Recent advances in Alzheimer’s treatment.
What is Alzheimer’s?
It was in 1906, when Herr Alois Alzheimer, a psychiatrist and neuroanatomist in Germany, addressed a gathering of psychiatrists regarding “a peculiar disease process of the cerebral cortex.” His case was a 50-year-old woman ailed by memory loss, delusions, hallucinations, aggression, and confusion – all of which worsened until her untimely death five years later.
During the autopsy, Alzheimer noticed distinctive plaques in her brain tissue. These plaques – the clumps of a protein we now know as amyloid-beta – are considered to be the hallmark of Alzheimer’s disease or Alzheimer’s dementia (AD).
Dementia is an insidious condition that irreversibly damages your cognitive abilities and seriously impair your quality of life. Dementia has various forms and aetiologies. The vascular dementia, the frontotemporal dementia and the dementia due to Huntington’s are well known. The lesser-known causes of dementia are Lewy Body disease, primary supranuclear palsy, dementia secondary to parkinsonism, dementia secondary to addictions among the others.
Alzheimer’s disease is the most common type of pathological dementia seen in the practice. Contrary to the usual jests about grey hair and forgetfulness, Alzheimer’s is not a part of normal aging. This chameleon of the disease, with its confounding symptoms, causes an abnormal protein build-up (the tau tangles and the amyloid plaques) in your brain cells. These built-ups are toxic to the brain cell physiology and result in the eventual loss of synapses triggering progressive neurotransmitter deficits; hastening the neuronal cell death. Recent studies propose the an additional role of an altered glucose metabolism in the cells, an autoimmune or a pernicious inflammatory process in triggering the neurodegenerative plaques along with an imbalance in acetylcholine and glutamate pathways. The exact molecular pathophysiology in AD is yet under research, however, we do know that the AD aetiology is way different compared to vascular dementias or other neurodegenerative diseases, as vascular dementias do not respond to AD therapy.
The hippocampus and the limbic system is one of the brain areas affected in the earliest phases of AD. This could be because the hippocampal microglia are more immunologically active than the other regions of the brain. In fact, the atrophy of medial temporal and hippocampal regions are the structural markers in magnetic resonance imaging (MRI).
What are the signs and symptoms of AD?
The loss of the sense of smell is historically considered to be the earliest sign of dementia. The other common manifestations are loss of short-term memory (e.g., asking repetitive questions, frequently misplacing objects, or forgetting appointments).
In later stages, impaired reasoning, difficulty handling complex tasks, and poor judgment (e.g., being unable to manage a bank account, or making poor financial decisions) may be seen. Some patients are brought by relatives due to gradual worsening of handwriting, inability to manage their household tasks (cooking, cleaning the home, self-care) or simply depression masked as dementia.
Language dysfunction (e.g., difficulty finding common words, errors speaking, abnormal intonations while speaking) and visuospatial dysfunction (e.g., inability to recognize faces, addresses or common objects) occur rarely or in very advanced stages. (Classically, severe and acutely progressing dementia – within weeks should invoke suspicion of other neurodegenerative diseases like Lewy Body disease or primary supranuclear palsy).
Alzheimer’s disease progresses gradually and may plateau for periods of time. In untreated cases, wandering, agitation, yelling, persecutory ideation, depression delirium) are common. Causes of death are often lung infections (aspiration pneumonia), falls, malnutrition, and dehydration.
What are the current treatments for AD?
Other than lifestyle interventions like physical activity, solving crosswords, and maintaining ideal body weight, blood sugars, blood pressure, we do have some medicines in our arsenal.
Galantamine, rivastigmine, and donepezil are cholinesterase inhibitors prescribed for mild to moderate Alzheimer’s symptoms. These help reduce the acetylcholine breakdown in the brain’s neurons. As Acetylcholine has a role in cognitive processing, formation of new memories and impregnation of memories during sleep, the acetylcholine surge helps stave off the symptoms for some time.
However, as Alzheimer’s progresses, the brain produces less and less acetylcholine and, over time, these medicines eventually lose their effectiveness. The cholinergic side effects of the medications like diarrhea, nausea, hypersalivation, ECG abnormalities are often a major consideration in geriatric population while prescribing and titrating their doses.
Memantine, an NMDA antagonist, helps cope with the symptoms by keeping the glutamate levels in the brain in check. However, it also can trigger side effects like hallucination, confusion, dizziness, headache and tiredness, it also warrants caution in cases of various organ dysfunctions.
What are the obstacles in AD drug development?
They say the capacity of the brain is infinite. It can relearn via neuronal plasticity, retain via the so-called muscle memory, and protect itself from the noxious chemicals via its own fortress of solitude, the blood-brain barrier. But when treating Alzheimer’s this protection becomes its albatross. The scope of medications that act on the brain is limited as most drugs fail to penetrate the barrier. The following drug formulations were attempted but resulted in failure in Phase III RCTs.
- Vaccines against AD: The risk of meningoencephalitis have nipped the idea of an amyloid protein vaccine in the bud.
- Extreme drug toxicity: The BACE-1 and γ-secretases inhibitors which repaired the molecular changes in the affected neurons displayed extreme neurotoxicity in the long run.
