Overview

Alzheimer’s disease (AD) is a neurodegenerative disease thought to be the main cause of dementia. It is characterised by progressive loss of memory and cognitive function, caused by protein misfolding and aggregation.¹ 

AD is a recognised epidemic, affecting 6.7 million Americans age 65 and older in 2023. It has been predicted that this number could grow to 13.8 million by 2060.² The mean life expectancy is 7 years, with age being the single biggest risk factor affecting 30%–50% of all people by the age of 85.^3,4 

The treatments currently available for treating AD act symptomatically, unable to prevent the progression of the disease. Therefore, the discovery and approval of disease-modifying therapies (DMTs) is critical. Due to the burden of Alzheimer’s, intensive research is constantly ongoing.³ 

Causes of alzheimer's disease

There are various hypotheses for the cause of Alzheimer’s disease. These varying hypotheses are important to consider when developing novel therapeutic targets. 

Cholinergic hypothesis 

The cholinergic hypothesis involves the observed decrease in the neurotransmitter acetylcholine in the brain, causing cognitive dysfunction in AD.^2,3 

Glutamatergic hypothesis 

Excessive activity of a cell-surface receptor called NMDAR causes increased calcium inside cells and thus excitotoxicity, promoting neuronal death. This may be a potential mechanism of neurodegeneration occurring in AD.^2,3 

Amyloid cascade hypothesis

The amyloid precursor protein (APP) is a neuronal protein involved in the normal functioning of the brain. APP is modified by enzymes called secretases, producing amyloid-beta (Aβ) molecules. Certain versions of these are more prone to aggregation, which clump together to form plaques. These disrupt brain function. These are at the heart of AD pathology and can be seen under a microscope.

There have been many genetic studies to support the role of Aβ accumulation in the development of AD. Down syndrome patients with trisomy have an extra copy of the APP gene, hence they typically develop Alzheimer’s disease.³ 

Mutations in APP Presenilin 1 (PSEN1) and Presenilin 2 (PSEN2) genes increase Aβ production. These mutations promote plaque formation to cause autosomal dominant early-onset familial AD (FAD). This is very uncommon.³

Neurofibrillary tangles 

Tau is a neuronal protein involved in normal brain function. However, during AD, tau becomes structurally altered, causing it to become abnormal, meaning it can no longer perform its functions. The modified tau proteins eventually form neurofibrillary tangles (NFTs). It has been suggested that NFTs disrupt neuronal transport systems, which cause neurodegeneration in AD.^2,3,4 

Neuronal loss and apoptosis 

The formation and accumulation of insoluble Aβ plaques and NFTs causes neuronal toxicity. This leads to neuronal death (apoptosis) and neuronal loss. Neuronal loss in the hippocampus and cortex leads to the associated symptoms of AD including loss of declarative memory and cognitive function, respectively.^2,3,4

Symptoms and disease progression

AD is characterised by a gradual and irreversible decline of cognitive and functional abilities. AD is usually categorised into three stages:

• Early stages: There are often mild symptoms in the early stages of the disease, such as memory loss, difficulty with planning and language, and changes in mood and personality
• Middle stages: As AD progresses, these symptoms become more pronounced, including increased memory loss, confusion surrounding communication and complex tasks and significant behavioural changes including increased agitation and aggression
• Late stages: In the late stages, individuals experience severe memory loss, loss of physical abilities and communication skills, and increased vulnerability to infections 

Current treatments

Cholinesterase inhibitors

The most common current treatment involves the use of cholinesterase inhibitors (ChEIs) which alleviate cognitive impairment by preventing the degradation of acetylcholine in the synaptic gap. The level of acetylcholine is thus increased. This approach is on the basis that cholinergic deficits have been observed in AD as part of the cholinergic hypothesis. Currently, donepezil, galantamine, and rivastigmine are approved for use in AD.⁵

NMDA receptor antagonists

NMDA receptor antagonists such as memantine target glutamatergic dysfunction observed in AD. NMDA receptor antagonists modulate glutamatergic neuronal transmission, thus preventing impaired synaptic plasticity and neuronal damage.⁶ 

Limitations of current treatments

Current therapies do not slow or stop disease progression, only offering mild and short-term relief of symptoms. There is only weak evidence that ChEIs improve cognitive impairment, playing no role in slowing or reversing disease progression.⁷ 

Recent advances in drug therapies

There are various challenges associated with targeting AD, evident from the difficulty faced in translating preclinical findings to clinical trials for AD. Nevertheless, recent advances in novel therapeutics have been made, with 141 unique treatments of which 111 are disease-modifying therapies (DMTs) as of January 1, 2023.^8,9 

Amyloid-targeting drugs

Monoclonal antibodies

Two monoclonal antibodies, aducanumab and lecanemab, recognise the plaques and remove them. They bind to the ends of amyloid protofibrils to prevent Aβ aggregation. 

