Alzheimer’s disease remains, to this day, one of the greatest medical and social problems of our time1. It is a progressive, irreversible neurodegenerative disorder that corrodes memory, cognition, and autonomy, making it the most common cause of dementia among older people. Since Alois Alzheimer first describing the illness back in 1906, our understanding of its biology has advanced, yet no therapy to prevent or treat it has been identified so far2. With rapidly aging populations, the number of individuals affected worldwide is expected to increase dramatically, reaching a staggering 139 million in 2050. This is sure to put tremendous pressure on our healthcare systems, caregivers, and society at large. Understanding the mechanisms of this disease and developing effective therapies are the biggest challenges of contemporary medicine.
Pathophysiology: the hallmarks of the Alzheimer’s brain
The Alzheimer’s brain is characterized by overlapping processes that progressively damage networks of neurons and cause a decline of function.
Amyloid-beta plaques
One of the earliest events is the accumulation of amyloid-beta (Aβ) peptides, produced when the amyloid precursor protein is abnormally cleaved1. A particularly toxic variant, Aβ42, clumps outside neurons into dense plaques that block signaling and trigger downstream damage1. This forms the basis of what is known as the “amyloid cascade hypothesis”3.
Neurofibrillary tangles
Inside neurons, abnormal phosphorylation of the tau protein destabilizes microtubules that carry signals and nutrients4. The tau proteins thus freed undergo misfolding and aggregate into insoluble tangles that eventually lead to dysfunction and cell death.
Neuroinflammation
The brain’s immune and support cells, microglia and astrocytes, get activated in response to plaque and tangle build-up5. While they attempt clearance, prolonged activation fuels release of inflammatory molecules that accelerate degeneration.
Neuronal loss and synaptic dysfunction
Combined effects of these lead to massive cell death, especially in the hippocampus and cortex areas, disrupting memory, reasoning, and language6. Neurotransmitter balance is severely disrupted, with acetylcholine deficiency playing a central role in cognitive decline7.
Risk factors for Alzheimer’s disease
The causes of Alzheimer’s are multifactorial, influenced by both non-modifiable and preventable risks.
Non-modifiable risks
- Age is the single greatest factor, with prevalence doubling every five years after 658.
- Genetics: The APOE4 allele significantly increases the risk9. Mutations in APP, PSEN1, and PSEN2 cause rare familial Alzheimer’s before 6510. Other small-effect genes identified in population studies, such as TREM2 and CD33, contribute to further vulnerability11.
- Having a family history raises risk9. Additionally, females are associated with a higher prevalence of Alzheimer’s, influenced by longevity and possible hormonal factors12.
Modifiable risks
Lifestyle and environment strongly shape risk:
- Cardiovascular factors like hypertension, diabetes, obesity, smoking, and hypercholesterolemia damage brain vessels13.
- Sedentary behavior, poor diet, and excessive alcohol consumption worsen vulnerability14-16.
- Severe head injury leaves lasting risk17.
- Poor quality of sleep, including sleep apnea, could slow down clearance of toxic proteins18.
- Limited mental activity and education reduce “cognitive reserve”19.
- Social isolation and exposure to pollution are emerging contributors20, 21.
Stages and symptoms of Alzheimer’s disease
Alzheimer’s progresses gradually, passing through distinct stages.
1. The preclinical stage occurs decades before the symptoms even start to appear, marked by silent amyloid accumulation22. This is detectable only through advanced biomarkers such as positron emission tomography (PET) imaging or cerebrospinal fluid (CSF) assays.
2. This may progress to mild cognitive impairment (MCI), in which individuals experience subtle declines—frequent forgetfulness, difficulty with complex tasks, and impaired judgment22. While not all MCI cases become dementia, Alzheimer’s -related MCI carries a high conversion rate.
3. In mild dementia, memory lapses begin to disrupt daily life23. Orientation starts to fail, language declines, and mood shifts arise. Independence is reduced but not entirely lost.
4. Moderate dementia, often the longest stage, is marked by profound disorientation, hallucinations, disturbed sleep, inability to recognize close family, and behavioral problems such as agitation or wandering24. Patients in this stage require regular functional assistance.
5. The final, severe stage is one of complete dependence25. Patients lose communication skills, mobility, and the ability to swallow, and thus become bedridden and often highly vulnerable to fatal infections26.
Diagnosis of Alzheimer’s disease
Diagnosis requires the integration of clinical expertise with technological tools.
It is initially assessed via a comprehensive assessment of medical history, reports from family, and neurological and cognitive tests such as the MMSE or MoCA27.
