Patients with early-onset Alzheimer's disease, whose symptoms start before age 65, have more extensive deposits of tau, a hallmark protein of the condition, compared with patients whose symptoms start at 65-plus, a new study found. What's more, tau accumulates at more than twice the rate in younger compared to older patients and spreads widely throughout the brain.
The findings may help explain why early-onset Alzheimer's typically progresses faster and is more likely to produce unusual syndromes involving language, visual and spatial abilities, and executive functioning, experts said.
The study was supported by funding from the National Institute on Aging. It was published in Science Translational Medicine on Nov. 4.
The study is the largest to examine tau in patients with early-onset disease – who make up 5% of all Alzheimer's patients – and compare them with late-onset patients.
"Patients with early-onset Alzheimer's are more likely than older patients to present with symptoms unrelated to memory, at least initially," said co-senior author Renaud La Joie , PhD, Edward and Pearl Fein Endowed Professor in Precision Care for Memory Disorders at UCSF.
"They might have difficulty interpreting what they are seeing despite a normal eye exam. They might struggle with judging distances and may have trouble reading," La Joie continued. "Some patients may experience a decline in language abilities in which they have difficulty retrieving words and following long sentences, although speech remains fluent. Others may struggle with executive functioning, such as attention, problem-solving, planning, and adapting to changing situations."
The researchers studied 390 patients from the Longitudinal Early-Onset Alzheimer's Disease Study, whose average age was 59, and 211 late-onset patients from the Alzheimer's Disease Neuroimaging Initiative, whose average age was 78.
All had mild cognitive impairment or mild dementia due to Alzheimer's, with PET scans showing accumulation of amyloid, an early biomarker of the disease. A subset underwent repeat tau PET scans over an average follow-up of two to three years, enabling researchers to track how tau changed over time.
Among early-onset patients, 1 in 5 had a non-memory-dominant presentation, while more than 99% of the late-onset patients whose presentations had been documented had a memory-dominant form.
Understanding genetics could lead to new treatment targets
"We don't fully understand why Alzheimer's develops so early in some people," said first author Konstantinos Chiotis, MD, PhD, formerly of the UCSF Edward and Pearl Fein Memory and Aging Center and currently an assistant professor at the Karolinska Institutet in Stockholm. "A small minority carry a known disease-causing mutation, but these were excluded from our study. A key question is whether other genetic factors explain this more aggressive tau pathology. Understanding how genetics shape the differences we see in younger patients could reveal new treatment targets."
The two drugs approved to slow Alzheimer's progression target amyloid. Yet the differences between early- and late-onset disease were much greater for tau than amyloid in this study. Though the study did not test Alzheimer's treatments, the findings raise important questions about how patients with early-onset disease might respond to them.
"We found that tau accumulation and spread was particularly aggressive in patients with early-onset disease and was more strongly related to progression in memory loss, said senior author Gil Rabinovici , MD, who holds the Edward and Pearl Fein Distinguished Professorship in Memory and Aging at UCSF.
"Treatments that target tau may be particularly important in early-onset Alzheimer's, and therefore younger patients may be good candidates for clinical trials combining treatments targeting both amyloid and tau."
Authors: Please see the study
Funding: National Institute on Aging (U01-AG057195, NIH/NIA P30-AG062422) and Alzheimer's Association.
Disclosures: Please see the study
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