Increased accumulation of β-amyloid may be linked to the risk of Alzheimer’s dementia in the elderly

A new study shows that the severity of amyloid deposition in the brain -? not just age -? may be the key to determining who will benefit from new anti-amyloid therapies to delay the progression of Alzheimer’s disease.

The accumulation of toxic masses of beta-amyloid that mark the pathology of Alzheimer’s disease accelerates in old age, but baseline amyloid burden and overall brain health are stronger predictors of this acceleration, University of Pittsburgh scientists and clinicians report. factors in who is more likely to progress to Alzheimer’s. The paper was published today at Neurologythe medical journal of the American Academy of Neurology.

“Understanding the complexity of increased amyloid accumulation when individuals are cognitively normal is critical for improved implementation of dementia therapies.”

Oscar Lopez, MD, corresponding author, professor of neurology at Pitt and chief of cognitive and behavioral neurology at UPMC

The presence and overall amount and distribution of beta or A-beta amyloid blocks in the brain are some of the most common neuropathologies associated with Alzheimer’s disease. However, while people aged 80 and older have the highest prevalence of Alzheimer’s-related dementia, most studies that have measured A-beta burden in the brain using imaging techniques have focused on younger populations. Therefore, the link between A-beta and dementia in the oldest old has remained unclear.

Lopez and his colleagues set out to change that by examining the relationship between A-beta deposition and new cases of dementia in 94 elderly people who were not cognitively impaired when the study began. Participants enrolled in the study at an average age of 85 and were followed for 11 years or until they died, receiving at least two PET-scans during the study. The rate of amyloid deposition in the brain of these subjects was compared with a younger cohort from the Australian Imaging, Biomarker, and Lifestyle (AIBL) study.

The researchers observed a steady increase in A-beta accumulation in all participants over time, regardless of their A-beta status at the start of the study. But this accumulation was significantly faster in patients aged 80 and older compared with participants in their late 60s, explaining the higher prevalence of A-beta in the older adults.

In the end, very few participants developed dementia without having A-beta deposits in the brain. Importantly, people whose brain scans were positive for amyloid at the start of the study developed dementia two years earlier than those who were negative for amyloid.

The researchers also found that short-term change in A-beta alone over a 1.8-year period could not predict future dementia risk. In contrast, the severity of basal A-beta burden, along with other markers of brain damage defined by the presence of white matter lesions (a marker of small vessel disease) and reduction in gray matter thickness in the cerebral cortex (a marker of neurodegeneration) were the strongest predictive risk factors, indicating that an active pathological process was already in place when the study began.

“Our findings are consistent with studies showing that amyloid accumulation in the brain takes decades to develop and occurs in the context of other brain pathologies, especially small vessel disease,” said Lopez, who also directs the Center for Brain Research Pete’s Alzheimer’s disease. “Whether there is a vascular process that occurs in parallel with A-beta deposition could not be addressed in this study. However, understanding the timing of these pathologies will be critical for implementing future primary prevention therapies.”

Additional authors of this research include Victor Villemagne, MD, YueFang Chan, Ph.D., Anne Cohen, Ph.D., William Klunk, MD, Chester Mathis, Ph.D., Tharick Pascoal, MD, Milos Ikonomovic, MD , Beth Snitz, Ph.D., Brian Lopresti, Ph.D., Ilyas Kamboh, Ph.D. and Howard Aizenstein, MD, all of Pitt.

This study was supported by the National Institutes of Health National Center for Complementary and Integrative Health and the Office of Dietary Supplements (grant U01 AT000162) and the National Institute on Aging (grants P30 AG066468, P01 AG025204, and RF1 AG052525).