Comparison of symptomatic and asymptomatic persons with Alzheimer disease neuropathology

We sought to identify demographic and clinical features that were associated with expression of symptoms in the presence of Alzheimer disease (AD) neuropathologic changes.

We studied 82 asymptomatic (Clinical Dementia Rating global score = 0) and 824 symptomatic subjects (Clinical Dementia Rating score >0) with low to high AD neuropathologic changes at autopsy who were assessed at 1 of 34 National Institute on Aging-funded Alzheimer's Disease Centers. All subjects underwent a clinical examination within 1 year of death. Logistic regression was used to evaluate factors associated with the odds of being asymptomatic vs symptomatic.

Asymptomatic subjects tended to have low neurofibrillary tangle scores but a wide range of neuritic plaque frequencies. There were, however, a few asymptomatic subjects with very high tangle and neuritic plaque burden, as well as symptomatic subjects with few changes. In the multivariable model, asymptomatic subjects were older (odds ratio [OR] = 1.04; 95% confidence interval [CI] = 1.01-1.07), had lower clinical Hachinski Ischemic Score (OR = 0.82; 95% CI = 0.69-0.97), were less likely to have an APOE ε4 allele (OR = 0.36; 95% CI = 0.16-0.83), and had lower neurofibrillary tangle score (OR = 0.28; 95% CI = 0.17-0.45) compared with symptomatic subjects.

Dissociating clinical symptoms from pathologic findings better allows for investigation of preclinical AD. Our results suggest that although the severity of the pathology, particularly neurofibrillary tangles, has a large role in determining the extent of symptoms, other factors, including age, APOE status, and comorbidities such as cerebrovascular disease also explain differences in clinical presentation.