The more typical "late onset" cases of AD occurring after age 60 may have underlying genetic defects. A genetic locus on chromosome 19 encodes for a cholesterol transporter called apolipoprotein E (apoE). The E4 variant of apoE, which increases deposition of fibrillar beta-amyloid, can be found in 40% of AD cases. However, the presence of apoE4 is neither necessary nor sufficient for development of AD, so testing for it is not warranted. A genetic locus on chromosome 12 that encodes for alpha-2-macroglobulin may be found in 30% of AD cases. Mutations in the tau gene which codes for tau, a protein that is associated with microtubules, can be found in some AD cases. The abnormal tau may account for helical filaments found in neurofibrillary tangles.
Regardless of the cause, the diagnosis of AD is made clinically by the finding of progressive memory loss with increasing inability to participate in activities of daily living. Late in the course of the disease, affected persons are not able to recognize family members and may not know who they are. The definitive diagnosis is made pathologically by examination of the brain at autopsy. Grossly, there is cerebral atrophy, mainly in frontal, temporal, and parietal regions. As a consequence, there is ex vacuo ventricular dilation.
The confirmation of a diagnosis of AD is made at autopsy. The pathognomonic microscopic feature of AD is an increased number of neuritic plaques in the cerebral cortex. These neuritic plaques are composed of tortuous neuritic processes surrounding a central amyloid core. Reactive astrocytes and microglia may appear at the periphery of these plaques. Though plaques may easily be found in the hippocampus, their presence in increased numbers in neocortex is necessary for a diagnosis of AD. The amyloid core consists primarily of a small peptide known as Aß which is derived from the larger amyloid precursor protein (APP). Plaques that have the amyloid proteins but lack the neuritic processes are known as diffuse plaques, which do not count toward the diagnosis of AD. Since the number of plaques increases with age, the number needed for diagnosis of AD is age-dependent. Other histologic features of AD include neurofibrillary tangles, amyloid angiopathy, and granolovacuolar degeneration.
Biochemical evidence points to a loss of the choline acetyltransferase and acetylcholine in the cerebral cortex of patients with Alzheimer's disease. However, the significance of this finding is not clear. There is loss of higher brain functions with AD leading to profound dementia. The course is usually over 5 to 7 years. The immediate cause of death for most persons with Alzheimer's disease is pneumonia, typically an aspiration pneumonia.
Alzheimer's disease, neurofibrillary tangle. The neurons demonstrate intracytoplasmic proliferation of twisted filaments producing the visible "neurofibrillary tangle" under the microscope. These are commonly found in the pyramidal cells of the Hippocampus and the cerebral cortex. H and E stain, microscopic.
