Association Between Amyloid and Tau Accumulation in Young Adults With Autosomal Dominant Alzheimer Disease

Abstract

IMPORTANCE It is critically important to improve our ability to diagnose and track Alzheimer disease (AD) as early as possible. Individuals with autosomal dominant forms of AD can provide clues as to which and when biological changes are reliably present prior to the onset of clinical symptoms. OBJECTIVE To characterize the associations between amyloid and tau deposits in the brains of cognitively unimpaired and impaired carriers of presenilin 1 (PSEN1) E280A mutation. DESIGN, SETTING, AND PARTICIPANTS In this cross-sectional imaging study, we leveraged data from a homogeneous autosomal dominant AD kindred, which allowed us to examine measurable tau deposition as a function of individuals' proximity to the expected onset of dementia. Cross-sectional measures of carbon 11-labeled Pittsburgh Compound B positron emission tomography (PET) and flortaucipir F 18 (previously known as AV 1451, T807) PET imaging were assessed in 24 PSEN1 E280A kindred members (age range, 28-55 years), including 12 carriers, 9 of whom were cognitively unimpaired and 3 of whom had mild cognitive impairment, and 12 cognitively unimpaired noncarriers. MAIN OUTCOMES AND MEASURES We compared carbon 11-labeled Pittsburgh Compound B PET cerebral with cerebellar distribution volume ratios as well as flortaucipir F 18 PET cerebral with cerebellar standardized uptake value ratios in mutation carriers and noncarriers. Spearman correlations characterized the associations between age and mean cortical Pittsburgh Compound B distribution volume ratio levels or regional flortaucipir standardized uptake value ratio levels in both groups. RESULTS Of the 24 individuals, the mean (SD) age was 38.0 (7.4) years, or approximately 6 years younger than the expected onset of clinical symptoms in carriers. Compared with noncarriers, cognitively unimpaired mutation carriers had elevated mean cortical Pittsburgh Compound B distribution volume ratio levels in their late 20s, and 7 of 9 carriers older than 30 years reached the threshold for amyloidosis (distribution volume ratio level > 1.2). Elevated levels of tau deposition were seen within medial temporal lobe regions in amyloid-positive mutation carriers 6 years before clinical onset of AD in this kindred. Substantial tau deposition in the neocortex was only observed in 1 unimpaired carrier and in those with mild cognitive impairment. β-Amyloid uptake levels were diffusely elevated in unimpaired carriers approximately 15 years prior to expected onset of mild cognitive impairment. In carriers, higher levels of tau deposition were associated with worse performance on the Mini-Mental State Examination

Biological and Cognitive Markers of Presenilin1 E280a Autosomal Dominant Alzheimer’s Disease: A Comprehensive Review of the Colombian Kindred

“…Aβ 1–42 aggregation was most evident in the anterior cingulate and precuneus [36]. Consistent with this initial study, a recent report using the Pittsburgh-compound-B (PiB) tracer showed cortical Aβ 1–42 aggregation beginning in carriers with an average of −15 EYO [37]. Flortaucipir PET imaging of tau in the brain of carriers has shown progressive accumulation of tau in the entorhinal cortex and inferior temporal lobe an average of −6 EYO, and an estimated 10 years after the first evidence of cortical Aβ 1–42 [37].…”

“…The right visuo-perceptual area, which showed greater activity in younger carriers, was conversely found to have decreased activity in carriers close to clinical onset [29]. In the context of other markers of AD, the change from EEG-measured cortical hyperactivity to hypoactivity in PSEN1 E280A carriers appeared to coincide with elevated levels of in vivo cortical Aβ 1–42 in mutation carriers [36,37]. …”

“…Flortaucipir PET imaging of tau in the brain of carriers has shown progressive accumulation of tau in the entorhinal cortex and inferior temporal lobe an average of −6 EYO, and an estimated 10 years after the first evidence of cortical Aβ 1–42 [37]. Tau aggregation was strongly related to performance on tests of verbal memory and global cognition, and could be seen in the junctions of the parietal, temporal, and occipital lobes, as well as in the posterior cingulate cortex and precuneus among carriers with MCI [37]. …”

“…Through the cumulative, synthesized findings of our review, we propose a hypothetical “tipping point” of hyper to hypo-activity in memory and visuo-perceptual regions in carriers in their mid-thirties (~10 -EYO), which aligns with the mid-point between cortical Aβ deposition (median of −16 EYO) and regional tau deposition (median of −6 EYO) [36,37]. Significant debate persists, however, about whether changes in cortical activation and functional activity are not compensatory, but reflective of poor brain maintenance.…”

Regional multimodal relationships between tau, hypometabolism, atrophy, and fractional anisotropy in atypical Alzheimer's disease

“…According to the current understanding of AD, Aβ deposition begins years, if not decades, before the clinical symptoms of cognitive decline, which are directly caused by neurodegeneration, and tau accumulation happens in between the two (C. R. Jack, Jr. et al, 2013; Quiroz et al, 2018). Therefore, the natural continuation of this research will be to gather longitudinal data and integrate the current findings with the temporal associations between protein accumulation, atrophy, hypometabolism and white matter disruption.…”