Epidemiology, pathology, and pathogenesis of Alzheimer disease
Hallmark neuropathologic features
Neuropathologic changes of Alzheimer disease (AD) include neuritic plaques, extracellular deposits of amyloid beta, and neurofibrillary degeneration.
Pathogenesis
While the pathogenesis of AD remains unclear, all forms of AD appear to share overproduction and/or decreased clearance of a family of proteins known as amyloid beta peptides. The pathogenesis of AD also involves tau, a microtubule-associated protein that aids in microtubule assembly.
Case definition
A definitive diagnosis of AD requires histopathologic examination. Clinical criteria for the diagnosis of AD have evolved over time, and the ability to accurately diagnose AD has improved with the development of techniques for in vivo measurement of pathophysiologic features of AD. The diagnosis of AD requires a decline in both cognition, especially memory, and function, as well as specific neuropathology.
Presymptomatic disease
There is a long presymptomatic period between the onset of biochemical changes in the brain and the development of clinical symptoms of AD, suggesting that long-term epidemiologic studies beginning at an early age are needed to properly study the gene-lifestyle environmental determinants of amyloid vascular disease and neurodegeneration.
Epidemiology and risk factors
AD is increasingly prevalent with advancing age, and the overall burden of AD is substantial worldwide. It has been estimated that the global prevalence of dementia will rise to >100 million by 2050.
•Advanced age
The age-standardized prevalence of dementia ranges from 5 to 7 percent in most regions of the world.
•Genetic factors
Aside from age, the most clearly established risk factors for AD are a family history of dementia, rare dominantly inherited mutations in genes that impact amyloid in the brain, and the apolipoprotein E (APOE) epsilon 4 (e4) allele.
•Vascular risk factors
Risk factors for vascular disease, including hypertension, obesity, and diabetes, increase the risk of dementia and may impact AD, particularly when they are present in midlife. The pathogenic mechanisms linking various cardiometabolic factors and AD are not well understood, and both vascular and nonvascular mechanisms may be involved.
Brain cholesterol metabolism may be an important determinant of AD. The relationship between diet, genetics, blood lipoproteins levels, and AD is complex and inconsistent.
Cerebrovascular disease and AD frequently coexist. Hypertension is the primary risk factor for vascular brain injury. Cerebrovascular disease is associated with worse cognitive performance in patients with AD, and clinicopathologic studies suggest that cerebrovascular disease lowers the threshold for clinical dementia in patients with a neuropathologic diagnosis of AD.
•Lifestyle risk factors
Accumulating data suggest that social, cognitive, and physical activities are inversely associated with the risk of AD and other forms of dementia, and there is considerable interest in their potential as preventive strategies.
