Tau Accumulates More Than Twice as Fast in Early-Onset AD

Tau protein accumulated more than twice as fast in patients with early-onset Alzheimer’s disease (AD) than in those whose symptoms develop after age 65, a new longitudinal observational cohort study showed.Researchers also found that tau, a hallmark protein of AD, was more widespread in the frontal, temporal, and parietal brain regions in younger patients.“We don’t fully understand why Alzheimer’s develops so early in some people. A key question is whether other genetic factors explain this more aggressive tau pathology,” lead investigator Konstantinos Chiotis, MD, PhD, assistant professor in the Department of Neurobiology, Care Sciences and Society at Karolinska Institutet in Stockholm, Sweden, said in a statement.“Understanding how genetics shape the differences we see in younger patients could reveal new treatment targets,” added Chiotis, who is also a neurologist at Karolinska University Hospital.The study was published online on November 4 in Science Translational Medicine.Early-Onset and Late-Onset ADAbout 5% of people with AD develop symptoms before age 65. In addition to memory problems, these early-onset patients may have less typical symptoms associated with language, visual processing, planning, and decision-making, which can make diagnosis more difficult.Although previous research has shown greater tau buildup in younger patients, it is unclear whether this reflects more advanced disease at diagnosis or differences in how early- vs late-onset disease progresses.To investigate, researchers compared 390 people with early-onset AD (mean age, 59.2 years; 54.4% women) enrolled in the Longitudinal Early-Onset Alzheimer’s Disease Study with 211 people with late-onset AD (mean age, 77.7 years; 42.2% women) from the Alzheimer’s Disease Neuroimaging Initiative. All participants had mild cognitive impairment or dementia due to AD and positive amyloid PET scans. Most were non-Hispanic White individuals (87.6% and 82.5%, respectively), while 5.7% and 9.5% were Black individuals.Researchers used PET imaging with the tracer fluorine-18 flortaucipir to measure tau in several brain regions, including the temporal, temporoparietal, and frontal areas. Follow-up scans were available for 245 participants with early-onset and 99 with late-onset AD, with average follow-up periods of 2.1 and 2.8 years, respectively.Early Faster Tau BuildupAt baseline, 72.3% of those with early AD had dementia compared with 36.5% of those with late AD. The early-onset group also had lower average scores on the Mini-Mental State Examination (21.3 vs 25.6), indicating greater cognitive impairment.Nearly 20% of participants in the early group had symptoms that did not primarily involve memory compared with 0.8% of those with late AD.The early-onset group had higher tau levels across the brain regions scanned, although the difference was less pronounced in the medial temporal region, which is important for memory. These differences persisted after accounting for amyloid burden and cognitive impairment and in additional analyses that excluded participants with atypical presentations.Tau accumulation was faster in the early group across individual brain regions and was more closely associated with cognitive and functional impairment in early-onset AD.The study had several limitations, including the use of baseline age rather than confirmed symptom onset to define late-onset AD. There were also differences between the research cohorts, limited racial and ethnic diversity, and a lack of assessment of other brain conditions that may have contributed to cognitive decline.Future of Treatment and ResearchThe differences in tau accumulation between younger and older patients may have important implications for how future AD treatments are studied, particularly therapies targeting tau and amyloid.Evidence from trials of amyloid-targeting drugs suggests that patients with lower tau may experience greater clinical benefit. Because younger patients in this study had more extensive tau pathology, treatment timing may be an important consideration in early-onset AD, researchers wrote.The investigators also considered whether combining amyloid- and tau-targeting therapies could benefit these patients.“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,” said senior study investigator Gil Rabinovici, MD, who holds the Edward and Pearl Fein Distinguished Professorship in Memory and Aging at the University of California in San Francisco, in a statement.Further research is needed to understand why tau accumulates more rapidly in some patients. “Developing a deeper understanding of the similarities and differences in AD pathophysiology across the age spectrum will advance our ability to identify optimal therapeutic approaches,” said Chiotis.Disclosure information for study authors is available in the original study publication.