What causes Alzheimer's disease?

From the Guidelines

Alzheimer's disease is caused by a complex interplay of genetic, environmental, and lifestyle factors that lead to progressive brain damage, with the primary mechanism involving the abnormal buildup of proteins in and around brain cells, specifically beta-amyloid plaques outside neurons and tau tangles inside neurons, as supported by recent research 1. The disease is characterized by the accumulation of extracellular plaques comprised of abnormal amyloid β (Aβ) proteins, neurofibrillary tangles consisting of abnormally hyperphosphorylated tau protein, and neuronal degeneration in brain regions critical for cognitive function. Key factors that contribute to the development of Alzheimer's disease include:

• Age, with most cases developing after age 65
• Genetic factors, particularly the APOE-e4 gene variant which increases risk
• Cardiovascular health problems, such as high blood pressure, heart disease, and stroke
• Diabetes, obesity, smoking, and head injuries
• Chronic inflammation in the brain and oxidative stress These factors lead to the characteristic brain changes and cognitive decline seen in Alzheimer's, with the disease typically progressing gradually over years, beginning with mild memory problems and eventually affecting all aspects of cognition and daily functioning 1. Recent estimates suggest that approximately 22% of individuals aged 65 and older have mild cognitive impairment (MCI) and up to 10% have dementia, with Alzheimer’s disease being the most common cause of dementia, accounting for approximately 60%–80% of dementia cases 1. The advent of disease-modifying treatments that slow the clinical progression of AD by acting on the underlying pathophysiological mechanisms is expected to trigger a surge in patients seeking a determination of eligibility for these therapies, highlighting the need for biomarker testing to facilitate timely diagnosis of AD 1.

From the Research

Causes of Alzheimer's Disease

The exact cause of Alzheimer's disease is still unclear, but several factors are thought to contribute to its development. These include:

• Genetic factors, such as mutations in the APP, PSEN1, and PSEN2 genes, which can lead to early-onset Alzheimer's disease 2
• Non-genetic factors, such as occupational exposures, pre-existing medical conditions, and lifestyle factors, which can increase the risk of developing Alzheimer's disease 2
• The accumulation of amyloid-beta plaques and neurofibrillary tangles in the brain, which are characteristic hallmarks of the disease 3, 4

Risk Factors

Several risk factors have been identified that can increase the likelihood of developing Alzheimer's disease, including:

• Age, with the risk increasing significantly after the age of 65 2
• Family history, with individuals having a first-degree relative with Alzheimer's disease being at higher risk 2
• Certain medical conditions, such as cerebrovascular disease, hypertension, diabetes, and traumatic brain injury 2
• Lifestyle factors, such as smoking, physical inactivity, and social isolation 2

Pathophysiology

The pathophysiology of Alzheimer's disease is complex and involves multiple pathways, including:

• The accumulation of amyloid-beta plaques, which can lead to neuronal damage and death 3, 4
• The formation of neurofibrillary tangles, which can disrupt normal neuronal function 3, 4
• The activation of inflammatory pathways, which can contribute to neuronal damage and disease progression 3, 4