Pharmacological Approaches in Alzheimer’s Disease: From Symptomatic Care to Future Disease Modification

Alzheimer’s disease (AD) has emerged as one of the most pressing neurological disorders of the 21st century. First described in 1906 by Alois Alzheimer in a patient with profound memory loss, emotional instability, and neuropathological hallmarks of amyloid plaques and neurofibrillary tangles, the disease has since become a global health challenge. Currently, over 55 million individuals are living with dementia, of which 60–70% are attributable to AD¹. This number is projected to triple by 2050 due to aging populations, particularly in low- and middle-income countries².The burden of AD extends beyond patients to families, caregivers, and health systems. Annual global costs are estimated to exceed USD 1 trillion, with both direct medical expenses and indirect costs such as lost productivity and caregiver stress³. Importantly, AD is not merely a neurobiological condition but also a deeply human disease that strips individuals of memory, identity, and independence, creating emotional suffering for patients and loved ones.Pharmacological interventions, although essential, remain limited in their ability to halt or reverse disease progression. Current therapies primarily offer symptomatic relief, modestly improving cognition and daily functioning. However, recent scientific breakthroughs — including monoclonal antibodies targeting amyloid-β — represent a paradigm shift toward disease-modifying treatments?. Despite controversies, these innovations signal a hopeful transition from palliative symptom control to potentially altering the disease trajectory.This review aims to provide a comprehensive, detailed exploration of the pharmacological landscape of AD. It integrates historical context, molecular insights, current and emerging drug therapies, adjunctive approaches, and future directions. In doing so, it highlights not only scientific progress but also the urgent need for compassionate, patient-centered strategies that preserve dignity and quality of life.

2. Historical Background of Alzheimer’s Disease

The story of Alzheimer’s disease began in 1906, when Alois Alzheimer presented the case of Auguste Deter, a 51-year-old woman with progressive memory loss, paranoia, and cognitive decline. Upon her death, postmortem examination revealed hallmark neuropathological features — extracellular “senile plaques” and intracellular “neurofibrillary tangles.” These observations laid the foundation for identifying AD as a distinct neurodegenerative disorder¹.

Over the decades, advances in neuropathology, biochemistry, and genetics deepened understanding of the disease. In the 1970s, researchers highlighted the cholinergic deficit hypothesis, noting significant reductions in acetylcholine levels in AD patients. This led to the development of cholinesterase inhibitors, the first class of FDA-approved drugs for AD². The 1980s and 1990s brought two landmark discoveries: the amyloid cascade hypothesis, which proposed amyloid-β accumulation as a key driver of pathology, and the tau hypothesis, which focused on abnormal tau hyperphosphorylation and tangle formation³.

The late 1990s and early 2000s witnessed approval of memantine, an NMDA receptor antagonist, as well as large-scale clinical trials targeting amyloid-β. Despite repeated trial failures, these efforts shaped the modern research landscape. By the 2010s, genetic insights — particularly the role of the APOE ε4 allele — underscored the interplay between genes and environment?.

The 2020s marked a turning point with the controversial approval of aducanumab in 2021, followed by promising results for lecanemab and donanemab. For the first time, therapies aimed not just to relieve symptoms but to modify the underlying disease process?. Though debates continue regarding efficacy, safety, and affordability, these approvals represent historic milestones in the century-long fight against AD.

Table 1: Key Historical Milestones in Alzheimer’s Disease Research

3. Epidemiology, Burden, and Risk Factors

Alzheimer’s disease (AD) is the leading cause of dementia, accounting for 60–70% of cases worldwide¹. According to the World Health Organization, more than 55 million people live with dementia in 2023, a number projected to rise to 139 million by 2050 due to aging populations². This makes AD not only a medical challenge but also a global public health crisis.

