Brain Amyloid Levels Mirror Dementia Severity in Alzheimer’s Disease

abstract & commentary

Source: Naslund J, et al. Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline. JAMA 2000;283:1571-1577.

A plethora of evidence from genetic, biochemical, and physiologic studies suggests that amyloid beta protein (a b accumulation is among the earliest steps in a cascade of events that leads to the pathogenesis of Alzheimer’s disease [AD]). Nevertheless, several past investigations have failed to find a correlation between amyloid burden in the brain and the severity of dementia in AD. Instead, neurofibrillary tangles and neuronal/synaptic loss have been found to correlate more closely with the degree of cognitive impairment. This issue is potentially important to future treatment strategies. If amyloid accumulation is relevant only to the preclinical stages of the illness, anti-amyloid therapy is less likely to be valuable in treating patients already suffering from dementia. Naslund and colleagues, however, provide evidence that brain amyloid levels are already elevated prior to the clinical onset of AD and continue to rise in direct correlation with the severity of dementia.

This study examined the autopsied brains of 79 nursing home residents whose cognitive and behavioral status was evaluated during the last six months of life using the Clinical Dementia Rating (CDR) scale. The cohort included 16 cognitively normal individuals (CDR = 0), 11 with questionable dementia (CDR = 0.5) and comparable numbers of cases with mild (CDR = 1), moderate (CDR = 2), and severe dementia (CDR = 4 or 5). All subjects with dementia had definite AD by formal neuropathological criteria. The levels of Ab peptides ending at the 40th or 42nd amino acid position were assayed using a sensitive ELISA technique in tissue homogenates derived from five cortical regions. Immunostaining for the tau protein in frontal cortex was also performed, and the correlation between tau pathology and amyloid burden was examined as a function of CDR stage.

Levels of both the 40 and 42 species of Ab were found to be elevated at early stages of dementia in the five brain areas examined. Ab peptide levels increased with progression to higher CDR stages, indicating that the intracerebral amyloid burden increases with progression of cognitive decline. In frontal cortex, increased Ab levels preceded the appearance of abnormal tau staining in neurons, consistent with amyloid accumulation being one of the initial events in development and subsequent propagation of AD neuropathology throughout the brain.

Commentary

Several past studies that failed to find a correlation between regional amyloid plaque density and the severity of AD-related dementia used conventional histologic immunohistochemical techniques. The Naslund study used well-characterized, highly specific antibodies against the major Ab species, and assayed both soluble and fibrillar forms of Ab in multiple brain regions. Another advantage to the current investigation was the availability of brain tissue from a sizable number of early-stage dementia patients and mildly impaired individuals considered at increased risk for AD. Shortcomings include the absence of immunohistochemical studies of the amyloid pathology (i.e., stereologic plaque counts) and the correlative nature of the analyses performed. Nevertheless, the study provides strong additional evidence in favor of the amyloid hypothesis and suggests that Ab is important to the progression of AD as well as its initiation. Work is ongoing to develop and test anti-amyloid therapies for AD. The demonstration that levels of Ab in the brain are elevated in preclinical stages of dementia and continue to rise in association with disease progression provides an important rationale for vigorously pursuing this promising line of therapy. —nrr

Amyloid levels in the brain:

a. rise before the onset of Alzheimer’s, then plateau thereafter.

b. do not rise until late in Alzheimer’s disease.

c. are normal at the onset of Alzheimer’s, then decline.

d. rise before the onset and throughout the course of AD.