Neurology · Dementia
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Alzheimer disease is the most common cause of dementia, characterized by an insidious onset and gradual, progressive decline in memory and cognitive function.
The earliest and most prominent clinical feature is short-term memory impairment due to early involvement of the hippocampus and entorhinal cortex.
Pathologically, the disease is defined by the accumulation of extracellular amyloid-beta plaques and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein.
Genetic risk is significantly increased by the APOE-ε4 allele, while early-onset familial cases are associated with mutations in APP, PSEN1, or PSEN2 genes.
Neuroimaging typically reveals diffuse cortical atrophy with ventriculomegaly and widening of the sulci (hydrocephalus ex vacuo).
First-line pharmacologic treatment for symptomatic management involves cholinesterase inhibitors (e.g., donepezil, rivastigmine, galantamine) to increase synaptic acetylcholine levels.
For moderate to severe disease, the NMDA receptor antagonist memantine is added to modulate glutamate excitotoxicity.
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A 78-year-old male is brought to the clinic by his daughter, who reports that he has become increasingly forgetful over the past three years. He frequently misplaces his keys, struggles to recall recent conversations, and recently got lost while driving in his own neighborhood. His physical examination is unremarkable, and he scores 22/30 on the Mini-Mental State Examination (MMSE), showing deficits in delayed recall and orientation. Laboratory workup, including TSH and B12 levels, is within normal limits. MRI of the brain demonstrates hippocampal atrophy and enlarged ventricles.
What is the most likely diagnosis?
Alzheimer disease
The patient's presentation of insidious, progressive memory loss combined with hippocampal atrophy on MRI is classic for Alzheimer disease, which is the most common cause of dementia in the elderly.
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Etiology / Epidemiology
Most common cause of dementia; advanced age and family history are primary risk factors.
Clinical Manifestations
Progressive short-term memory loss is the hallmark; aphasia and apraxia develop later.
Diagnosis
Clinical diagnosis supported by Mini-Mental State Exam (MMSE) or MoCA; definitive diagnosis is post-mortem (autopsy) histopathology.
Treatment
Donepezil is first-line; avoid anticholinergics which worsen cognitive decline.
Prognosis
Average survival is 8-10 years post-diagnosis; death usually results from aspiration pneumonia.
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Epidemiology & Etiology
Alzheimer disease is the leading cause of dementia in patients >65 years old. Major genetic risk factors include the APOE-e4 allele. Incidence doubles every 5 years after age 65.
Pertinent Anatomy
Early atrophy involves the hippocampus and entorhinal cortex, explaining the classic deficit in short-term memory. Later stages show diffuse cerebral cortical atrophy and ventricular enlargement.
Pathophysiology
Extracellular amyloid plaques (beta-amyloid) and intracellular neurofibrillary tangles (tau protein) lead to synaptic loss. A profound cholinergic deficit is the primary neurochemical hallmark driving cognitive impairment.
Clinical Manifestations
Patients present with insidious short-term memory impairment followed by executive dysfunction. Look for aphasia, agnosia, and apraxia as the disease progresses. Red flags include rapid onset or focal neurologic deficits, which suggest vascular or secondary causes.
Diagnosis
Diagnosis is clinical, utilizing the Mini-Mental State Exam (MMSE) or MoCA to quantify cognitive decline. MRI brain is used to rule out reversible causes like normal pressure hydrocephalus or tumors. Definitive diagnosis requires post-mortem (autopsy) histopathologic examination showing plaques and tangles.
Treatment
Donepezil (an acetylcholinesterase inhibitor) is the first-line treatment for mild-to-moderate disease. Memantine is added for moderate-to-severe cases to antagonize NMDA receptors. Avoid anticholinergics (e.g., diphenhydramine) as they exacerbate cognitive impairment.
Prognosis
The disease is progressive and irreversible with a mean survival of 8-10 years. Aspiration pneumonia and secondary infections are the most common causes of mortality. Regular monitoring of functional status is required.
Differential Diagnosis
Vascular dementia: stepwise decline with focal neurologic deficits
Lewy body dementia: visual hallucinations and parkinsonism
Frontotemporal dementia: personality changes and disinhibition
Normal pressure hydrocephalus: wet, wobbly, and wacky triad
Depression (pseudodementia): patient expresses distress over memory loss