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Alzheimer Disease and Dementia: New Insights

For the nearly 900 million older individuals worldwide, there has been an epidemiologic transition linking chronic illness in older age to increased dietary fat, salt and sugar diets, sedentariness, and tobacco use. This in combination with the transition toward urbanization and its profound demographic impact on traditional societies has been a recipe for epidemic rates of dementia we now observe. 

The incidence of dementia notably Alzheimer disease (AD) has been increasing worldwide due to increasing prevalence of obesity, diabetes, and cardiovascular disease especially in less well-developed nations aspiring to Western life styles. At the same time, there has been an age-specific decrease in AD due to improvements in management of chronic illness of varying types in rich nations despite longer life expectancy.  There are an estimated 46.8 million people with dementia worldwide, with numbers projected to double every two decades, leading to 9.9 million new cases or one every 3.2 seconds. The global societal economic cost of dementia has been estimated at $818 billion, with staggering quality of life (QoL) impacts both for individuals living with dementia, and their families and caregivers. 

The National Institute on Aging and the Alzheimer Association (NIA-AA) recognizes 3 stages: Preclinical AD or pre-symptomatic, due to the presence of early brain changes detected by neuroimaging or traditional biomarker studies; Mild cognitive impairment in which individuals can maintain the activities of daily living (ADL) despite cognitive impairment; and frank AD typified by pronounced cognitive impairment that interferes with ADL.  The long pre-clinical phase or latent phase of AD is probably due to the insidiously slow progression of neuronal loss, the formation of neurofibrillary tangles (NFT) and amyloid plaque deposition in the brain.  The prevailing hypothesis is that neurodegeneration in AD is the result of the cascade of aberrant digestion and processing of amyloid precursor protein (APP) resulting in the accumulation of neurotoxic Aβ proteins that aggregate to form insoluble amyloid plaques seen microscopically at postmortem examination in the brains of affected individuals. 

Future therapy in AD especially in the preclinical stages, where an impact could preserve existing functioning neural network, has been the rationale for the widespread implementation of disease biomarkers that can be targeted to high risk individuals at specific age groups. Such biomarkers include high levels of cerebrospinal fluid Aβ42 and tau levels, increased amyloid tracer and tau uptake on brain positron emission tomography, and incipient brain atrophy on brain magnetic resonance imaging. 

Differential Diagnosis
It is important to establish the exact cause of dementia in clinically apparent or suspected patients. Atypical presentations may be a clue to the presence of an alternative diagnosis such as Lewy body disease, Parkinson disease, frontotemporal lobe dementia, multiple cerebral infarctions, neuroacanthocytosis, Wilson disease, adult ceroid lipofuscinosis, Huntington disease, Creutzfeldt-Jakob disease, and the two infectious illnesses, Whipple and Lyme disease.      

Treatment is directed at the cognitive symptoms and the psychiatric disturbances. Therapy of the cognitive disorder includes the use of cholinesterase inhibitors early stages of the condition which can be continued well into the disease as long as they are tolerated, although data regarding efficacy of these agents after the first 2 to 3 years is inconsistent.  NMDA receptor medications have the capacity to reduce glutamate-mediated neurotoxicity of vulnerable neurons in moderate to severe AD. Patients treated with a combination of a cholinesterase inhibitor and an NMDA receptor fared better than those given either drug alone. Antipsychotic medication may be effective in treating psychotic symptoms and agitation with few side effects, while a serotonin reuptake agent may be efficacious in treating associated depression.