Biomarker advances also offer strong confirmation. Cerebrospinal fluid analysis shows characteristic changes in amyloid and tau22. Amyloid and tau PET scans visualize pathology directly22. Blood biomarkers—especially assays detecting phosphorylated tau—are emerging as non-invasive, scalable tools, which have the potential to transform early detection28.
Structural imaging with MRI or CT further supports diagnosis by ruling out mimicking conditions and revealing atrophy, particularly in the hippocampus region29.
Current treatment approaches
While there is no cure, several approaches aim to relieve symptoms or alter disease course.
Symptomatic treatments focus on neurotransmitter systems. Cholinesterase inhibitors, like Donepezil, Rivastigmine, and Galantamine, boost acetylcholine, and thus provide modest cognitive benefits in mild to moderate disease30. Memantine, an NMDA receptor antagonist, regulates glutamate signaling to support cognition and behavior in more advanced stages30.
More recently, disease-modifying monoclonal antibodies, such as Aducanumab, Lecanemab, and Donanemab, have been approved in some settings31. These drugs clear amyloid and slightly slow decline in early patients. However, their benefits remain limited; and risks, such as amyloid-related brain swelling, require close monitoring.
Non-drug strategies are equally important.
- Regular exercise, cognitive stimulation, and brain-healthy diets are crucial to build resilience32.
- Structured behavioral interventions are important for easing agitation and sleep disruption33.
- Caregiver support is vital, given the heavy emotional and physical toll that comes with prolonged care34.
Challenges in research and treatment
Despite major advances, Alzheimer’s poses a formidable challenge to our healthcare system.
- Complexity of disease: Alzheimer’s stems from multiple interacting mechanisms—amyloid, tau, vascular dysfunction, and inflammation—which makes a single-drug cure unlikely. Studies are increasingly shifting the focus towards combination therapies35. Addressing this complexity requires systems-level strategies like network pharmacology, which uses multi-omics data and computational modeling to analyze the entire disease network and predict synergistic multi-target drug combinations for optimal intervention.
- Delayed diagnosis: Symptoms typically appear after the brain has undergone irreparable changes. To counter this, researchers are developing sensitive blood-based biomarkers and AI-driven risk models to detect the disease in earlier stages36.
- Blood-brain barrier: The barrier excludes most drugs from reaching their targets. Scientists are exploring novel strategies, such as nanoparticles, intranasal delivery, and ultrasound-assisted openings37.
- Disease variability: The rate and pattern of progression vary in each patient. Precision medicine approaches using genetic and biomarker profiles are being developed to personalize treatment38.
- Incomplete biomarkers: Current PET and CSF tests are expensive and invasive. However, global efforts are ongoing to make blood assays affordable to ensure that Alzheimer’s screening is accessible to everyone.
- Clinical trial hurdles: Slow disease progression makes trials long and costly39. Adaptive trial frameworks, biomarker-guided patient selection, and digital monitoring tools are being introduced to improve efficiency.
- Side effects of new drugs: Anti-amyloid antibodies carry risks of swelling and bleeding in the brain40. Adjusted dosing protocols and careful monitoring are being adopted to minimize these risks.
Emerging research and future directions
A number of ongoing research avenues are offering hope. Experimental anti-tau and neuroinflammation-modulating drugs are being tested alongside compounds that enhance synaptic plasticity41. Efforts to improve vascular health and investigate the gut-brain axis are underway which can provide fresh perspectives42, 43.
There has been rapid progress in diagnostics, especially blood biomarkers and artificial intelligence analyses of imaging and genomic data28, 44. This could enable early personalized interventions.
Advances in therapies such as gene editing, CRISPR-based tools, and stem cells are still at an experimental stage, but they nonetheless reflect the overall momentum of this field45, 46.
Researchers are increasingly thinking of future treatments as a combination of drugs that can target several of Alzheimer’s pathological pathways at once35.
Socio-economic impact and caregiver burden
Alzheimer’s disease imposes numerous social and economic strains. Medical costs for care and long-term support are huge, and indirect costs from lost productivity magnify the challenge47. The illness strips away a patient’s autonomy, dignity, and personal identity, while placing an overwhelming toll on caregivers and family, which can result in stress, depression, and financial hardship48. Sustained policy action and community support are therefore equally essential alongside scientific progress49, 50.
Conclusion
Alzheimer’s disease continues to be a debilitating condition of aging, defined by complex pathology and immense human and societal costs. While a cure remains elusive, advances in early detection, disease-modifying therapies, and supportive care are bringing hope. The future lies in integrating scientific innovation with compassionate care, which ensures that progress at the laboratory bench translates to improved ways of life for patients and their families.