3.1 Global Prevalence

Prevalence rates vary significantly across regions. In North America and Europe, where life expectancy is higher, prevalence of AD in individuals above 65 years ranges from 5–8%. In Asia, rapid aging, especially in China and India, is expected to contribute to a majority of global dementia cases by mid-century³. Meanwhile, in Africa and low-income countries, prevalence data remain limited, but underdiagnosis is common due to poor healthcare infrastructure?.

3.2 Socioeconomic Burden

The economic burden of AD is staggering. The global cost of dementia was estimated at over USD 1 trillion in 2020 and is expected to double by 2030?. Direct medical costs include diagnosis, hospitalizations, and medications, while indirect costs include caregiver time, lost productivity, and social support. Importantly, up to 80% of dementia care is provided by unpaid family caregivers, leading to financial strain, emotional exhaustion, and health issues?.

Figure-1

3.3 Risk Factors

AD arises from a complex interplay of non-modifiable and modifiable risk factors.

• Non-modifiable factors: Age remains the strongest risk factor. Genetics, particularly the APOE ε4 allele, increases risk up to 3-fold for heterozygotes and 12-fold for homozygotes?.
• Modifiable factors: Cardiovascular health, diabetes, hypertension, obesity, smoking, and physical inactivity contribute significantly to risk. Increasing evidence also links diet, social isolation, depression, and chronic stress to AD onset?.
• Protective factors: Higher education, cognitive reserve, active lifestyles, and Mediterranean-style diets appear to lower risk?.

Table 2: Global Prevalence and Burden of Alzheimer’s Disease

Alzheimer’s disease (AD) is characterized by progressive neurodegeneration involving multiple molecular and cellular pathways. While the amyloid cascade and tau hypotheses remain central, it is now understood that AD arises from a multifactorial process involving oxidative stress, mitochondrial dysfunction, neuroinflammation, synaptic failure, and even systemic factors such as metabolic dysfunction and the gut–brain axis¹.

4.1 Amyloid Cascade Hypothesis

The amyloid cascade hypothesis suggests that the overproduction or impaired clearance of amyloid-β (Aβ) peptides, derived from amyloid precursor protein (APP), leads to extracellular plaque accumulation². Oligomeric forms of Aβ are considered highly neurotoxic, disrupting synaptic transmission, inducing oxidative stress, and triggering neuroinflammatory responses³.

Key evidence supporting this hypothesis comes from genetic studies: mutations in APP, presenilin-1, and presenilin-2 genes (familial AD) result in increased Aβ production?. In sporadic AD, impaired clearance mechanisms, including reduced proteolytic degradation and dysfunction of the glymphatic system, contribute to accumulation?.

4.2 Tau Pathology

Tau is a microtubule-associated protein that stabilizes neuronal structure. In AD, tau undergoes abnormal hyperphosphorylation, leading to its detachment from microtubules and aggregation into **neurofibrillary tangles (NFTs)**?. This process disrupts axonal transport, causes cytoskeletal collapse, and contributes to synaptic dysfunction?.

Unlike amyloid pathology, tau deposition correlates more strongly with disease severity and cognitive decline?. Recent therapeutic efforts are increasingly focused on targeting tau aggregation and its spread across neural networks.

4.3 Neuroinflammation

Microglial activation plays a dual role in AD. While microglia initially aid in clearing Aβ aggregates, chronic activation leads to excessive release of cytokines, chemokines, and reactive oxygen species?. Genome-wide association studies (GWAS) have identified risk genes such as TREM2, highlighting the contribution of innate immunity to AD¹?.

Astrocytes also contribute to inflammation and blood–brain barrier dysfunction, further exacerbating neurodegeneration¹¹.

4.4 Oxidative Stress and Mitochondrial Dysfunction

Oxidative damage is one of the earliest events in AD pathology. Aβ accumulation leads to excessive production of reactive oxygen species (ROS), lipid peroxidation, and DNA damage¹². Mitochondrial dysfunction, characterized by impaired ATP generation and altered calcium homeostasis, contributes to synaptic failure and neuronal apoptosis¹³.