- Passive immunisation: The IVIG against amyloid proteins derived from the plasma of healthy donors (akin to the passive immunisation) demonstrated no efficacy in human trials.
- Calcium channel blocker: Nilvadipine reduced amyloid production, increased cerebral blood flow, and demonstrated anti-inflammatory and anti-tau activity in preclinical studies. However, the outcome in clinical trials has been disappointing.
- Insulin: The Intranasal glulisine, an insulin analog with hopes to control dementia by repairing the altered cell glucose metabolism failed in therapeutic effects on humans.
- Pioglitazone: The antiapoptotic effect of pioglitazone on the cells, failed to demonstrate the efficacy in AD in RCTs.
What are the latest drugs in AD treatment?
Two decades after memantine approval, the biologics proved to be a ray of hope in AD management.
The United States (US) Food and Drug Administration (FDA) approved aducanumab, the first monoclonal antibody anti-Aβ in 2021. This AD drug is only approved for the management of early AD. It crosses the blood-brain barrier and selectively targets and binds to the aggregated soluble oligomers and insoluble fibril conformations of Aβ plaques in the brain when administered as an intravenous infusion. The side effects include amyloid-related imaging abnormalities (ARIA). In ARIA, the white spots in the MRI, which represent vasogenic edema, were mostly found in the participants receiving high doses, microhaemorrhages in the nervous system, neuronal edema, falls, diarrhoea and anaphylaxis. The cost and deficiency of long term safety data are currently the major hurdles in its use.
Another biomolecule approved by FDA in the early 2023 is Lecanemab. This monoclonal antibody has been shown to moderately slow cognitive and functional decline in early-stage cases of the disease. A trial that involved 1,795 participants with early-stage, symptomatic Alzheimer’s, lecanemab slowed clinical decline by 27% after 18 months of treatment compared with those who received a placebo. It selectively targets protofibrils, a species of soluble aggregated amyloid-beta (Aβ). Its hitherto-reported adverse events include brain haemorrhages and brain edema in susceptible populations.
Donanemab is another antibody that targets the deposited plaque to clear existing amyloid burden from the brain, rather than merely prevent deposition of new plaques or growth of existing plaques. The evidence from the trial suggests that the earlier in the disease the treatment was given, the greater the benefit. This means that there was more slowing in memory and thinking decline in people with fewer changes in their brains associated with Alzheimer’s disease. The trial showed a 40% slowing in decline of everyday activities such as driving, doing hobbies and managing finances. It should be available on the market somewhere around 2025.
A number of MAO-B inhibitors (MAO-Bi) have been studied for AD and Parkinson’s disease. These are mostly in the pipeline. A selective MAO B inhibitor called sembragiline has demonstrated a good safety profile and potential effect on neuropsychiatric symptoms and behavioral impairment in. However, more multicentric RCTs are needed to obtain information about its posology and safety profile.
Azeliragon is an antagonist of the receptor for advanced glycation end products (RAGE). Theoretically it regulates multiple physiological effects, including the inflammatory process, oxidation stress, and cerebral blood flow. Two phase 3 clinical trials were discontinued because of the failure to achieve their primary endpoints in June 2018. The ongoing phase 3 trial to test the effect of azeliragon on patients with mild AD and impaired glucose tolerance started on June 27, 2019. It is scheduled to end in 2023.
What are the long pharmacological modalities in AD?
Cognitive Behavioural Therapy – Working together with licenced therapists using pictures, puzzles, art forms, music as well as sessions to combat the accompanying symptoms of depression, anxiety and irritability is useful to assist with adjustment to the initial diagnosis and further treatment plans.
Behavioural Management Therapy – These sessions may help may be useful in targeting challenging (difficult to manage) behavioural patterns in persons with dementia. Such behaviours may include wandering, agitation and repetitive questioning.
Environmental approaches/modification – Creative solutions to dementia symptoms, targeting the environment of the person with dementia. Pottery, painting, mandalas, meditation sessions, massages may help calm the agitated patients.
Dementia support groups – These can help people as well as their families to cope with the diagnosis.
Memory training and using external memory aids (visual and auditory) can assist a person in the early stages of dementia to maximise their cognitive functioning and independence.
Alternative therapies – light massage and aromatherapy, music and dance therapy, animal assisted therapy, multi-sensory therapy may help in dementia patients.
While the odyssey to seek the ambrosia that may revive the diseased brain continues, we may as well revert back to the age-old wisdom and practice stress management, meditation and follow satvic practices when it comes to food as well as thoughts to respect this wonderful puddle of grey white mush, which makes us the masters of the animal kingdom.
Ref
Huang, LK., Chao, SP. & Hu, CJ. Clinical trials of new drugs for Alzheimer disease. J Biomed Sci 27, 18 (2020).
Conti Filho CE, Loss LB, Marcolongo-Pereira C, Rossoni Junior JV, Barcelos RM, Chiarelli-Neto O, da Silva BS, Passamani Ambrosio R, Castro FCAQ, Teixeira SF, Mezzomo NJ. Advances in Alzheimer’s disease’s pharmacological treatment. Front Pharmacol. 2023 Jan 26;14:1101452.