- M/C type of dementia (⅔ cases of dementia in ≥ 65 years)
- Early onset AD (onset < 65 years) (< 10% cases)
- #6 leading cause of death in the United States.
In 1907, Aloysius “Alöis” Alzheimer carefully described the symptoms of a 51-year-old woman, Auguste Deter, who was under his care at the state asylum in Frankfurt Germany. Alzheimer’s description of her symptoms is almost certainly the first neuropsychological characterization of the disease.
When Auguste Deter died, Alzheimer used the then-new silver staining histological technique to examine her brain microscopically. When he did so, he observed the neuritic plaques, neurofibrillary tangles, and amyloid angiopathy that were to become the hallmarks of the disease that now bears his name. Alzheimer himself did not claim to have discovered “Alzheimer’s disease,” although his mentor Emil Kraepelin at the Munich Medical School rightly credited him with doing so by coining the term in his own Handbook of Psychiatry (Kraepelin, 1910). By 1911, the medical community was using Alzheimer’s depictions of the disease to diagnose patients both in Europe and the United States (Mauer & Mauer, 2003).
Cognitive reserve:Those with higher education levels, a cognitive reserve surrogate, are said to have reduced AD risk. It is heuristically reasoned high cognitive reserve individuals begin their decades-long cognitive decline further from the dementia finish line than low cognitive reserve individuals. Given equal pre-MCI cognitive decline trajectories, low cognitive reserve individuals will cross dementia thresholds before high cognitive reserve individuals.
APOE-4 gene:Disproportionately represented among patients with both late-onset and early-onset AD and that the APOE-4 allele shows a dose-dependent relationship with increasing risk for AD and decreasing age at onset.
Early-onset AD:Identified in patients with familial early-onset autosomal dominant AD, but these mutations are extremely rare, accounting < 1% of cases. All these genes appear to increase the cellular production of Aβ42 by selectively increasing the cleavage of APP by β- or γ-secretase.
- Amyloid precursor protein (APP) (chromosome 21)
- Presenilin-1 [PS 1] (chromosome 14) (M/C, 40-70% early-onset AD cases)
- Prescnilin-2 [PS 2] (chromosome 1)
Neuritic plaques and neurofibrillary tangles represent the pathological hallmarks of AD, and are respectively related to the accumulation of the amyloid-beta peptide (Aβ) in brain tissues, and to cytoskeletal changes that arise from the hyperphosphorylation of microtubule-associated Tau protein in neurons.
Senile neuritic plaquesDevelop first in brain areas associated with cognition, and spread to other cortical areas as the disease progresses.
- Amyloid p-peptide (Aβ): Overproduction of Aβ is a consequence of the disruption of homeostatic processes that regulate the proteolytic cleavage of the amyloid precursor protein (APP). Aβ seems toxic to the neuron either directly, or indirectly by causing inflammation or increasing the production of free radicals.
- Aβ42 (longer species): Deposited initially and initiate amyloid deposition
- Aβ40 (shorter species)
Neurofibrillary tangles in neurons:Accumulation in neurons, neurofibrillary tangles are formed by chemically altered (abnormally folded and phosphorylaled) tau protein (protein involved in microtubule formation).
Tangle formation is related to the severity of disease; the more advanced the stage of disease, the more tau tangles in the brain.
Brain tissue degeneration:
- Nucleus basalis of Meynert (nbM): Basal forebrain structure housing brain’s largest collection of cholinergic neurons. In AD the nbM suffers severe neuron loss and decreased production of acetylcholine, a neurotransmitter with an important role in learning and memory.
- Granulovacuolar degeneration: Found within cytoplasm of neurons of the hippocampus. An abnormally high number of fluid-filled spaces, called vacuoles, enlarge the cell’s body causing neuronal dysfunction or cell death.
Clinical manifestations of AD include disturbances in the areas of memory and language, visuospatial orientation, and higher executive function. Noncognitive changes include personality changes, decreased judgment ability, wandering, psychosis, mood disturbance, agitation, and sleep abnormalities.
Pre-symptomatic (or pre-clinical) AD:May last for several years or decades until the overproduction and accumulation of Aβ in the brain reaches a critical level that triggers the amyloid cascade
Pre-dementia phase of AD: Progressive, amnestic mild cognitive impairmentEarly-stage pathology is present, ranging from mild neuronal dystrophy to early-stage Braak pathology, and may last for several years according to individual resilience and brain reserve
Clinically defined dementia phase of AD:Cognitive and functional impairment is severe enough to surmount the dementia threshold; at this stage there is significant accumulation of neuritic plaques and neurofibrillary tangles in affected brain areas, bearing relationship with the magnitude of global impairment.
- Dementia: Clinical syndrome characterized by progressive decline in two or more cognitive domains, including memory, language, executive and visuospatial function, personality, and behavior, which causes loss of abilities to perform instrumental and/or basic activities of daily living.