Aducanumab was the first DMT, approved for AD in 2021. However, it was discontinued in 2024 over its long-term safety.¹⁰ 

Despite this setback, another monoclonal antibody lecanemab was more recently approved in 2023, after showing a significant reduction in Aβ levels, and a slowed decline in cognition and function when compared to a placebo.¹¹ 

Aducanumab and lecanemab’s development represents a major milestone in research shifting away from drugs which only alleviate symptoms and do not arrest the progression of AD.

Secretase inhibitors

Inhibiting APP enzymes using γ-Secretase inhibitors (GSI) and β-secretase inhibitors (BACE1) is another key therapeutic approach targeting AD by preventing the production of neurotoxic Aβ species:

• γ-secretase inhibitors: The inhibitor semagacestat showed a 25% reduction in Aβ in vitro during preclinical studies. However, worsening of cognition and increased incidence of skin cancers and infections was observed due to interference with physiological signalling ¹² 
• β-secretase inhibitors: The development of effective BACE1 inhibitors has become a focus of many drug trials such as the inhibitor verubecestat, which showed a reduction in Aβ by up to 94%¹³ 
• Secretase modulators: γ-secretase modulators (GSM) have been shown to regulate rather than block secretase activity by decreasing the ratio of aggregation-prone Aβ40 and Aβ42¹⁴ 

Tau-targeting therapies 

Recent studies have highlighted that the structurally modified tau may have a closer correlation to synaptic dysfunction and cognitive decline when compared to Aβ.¹⁵ Furthermore, postmortem brain examinations have shown that NFTs can exist independently from amyloid plaques, in opposition to the previous hypothesis that Aβ plaque formation occurs before tau.¹⁶ 

Consequently, some researchers are calling for a pivot, suggesting that Tau offers a better therapeutic target than Aβ for preventing AD progression. Critiques of the amyloid hypothesis highlight the 99.6% failure rate in translating preclinical findings into tangible clinical trials.⁸ This highlights the need for further research into tau-based therapeutics as well as continued insight into the optimal target for future therapeutics. 

Tau immunotherapy 

Although lecanamab is the only current immunotherapy treatment for AD, researchers are now considering applying this approach to targeting misfolded tau. AADvac1 showed a significant reduction of Tau in the brain of rats, by promoting misfolded Tau clearance. 

This is a promising therapy due to the high levels of immunogenicity, with 29/30 patients with mild-to-moderate AD producing antibodies against Tau.¹⁷  

A combinatorial approach using lecanamab in conjunction with AADvac1 to target both Aβ and tau could potentially offer a highly efficacious approach.¹⁷ 

Experimental therapeutic approaches

Many emerging experimental therapies are currently under investigation in various stages of clinical trials. 

Small molecule inhibitors

Interference of Aβ peptide interactions using small molecule inhibitors such as tramiprosate to maintain Aβ in a non-fibrillar form is an emerging therapeutic approach. Tramiprosate has been shown to decrease cerebral Aβ42 aggregation by up to 30% as well as a reduction of plasma Aβ by 60%, hence showing disease-modifying effects.¹⁸ 

A similar novel approach targets misfolded tau by targeting molecular chaperones that are normally involved in protein folding and degradation. Methylene blue has been shown to inhibit tau fibrillation in moderate AD.¹⁹ 

Both tramiprosate and methylene blue are promising drugs. However, further studies into their mechanisms are required.

Challenges and future directions

PET scans of AD patient brains reveal aggregation of Aβ and Tau occurs before the onset of symptoms.²⁰ This highlights the need for accurate biomarkers which can aid in earlier interventions. The recent development of novel biomarkers such as pTau181 is promising.²¹ The development of new diagnostic criteria that include biomarkers to diagnose early forms of AD is also vital for future AD therapeutics. 

Monotherapies (i.e., a single drug) are currently used, despite mixed pathology being present in 70% of AD patients.²² Therefore, combination therapies are necessary for a disease-modifying effect in a multifaceted disease like AD. 

Summary 

Current treatments like cholinesterase inhibitors and NMDA receptor antagonists alleviate symptoms but do not slow disease progression. These therapies offer only short-term relief and have a limited impact on cognitive impairment. New disease-modifying therapies have emerged, such as monoclonal antibodies and secretase inhibitors. These drugs aim to prevent Aβ aggregation and production, showing promise in clinical trials. Accurate biomarkers and diagnostic criteria are crucial for early intervention and effective treatment. Combination therapies targeting multiple pathological pathways may offer better disease-modifying effects, addressing the multifaceted nature of AD.