4.5 Synaptic Dysfunction and Neurotransmitter Deficits

Loss of synapses is the strongest correlate of cognitive impairment in AD¹?. Disruptions in glutamatergic and cholinergic signaling underlie memory deficits and behavioral changes. Reduced levels of acetylcholine form the basis of the cholinergic hypothesis, leading to the development of cholinesterase inhibitors as symptomatic treatments¹?.

4.6 Metabolic Dysfunction and “Type 3 Diabetes”

Recent evidence suggests AD may share mechanisms with metabolic disorders. Insulin resistance in the brain impairs glucose utilization, leading to neuronal energy deficits. Some researchers describe AD as a “Type 3 diabetes” due to overlapping pathways involving insulin signaling and amyloid accumulation¹?.

4.7 Gut–Brain Axis and Microbiome

Emerging studies highlight the role of gut microbiota in AD. Dysbiosis may increase systemic inflammation and alter amyloid deposition¹?. Preclinical data suggest that probiotics and dietary interventions modulate neuroinflammation and cognitive outcomes, though human evidence remains limited¹?.

Figure-2

Table 3: Major Pathophysiological Mechanisms in Alzheimer’s Disease

Despite decades of research, the pharmacological options for Alzheimer’s disease (AD) remain limited. Current therapies primarily provide symptomatic relief by enhancing neurotransmission or modulating excitotoxic pathways, but they do not halt disease progression¹.

5.1 Cholinesterase Inhibitors

The cholinergic hypothesis posits that memory impairment in AD is partly due to loss of cholinergic neurons and reduced acetylcholine levels in the basal forebrain². Cholinesterase inhibitors (ChEIs) prolong acetylcholine action by inhibiting its breakdown, thereby improving neurotransmission.

• Donepezil: The most widely prescribed ChEI, approved for all stages of AD. It improves cognition and global functioning, though benefits are modest³.
• Rivastigmine: Available in oral and transdermal formulations; effective in both AD and Parkinson’s disease dementia?.
• Galantamine: Enhances nicotinic receptor activity in addition to cholinesterase inhibition, providing dual action?.

Common side effects include nausea, vomiting, diarrhea, bradycardia, and weight loss. Clinical benefits often diminish after 12–18 months of therapy.

5.2 NMDA Receptor Antagonist

Excitotoxicity via glutamate overstimulation contributes to neuronal injury in AD. Memantine, an NMDA receptor antagonist, is approved for moderate-to-severe AD?. It reduces abnormal glutamatergic activity without disrupting normal synaptic signaling.

Memantine is often combined with donepezil, and clinical studies demonstrate modest improvements in cognition, daily function, and caregiver burden?.

5.3 Combination Therapy

Combining ChEIs with memantine is increasingly common in moderate-to-severe stages. Evidence suggests additive or synergistic effects, though long-term outcomes remain uncertain?.

5.4 Symptomatic Management of Behavioral and Psychological Symptoms

AD patients often develop agitation, psychosis, sleep disturbances, and depression. These symptoms significantly affect quality of life and caregiver stress. Pharmacological options include:

• Antidepressants (SSRIs, SNRIs) for depression and anxiety.
• Atypical antipsychotics (risperidone, quetiapine, olanzapine) for severe agitation and psychosis, though they carry risks of stroke and mortality?.
• Anxiolytics (benzodiazepines, buspirone) for short-term relief, but long-term use is discouraged due to cognitive side effects¹?.

These treatments are symptomatic and must be used with caution, emphasizing the need for safer, more effective drugs.

5.5 Limitations of Current Therapies

Although widely used, current pharmacological treatments offer only modest symptomatic benefit without altering the underlying disease process. Decline in cognition and function continues despite therapy. Side effects, poor tolerability, and diminishing efficacy further limit utility. These shortcomings highlight the urgent need for disease-modifying therapies (DMTs).