The diagnosis of AD is made by clinical history, documentation of functional decline, and ruling out other potential etiologies of cognitive decline.
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5):
- Major neurocognitive impairment: Objective cognitive decline that is severe enough to interfere with activities of daily living and is not caused by delirium or another neurologic, medical, or psychiatric disorder.
- Mild neurocognitive impairment: Milder cognitive decline that does not yet deprive them of the ability to lead an independent lifestyle and perform complex daily activities such as managing finances or driving a car.
NIA-AA criteria for dementia:Developed by the National Institute on Aging (NIA) and the Alzheimer’s Association (AA) spanning all three major stages of AD (ie, the preclinical, the prodromal, and the overt dementia stages)
- Single Photon Emission Computed Tomography (SPECT): 99mTc hexamethyl-propylene-aminoxime (HMPAO) SPECT
- Decreased blood flow in parietal, emporal and posterior cingulate cortex
- Positron Emission Tomography (PET): 18-fluorodeoxyglucose (18FDG) PET
Differential diagnosis:Other types of dementia (mixed, vascular dementia, Lewy body dementia, frontotemporal dementia, normal pressure hydrocephalus, HIV, and other rare forms of dementia), delirium, and, less frequently, seizure disorders.
- Frontotemporal dementia (FTD): Early marked behavioral disinhibition or apathy; early perseverative or compulsive behavior; hyperorality and dietary changes; executive function deficits but sparing of memory and visuospatial functions; prominent early aphasia (particularly loss of word and object knowledge, motor speech, and grammatical deficits).
- Dementia with Lewy bodies (DLB): Fluctuating cognition; recurrent visual hallucinations, typically well-formed and detailed; spontaneous features of parkinsonism; REM sleep behavior disorder; severe neuroleptic sensitivity; deficits on tests of attention, executive function, visuospatial ability.
- Vascular dementia (VD): Onset of dementia within 3 months of recognized stroke; abrupt deterioration in cognitive function; fluctuating, stepwise progression of cognitive deficits; early presence of gait disturbance; early urinary symptoms not due to urologic disease; pseudobulbar palsy (dysphagia, dysarthria, emotional lability, inappropriate laughter or crying); depression, emotional incontinence, psychomotor retardation and abnormal executive function. (Note: Sudden onset of aphasia suggests a vascular etiology.)
- Idiopathic normal pressure hydrocephalus (NPH): Urinary incontinence not due to urologic conditions (e.g., prostatism or chronic UTI); “glue-footed,” “magnetic” gait.
There is no cure for Alzheimer’s disease. Only symptomatic treatment is available.
Psychosocial treatment:These measures can improve functioning of AD patients. In attempting to maintain patients with AD in their homes for as long as possible, some adjustment of a patient’s environment is important.
- Environmental manipulation
- Family support
- Prevention of other medical comorbidities
Cholinesterase inhibitors: Treatment of choice for cognitive disturbanceUse is based on the cholinergic deficiency observed in the disease. There is an increase in the acetylcholine concentration available for synaptic transmission by inhibiting enzymes responsible for its hydrolysis (ie, acetylcholinesterase).
- Donepezil, tacrine, galantamine, rivastigmine
Estrogen replacement therapy: Treatment of cognitive disturbanceExert effect in brain by enhancing transcription and mediation of nongenomic events. It has been suggested that the abrupt decline of estrogen production in postmenopausal women increases the risk for these women developing AD; men, in contrast, have an intrinsic supply of estrogen by aromatizing testosterone in the brain.
Anti-inflammatory agents: Treatment of cognitive disturbanceHelp in modulating the course of the disease.
- Nonsteroidal anti-inflammatory drugs (NSAIDS): Indomethacin, ibuprofen, diclofenac, naproxen
- Steroids: Low-dose prednisone
- Other anti-inflammatory agents: Hydroxychloroquine, colchicine
Antioxidant agents: Treatment of cognitive disturbanceIncrease in free-radical formation may occur in AD and have a direct toxic effect. The brain may be vulnerable to the damaging effects of oxidative stress because of an abundance of catecholamines and a relatively low concentration of antioxidative enzymes (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase). Furthermore, Aβ has been implicated in increased free-radical formation.
- Vitamin E
Antidepressant therapy: Treatment of behavioral disturbanceDepression in patients with AD should be treated aggressively, with careful monitoring of cognitive function. Sufficient dosage and duration of treatment arc needed for clinical response in depressed patients without dementia. The depressed elderly may take up to 6 weeks to respond to antidepressant medication and patients with AD should be expected to take as long.
- Reversible MAO inhibitors: Brofaromine and moclobemide
- Tricyclic antidepressants (TCAs): Nortriptyline and desipramine (only these 2 TCAs, since they have fewer anticholinergic properties than their parent compounds amitriptylinc and imipramine)
- Newer antidepressants: Fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, nefazodone, bupropion, mirtazapine, and venlafaxine