Amyloid, Tau Accumulation Precede Symptoms in Autosomal Dominant Alzheimer’s

By Will Boggs MD

NEW YORK—Amyloid and tau deposits are detectable years before cognitive impairment develops in young adults with autosomal dominant Alzheimer disease (AD), according to findings from a Colombian kindred.

Carriers of the E280A mutation of presenilin 1 (PSEN1), which is responsible for one autosomal dominant form of AD, can provide clues about biomarker changes that precede the onset of clinical symptoms.

Dr. Yakeel T. Quiroz from Massachusetts General Hospital, Harvard Medical School, Boston, and colleagues used brain PET imaging from 12 PSEN1 E280A mutation carriers from the largest known autosomal dominant kindred, in Antioquia, Colombia, to characterize amyloid burden, tau accumulation, and their association.

Scans from nine cognitively unimpaired and three cognitively impaired mutation carriers were compared with those from 12 age-matched noncarriers from the same community.

No noncarriers showed any elevated amyloid accumulation. The youngest mutation carrier (age 28) showed no amyloid accumulation, but beginning at age 29, mutation carriers showed elevated amyloid accumulation, with 7 of 9 mutation carriers age 30 or older reaching the threshold for amyloid positivity.

Brain levels of Pittsburgh Compound B (PiB), a marker of amyloid accumulation, were highest among mutation carriers with mild cognitive impairment (MCI), lowest among noncarriers, and intermediate among unimpaired mutation carriers, according to the February 12 JAMA Neurology online report.

Tau accumulation, as measured by flortaucipir F 18 (FTP) uptake, was elevated in the entorhinal cortex, hippocampus, and parahippocampal gyrus of mutation carriers, compared to noncarriers, with different patterns for cognitively impaired and unimpaired carriers.

Among unimpaired carriers, the greatest tau accumulation was in the medial temporal lobe and inferior temporal regions, whereas carriers with MCI had the greatest accumulation in inferior and lateral temporo-parietal, parietal-occipital, and posterior cingulate/precuneus regions.

Greater entorhinal and interior temporal lobe accumulations of tau in mutation carriers were associated with worse performance on the Mini-Mental State Examination and the CERAD Word List Delayed Recall; amyloid accumulation was associated with worse performance only on the latter.

Elevated tau levels were not observed in mutation carriers younger than age 38.

Tau deposition levels were elevated in amyloid-positive mutation carriers 6 years before clinical onset of AD, whereas amyloid uptake levels were elevated about 15 years before the expected onset of MCI.

“The present findings add to the growing evidence that molecular markers can characterize biological changes associated with AD in individuals who are still cognitively unimpaired,” the researchers conclude. “They also suggest that tau PET imaging may be useful as a biomarker to distinguish individuals at high risk to develop the clinical symptomatology of AD, track progression of the disease, and evaluate response to disease-modifying treatments.”

“These findings are complementary with and supportive of ongoing studies from the Dominantly Inherited Alzheimer Network, which also found that the development of tau PET pathology is closely linked to the onset of symptoms,” write Dr. Eric McDade and Dr. Randall J. Bateman from Washington University School of Medicine, St. Louis, Missouri, in a related editorial. They go on to say that recent reports from that network "have indicated a remarkable link between symptom onset and the presence of tau pathology, long after cerebrospinal fluid tau changes have begun.”

“Taken together,” they conclude, “these findings suggest a modified pathobiological cascade of AD with tau in cerebrospinal fluid changing 10 to 15 years before neurofibrillary tau pathology begins.”

Dr. Richard J. Caselli from Mayo Clinic, Scottsdale, Arizona, who recently reviewed the latest scientific breakthroughs related to AD, told Reuters Health by email, "(This report) gives a first stab at a timeline for preclinical tau deposition in high-risk patients. More work is clearly needed in the majority of people who are not PSEN1 mutation carriers, but this certainly demonstrates the importance of the question.”

“If tau PET ever enters the clinical domain, then this would support its utility in identifying individuals at relatively imminent risk of symptomatic conversion,” he said. “That would have more immediate implications for clinical trial design.”

Dr. Michael Ewers from Ludwig Maximilian University Munich, in Germany, has also evaluated changes in amyloid and tau and other biomarkers in AD. He told Reuters Health by email, “The current findings suggest a successive spatial distribution of tau in the brain that is consistent with the pattern previously reported in late-onset AD. In these young subjects with autosomal dominant AD, the driving force of accumulation of tau was probably the early amyloid accumulation. Still, there was a remarkable discrepancy in the spatial distribution of amyloid and tau pathology. These observations renew the question of how amyloid pathology triggers tau pathology in distant brain regions.”

“The current findings suggest cortical spreading of tau into posterior parietal brain regions in temporal proximity to the onset of MCI, and thus, tau PET may have value for predicting the onset of dementia symptoms,” he said. “Yet, the small number of subjects and absence of longitudinal data currently do not allow for strong conclusions in that regard.”

Dr. Ewers added, “The assessment of tau PET in AD is still in its infancy. The results on tau PET markers are to be taken with caution, as the non-specific binding of tau tracers is not yet sufficiently known.”

Dr. Quiroz did not respond to a request for comment.

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JAMA Neurol 2018.

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