thinking, or impairments in semantic memory (memory of meanings, and concept relationships)
  • apathy

• the mean life expectancy following diagnosis is ~7 years with < 3% of individuals living more than 14 years after diagnosis

• in those who lack the apolipoprotein ε4 (APOE-ε4) allele:
  • long term (12-24 months) use of non-Aβ42-lowering NSAIDs appears to lower risk of all cause dementia as well as lowering AD risk with HR of 0.74 ³⁾
• trials will commence in 2019 for an Ultrasound Rx which appears to clear amyloid build up and delay dementia ⁴⁾
  • a 2026 study showed that Cu(ATSM) can increase the abundance of P-gp clearance pumps in a mouse Alzheimer's model, by 24% and over 56 days, reduced toxic amyloid-beta by 42% and improved spatial learning by nearly 44% ⁵⁾