Table 4: Currently Approved Pharmacological Therapies in Alzheimer’s Disease

The approval of aducanumab in 2021 marked a turning point in Alzheimer’s disease (AD) pharmacology, representing the first agent designed to alter disease progression rather than provide symptomatic relief¹. Since then, multiple disease-modifying therapies (DMTs), particularly monoclonal antibodies targeting amyloid-β (Aβ), have entered late-stage clinical development. Despite optimism, challenges remain regarding efficacy, safety, and accessibility.

6.1 Anti-Amyloid Monoclonal Antibodies

6.1.1. Aducanumab (Aduhelm)

• Approved by the FDA in 2021 via accelerated approval pathway².
• Targets aggregated Aβ, reducing plaque burden as shown in PET imaging.
• Clinical efficacy remains debated: while EMERGE trial showed modest slowing of cognitive decline, ENGAGE trial failed to replicate results³.
• Major concern: amyloid-related imaging abnormalities (ARIA), including cerebral edema and microhemorrhages.

6.1.2. Lecanemab (Leqembi)

• Received accelerated FDA approval in 2023, and full approval in 2024?.
• Binds soluble protofibrils of Aβ, leading to plaque clearance.
• CLARITY-AD trial demonstrated 27% slowing in cognitive decline at 18 months?.
• Lower ARIA incidence compared to aducanumab, but monitoring is still required.

6.1.3. Donanemab

• Eli Lilly’s antibody targeting a specific pyroglutamate-modified form of Aβ.
• TRAILBLAZER-ALZ2 trial showed 35% slowing in decline compared to placebo?.
• Regulatory approvals are expected in late 2024/2025.

6.1.4. Other Antibodies in Development

• Gantenerumab (Roche) and Crenezumab failed to meet primary endpoints in large trials, highlighting the challenge of translating amyloid clearance into clinical benefit?.

6.2 Anti-Tau Therapies

Given the strong correlation between tau pathology and cognitive decline, tau-targeting therapies are increasingly prioritized.

• Monoclonal antibodies (semorinemab, gosuranemab, tilavonemab) aim to block tau aggregation and spread, though early trials show limited efficacy?.
• Small molecules targeting tau phosphorylation and aggregation are under study.
• Ongoing research explores antisense oligonucleotides (ASOs) to reduce tau expression.

6.3 Active and Passive Immunotherapies (Vaccines)

Immunotherapy approaches aim to stimulate the immune system to clear amyloid or tau.

• AADvac1 (active vaccine targeting tau) showed safety and immunogenicity but modest clinical benefit?.
• Amyloid vaccines remain under investigation, with a focus on reducing adverse autoimmune reactions.

6.4 Small Molecule Disease-Modifying Approaches

Beyond biologics, small molecules offer practical advantages (oral route, lower cost).

• BACE1 inhibitors (e.g., verubecestat, lanabecestat) failed in clinical trials due to lack of efficacy or adverse effects¹?.
• Anti-aggregation agents and metal chelators are under development, though none are near approval.

6.5 Combination and Multi-Target Therapies

Given the multifactorial nature of AD, researchers are testing combinations of anti-amyloid, anti-tau, and anti-inflammatory agents. Multi-targeted approaches may provide synergistic effects by addressing overlapping pathological pathways¹¹.

Table 5: Recent Clinical Trials of Disease-Modifying Therapies (2020–2024)

While pharmacological therapies are essential in managing Alzheimer’s disease (AD), adjunctive and lifestyle-based interventions are equally critical. They address comorbidities, enhance quality of life, and often reduce the rate of functional decline¹.

7.1 Lifestyle Interventions

7.1.1. Dietary Modifications

• The Mediterranean diet and DASH (Dietary Approaches to Stop Hypertension) diet have been consistently linked with reduced AD risk and slower progression².
• Nutrients such as omega-3 fatty acids, polyphenols (from berries, green tea, and turmeric), and antioxidants may reduce oxidative stress and neuroinflammation³.
• The MIND diet (a hybrid of Mediterranean and DASH) has shown particular promise in observational studies, lowering AD risk by up to 53% when strictly followed?.

