Alzheimer’s Disease
DIAGNOSTIC SUMMARY
• Progressive mental deterioration, loss of memory and cognitive functions, inability to carry out activities of daily life
• Characteristic symmetrical, usually diffuse, EEG pattern
• Diagnosis usually made by exclusion
• Definitive diagnosis can be made only by postmortem biopsy of brain, demonstrating atrophy, senile plaques, and neurofibrillary tangles
GENERAL CONSIDERATIONS
Alzheimer’s disease (AD) is a neurodegenerative disorder of progressive deterioration of memory and cognition or dementia. Five percent of U.S. population older than 65 have severe dementia; another 10% have mild to moderate dementia. Frequency rises with increasing age: 50%-60% of all cases of dementia (senile and presenile) are caused by AD. “The disease of the twentieth century”: tenfold increase in AD in U.S. population older than age 65.
Neuropathology
Distinctive neuropathologic features: plaque formation, amyloid deposition, neurofibrillary tangles, granulovascular degeneration, massive loss of telencephalic neurons; particularly evident in cerebral cortex and hippocampal formation. Clinical features are believed to arise from cholinergic dysfunction by reduced activity of enzyme choline acetyltransferase (which synthesizes acetylcholine) and neuronal transfer of choline.
Etiology
Genetic factors play a major role: amyloid precursor gene on chromosome 21 (close association between Down’s syndrome and AD); presenilin genes on 14 and 1; apolipoprotein E (ApoE) gene on 19; mutations on 21, 14, and 1;—rare and associated with symptoms before age 50. The most significant genetic finding is the link with ApoE; ApoE of e4-type is linked to much greater risk; e2-type is linked to greater protection.
Genetically linked aberrant immune system regulation of inflammation may contribute. Innate immune function in brain normally removes plaque. Long-term excessive reaction to immune protofibrils of amyloid proteins can promote AD. Immunotherapeutic trials resulted in both beneficial and adverse effects. Antioxidants protect against untoward immune processes; consider natural antiinflammatories used for cardiovascular disease.
• Lifestyle factors: diet—excess saturated or trans fatty acids may predispose neurons to aluminum-induced toxicity. Sleep—abnormal sleep-wake cycles and decreased morning light exposure (see melatonin, later).
• Other factors: traumatic head injury; long-term exposure to aluminum, silicon, environmental neurotoxins, and free radicals; increased oxidative damage.
• Homocysteine: increased plasma (and perhaps urine) homocysteine is a strong, independent risk factor for dementia and AD, just as it is for atherosclerosis. Plasma level greater than 14 μmol/L nearly doubles risk of AD. Control homocysteine with folate and vitamins B12, B6, and C.
• Aluminum (AL): concentrated in neurofibrillary tangles and significantly contributes to AD; strong affinity for and cofactor with paired helical filament tau (PHFt) involved in forming neurofibrillary tangles. AL selectively binds to PHFt, induces PHFt aggregation, and retards brain’s ability to break down PHFt. Long-term exposure of animals to ecologic doses of AL induces ghostlike neurons with cytoplasmic and nuclear vacuolations, with AL deposits; neuritic plaques in hippocampus; amyloid deposits in cerebrovasculature; behavorial changes reminiscent of AD. Brain and serum AL levels increase with age as AD incidence increases with age. Patients with AD have much higher AL than normal people and patients with other dementias (ETOH, atherosclerosis, stroke). Efforts to remove AL help but probably are too late, after disease is well established. Even in those without mental disease, elevated AL is linked with poorer mental function. Sources of AL are water supply (immediately enters brain tissue), food, antacids, anti-perspirants.
DIAGNOSTIC CONSIDERATIONS
Only 50% of patients with dementia have AD; comprehensive diagnostic workup paramount. Diagnosis depends on clinical judgment. Workup: detailed history; neurologic and physical exam; psychological evaluation with particular attention to depression; general medical evaluation revealing subtle metabolic, toxic, or cardiopulmonary disorders inducing confusion in elderly; neurophysiology tests to document the type and severity of cognitive impairment; social worker mobilization of community resources; lab tests (ECG, EEG, CT scan, MRI).
• Diagnostic process: exclude other possible diagnoses.
— Step 1: diagnose dementia accurately. (10%-50% error rate when diagnosis is based only on first evaluation. Avoid misdiagnosing pseudodementing functional illness. Depression mimics dementia in the elderly.
Causes and Mechanisms of Development of Senile Dementia
| Etiology | Pathogenesis |
| Degenerative Etiology | Disturbances of gene expression and thus of protein metabolism |
| Altered genetic code | Disturbance of the synthesis of specific proteins |
| Alzheimer’s disease | Reduction in acetylcholine synthesis resulting from decreased ChAc activity |
| Huntington’s chorea | Disturbance of the GABAergic system |
| Idiopathic dementia, localized form | Decline in cognitive function |
| Parkinson’s disease | Reduction in dopamine turnover |
| Pick’s disease | Reduction in cholinergic activity |
| Loss of neuronal redundancy | Disturbance of cerebral metabolism after infection or trauma; reduction in cholinergic activity caused by loss of neurons and synapses |
| Cerebrovascular disease | |
| Chronic meningitis | |
| Tuberculosis, mycotic | |
| Encephalopathy after head injury (boxers) | |
| Viral encephalopathy | |
| Encephalomyelitis | |
| Epileptic dementia |
| Etiology | Pathogenesis |
| Nutritive Etiology | |
| Chronic alcoholism | |
| Diabetes mellitus | |
| Disturbances of electrolyte metabolism | |
| Hypoglycemia | Insulin, starvation |
| Hyponatremia | Diuretics |
| Hypothyroidism | |
| Korsakoff syndrome | Thiamine transketolase deficiency |
| Nicotinamide deficiency | |
| Vitamin B deficiency | Disturbances of energy formation |
| Toxic Etiology | |
| Addiction to barbituates, psychotropic drugs, etc. | |
| Chronic CO intoxication | |
| Chronic CO2 intoxication | |
| Mycotoxins | |
| Renal/hepatic encephalopathy | |
| Vincristine intoxication |
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