Another polymorphism, located in TREM2, is quite rare in comparison to the aforementioned Apo E variants but confers an equivalent risk of Alzheimer disease that has been shown in several populations in (Guerreiro et al and Jonsson et al). In sporadic Alzheimer disease, the TREM2 polymorphism that is implicated in Alzheimer disease putatively causes inadequate phagocytic clearance of amyloid. Another rare modifying gene has been found in familial cases at the UBQLN1 (ubiquilin 1) site, coding for a protein that interacts with PS1 and PS2 and participates in proteasomal degradation.
Studies with CT and MRI are useful, but not definitive ancillary tests (Fig. 38-3). In patients with advanced Alzheimer disease, the lateral and third ventricles are enlarged to about twice the normal size and the cerebral sulci are proportionately widened, both as a result of cerebral atrophy. Coronal MRI of the medial temporal lobes shows a disproportionate atrophy of the hippocampi and a corresponding enlargement of the temporal horns of the lateral ventricles. Early in the disease, however, the changes do not exceed those found in many mentally intact old persons. For this reason, one cannot rely solely on imaging procedures for diagnosis and CT and MRI are most valuable in excluding alternative causes of dementia such as brain tumor, subdural hematoma, cerebral infarction, and hydrocephalus. The EEG undergoes mild diffuse slowing, but only late in the course of the illness; it is useful again, in the exclusion of alternative causes of mental decline that manifest themselves in seizure activity or changes typical of metabolic encephalopathy. The CSF is also normal, although occasionally the total protein concentration is slightly elevated. Using the constellation of clinical data, cerebral imaging in the context of the age of the patient and time course of the disease, the diagnosis of dementia of Alzheimer type is made correctly in 85 to 90 percent of cases.
Of some value have been studies of cerebral blood flow (single-photon emission computed tomography [SPECT]) and metabolism (positron emission tomography [PET]), which early in the illness often, but not always, show diminished activity in the parietal association regions of the cortex and in the medial temporal lobes. In most cases, when such changes are evident, the diagnosis was already obvious on clinical grounds. Newer PET ligand agents that bind to amyloid, such as “Pittsburgh compound” and tau-ligands are more sensitive in identifying and observing the course of Alzheimer disease. Their main utility may be in detecting changes before brain atrophy is evident and in identifying patients who have the earliest changes of Alzheimer disease, whose disease course may be amenable to alteration by medications. They are currently used as biomarkers in therapeutic trials of various agents that reduce or remove brain amyloid.
Neuropsychologic tests in the typical case show disproportionate deterioration in memory and verbal access skills. Testing is particularly useful when there is a serial decline in ability. Certain aspects of attention and executive function in Alzheimer disease that also show changes in Alzheimer disease were reviewed by Perry and Hodges. The use of these examinations is described in Chap. 20.
Beyond PET and related imaging studies there are no established biologic markers of Alzheimer disease with the possible exception of the ratio of tau to Aβ 42 (tau-amyloid ratio) in the cerebrospinal fluid (the ratio is low in Alzheimer disease). This test is used in some clinics and in clinical trials (Maddalena et al). Schoonenboom and colleagues have shown that the incorporation of CSF phosphorylated tau (p-tau) with the typical CSF amyloid/tau ratio may provide additional specificity in distinguishing Alzheimer from other dementing diseases.
Differential Diagnosis of Alzheimer Disease (See Also Table 20-3)