7.1.2. Physical Activity

• Regular aerobic exercise improves cerebral blood flow, neurogenesis, and synaptic plasticity?.
• Both resistance training and yoga-based programs improve executive function and mood, while reducing caregiver burden?.

7.2 Cognitive and Social Engagement

• Cognitive stimulation therapy (CST) and memory training can delay functional decline?.
• Social connectedness reduces isolation, depression, and progression of symptoms, especially in early stages?.
• Music therapy and art-based interventions can evoke positive emotions and preserve communication abilities even in advanced AD?.

7.3 Psychological and Behavioral Support

• Behavioral symptoms such as agitation, aggression, and depression often cause greater caregiver distress than memory loss itself¹?.
• Non-drug approaches (environmental modification, music therapy, structured routines) are first-line before considering antipsychotics¹¹.
• Mindfulness and stress management interventions benefit both patients and caregivers.

7.4 Assistive Technology and Digital Tools

• Smartphone reminders, wearable devices, and AI-based monitoring systems help patients maintain independence longer¹².
• Virtual reality and serious gaming approaches are being tested to support memory training and emotional regulation¹³.

Table 6: Evidence-Based Non-Pharmacological Interventions in AD

Despite major advances, effective and widely accessible treatments for Alzheimer’s disease (AD) remain elusive. Ongoing research is pushing boundaries in molecular medicine, genetics, regenerative therapies, and digital health. At the same time, multiple challenges—scientific, ethical, and socioeconomic—must be addressed before breakthroughs translate into population-wide benefits.

8.1 Precision Medicine and Biomarker-Guided Therapy

• The recognition that AD is a heterogeneous disease is shifting focus toward personalized interventions.
• Biomarkers such as plasma phosphorylated tau (p-tau181, p-tau217), neurofilament light chain (NfL), and amyloid/tau PET imaging now enable early diagnosis and stratification of patients¹.
• Future clinical trials will likely rely on biomarker-based recruitment to identify subgroups most likely to benefit from specific interventions².

8.2 Regenerative Medicine and Stem Cell Therapy

• Stem cell-based approaches aim to replace lost neurons and restore synaptic networks.
• Induced pluripotent stem cells (iPSCs) allow patient-specific disease modeling and potential autologous transplantation³.
• Challenges remain regarding long-term survival, functional integration, and ethical concerns.

8.3 Gene Therapy and Genome Editing

• CRISPR-Cas9 and related genome-editing technologies offer potential to modify genes like APOE ε4, reducing lifetime risk?.
• Viral vector–based delivery of neuroprotective genes (e.g., NGF, BDNF) is under exploration.
• However, concerns about off-target effects and long-term safety need resolution before clinical application.

8.4 Multi-Target Drug Discovery

• Given the multifactorial pathology of AD, polypharmacology (drugs acting on multiple pathways) is gaining momentum.
• Novel agents target amyloid, tau, neuroinflammation, and mitochondrial dysfunction simultaneously?.
• Computational modeling and AI-driven drug discovery are accelerating candidate identification.

8.5 Digital Health and Artificial Intelligence

• AI-based platforms are improving early diagnosis by analyzing speech patterns, facial expressions, and cognitive test data?.
• Wearables and remote monitoring tools support personalized care and enable real-world data collection for clinical trials.
• Ethical concerns around privacy, bias, and digital inequality must be carefully managed.

8.6 Global and Societal Challenges

• Cost of DMTs (e.g., monoclonal antibodies priced at USD 25,000–35,000 annually) raises concerns about affordability and health equity?.
• In low- and middle-income countries, limited access to diagnostics and trained neurologists may widen disparities.
• Public health approaches emphasizing prevention, education, and community-based care will be essential to balance innovation with accessibility.

Table 7: Future and Emerging Approaches in AD Therapy