medwireNews: A study shows that about a quarter of people with clinically diagnosed mild or moderate Alzheimer’s disease (AD) have only minimal β-amyloid (Aβ) deposition on autopsy.
And nearly half of patients without significant Aβ deposition had marked tauopathy (neurofibrillary degeneration rated Braak stages III to VI), the researchers report in JAMA Neurology, making a “nonamyloidogenic variant resembling the clinical phenotype of AD… more common than previously expected”.
The prevalence of minimal Aβ deposition on autopsy was especially high in patients without the APOE4 genotype, found in 37 of these 100 patients. Significant neurofibrillary degeneration affected almost all patients who did have Aβ deposition, at 95.2%, but was also present in 43.2% of those with minimal Aβ levels.
Only 13 of the 100 APOE4 carriers studied had minimal Aβ levels, but six (46.2%) of these patients had significant neurofibrillary degeneration, as did 93.1% of those with Aβ deposition.
However, the team found that isolated tauopathy was unlikely to fully account for the clinical dementia in patients with minimal Aβ deposition. Among patients with severe dementia at their last evaluation, only about a third of those with minimal Aβ levels had significant tauopathy, consistent with the reported prevalence among cognitively normal people at death.
This suggests “that moderate to severe tauopathy may not be related to dementia but may simply be a manifestation of healthy aging”, say Eric Reiman (University of Arizona, Phoenix, USA) and study co-authors.
Among the 20 patients without the APOE4 genotype who had only minimal Aβ levels, 75% were given a primary neuropathological diagnosis that was not AD, including Lewy body disease, vascular disease and hippocampal sclerosis. Two patients had AD changes that did not fully account for their clinical symptoms and three had no neuropathological findings that explained their dementia.
The researchers note that, regardless of the drivers of dementia in patients with minimal Aβ deposition, Aβ-modifying treatments currently in development “seem unlikely to benefit participants in this situation, even if such treatments are shown to be effective in Aβ-positive individuals.”
They add: “Development of new treatment strategies will be required to accommodate this pathologic heterogeneity within the clinical diagnosis of mild to moderate AD dementia.”
In an accompanying editorial, Stephen Salloway (Alpert Medical School of Brown University, Providence, Rhode Island, USA) and Reisa Sperling (Brigham and Women’s Hospital, Boston, Massachusetts, USA) say that these and other findings “provide a strong rationale” for using imaging-based amyloid biomarkers in clinical trials of amyloid-targeted treatments.
In the clinic, they suggest that “[g]iven that APOE4 carrier status is a strong predictor of amyloid and AD pathology, it may be prudent to consider a hierarchical approach to amyloid biomarkers based on APOE genotyping.”
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