Alzheimer’s disease is the most common form of dementia. Being of unknown aetiology, slowly progressive, incurable and eventually leading to death makes it a visible target for researchers and pharmaceutical industry. In 2006, there were 26.6 million sufferers worldwide. Alzheimer's is predicted to affect 1 in 85 people globally by 2050.
No one knows for sure the cause of Alzheimer’s (except for 1% to 5% of cases where genetic differences have been identified) and that is the greatest challenge to the MD community. Different hypotheses for the cause of AD include:
- Cholinergic hypothesis (reduced synthesis of the neurotransmitter acetylcholine)
- Amyloid hypothesis (Amyloid plaques disrupting neuronal synapse)
- Tau hypothesis (Hyperphosphorylated tau protein forming intraneuronal neurofibrillary tangles that initiate apoptosis of the nerve cells)
- Inflammatory hypothesis (Oxidative stress, Myelin breakdown, Degeneration of Locus Coeruleus with decreased synthesis of norepinephrine)
- Infectious hypothesis (HSV type 1, CJD Prion protein)
- Genetic hypothesis (AβPP gene on chromosome 21, presenilin 1 gene on chromosome 14, presenilin 2 gene on chromosome 1, and ε4 allele of APOE gene on chromosome 19)
On the contrary, the pathophysiology is well understood, being characterised by loss of neurons and synapses in the cerebral cortex and certain subcortical regions with subsequent gross atrophy of the affected regions, including degeneration in the temporal lobe, parietal lobe, and parts of the frontal cortex and cingulate gyrus. On the microscopic level, both amyloid plaques and neurofibrillary tangles are clearly visible in these affected regions. Current management of AD is palliative based on slowing down the progression of the disease and offering symptomatic relief.
Conventional modalities of treatment for AD include pharmaceutical, psychosocial and caregiving. Five medications are currently approved by regulatory agencies as the FDA and the EMA to treat the cognitive manifestations of AD. Four are acetylcholinesterase inhibitors (Tacrine, Rivastigmine, Galantamine and Donepezil) and the fifth one (memantine) is an NMDA receptor antagonist. Low dose neuroleptics and antidepressants reduce aggression, psychosis and treat behavioral and emotional symptoms associated with AD. Psychosocial interventions are used as an adjunct to pharmaceutical treatment and can be classified within behaviour-oriented, emotion-oriented, cognition-oriented or stimulation-oriented approaches. Caregiving in the form of providing education and support for patient and family (day programs, respite care, support groups, home care, PSW) and considering long-term care plan (nursing home)
I think that hope lies within targeting the proposed cause not treating its’ consequence. Apomorphine is investigated for reducing the amyloid plaques. Immunotherapy or vaccination for the amyloid plaques is another treatment modality under study. Examples include the anti-amyloid vaccine ACC-001 and bapineuzumab, a monoclonal antibody designed as identical to the naturally induced anti-amyloid antibody. Methylthioninium chloride, a drug that inhibits tau protein aggregation, has shown positive results in 2 separate clinical trials. FKBP52 protein may prevent the tau protein from hyperphosphorylation and turning pathogenic. Therapeutic trials with melatonin have been effective in slowing the progression of AD due to its anti-inflammatory effect. Also AL-108, PBT2 (metal-protein interaction attenuation agent) and etanercept (TNF α receptor fusion protein) have been showing encouraging results. Some suggested stem cell therapy as an alternative approach. What do you think?