Alzheimer's Disease

Alzheimer's disease is a chronic neurodegenerative disease characterized by progressive cognitive decline and distinct neuropathological features, with no definitive cure currently available. ^[1] It is the most common type of dementia and typically manifests through a progressive loss of episodic memory and cognitive function, often accompanied by behavioral disorders such as apathy, aggressiveness, and depression. ^[2] It is a chronic illness with long preclinical and prodromal phases and an average clinical duration of 8 to 10 years, and most patients have the sporadic, late-onset form. ^[3]

The presence of extracellular plaques of insoluble beta-amyloid peptide and neurofibrillary tangles containing hyperphosphorylated tau protein in the neuronal cytoplasm is a remarkable pathophysiological feature in patients' brains. ^[2] The amyloid hypothesis holds that the disease is caused by the accumulation of amyloid beta protein in the brain, leading to neuronal toxicity, and the sporadic form is considered a consequence of the failure to clear the amyloid-beta peptide from the brain. ^{[4] [3]} Accumulating evidence highlights mitochondrial dysfunction, together with oxidative stress and disturbances in energy metabolism, as a central factor in disease pathogenesis. ^[1] The APOE ε4 allele remains the strongest genetic risk factor for sporadic Alzheimer's disease, with apoE4 seeding amyloid-β aggregation and impairing its clearance in the brain ^[5].

Alzheimer's disease is the leading cause of dementia, accounting for 50 to 70% of cases, and its global prevalence is expected to continue to rise as populations age. ^[6] The disease has an estimated prevalence of 10 to 30% in the population older than 65 years of age with an incidence of 1 to 3%. ^[3] Accumulation of amyloid-beta can now be detected in preclinical and prodromal phases using cerebrospinal fluid biomarkers and PET imaging. ^[3]

Approximately 70% of the risk of developing Alzheimer's disease can be attributed to genetics, but acquired factors such as cerebrovascular disease, diabetes, hypertension, obesity, and dyslipidemia increase the risk. ^[2] Around a third of dementia cases are attributable to modifiable risk factors such as physical inactivity, smoking, and hypertension, and exercise has emerged as a key intervention for positively influencing cognition. ^[7] Several approved drugs ameliorate some symptoms of the disease, but no current interventions can modify the underlying disease mechanisms. ^[3]