Associations between plasma neurofilament light, in vivo brain pathology, and cognition in non-demented individuals with autosomal-dominant Alzheimer's disease

BACKGROUND: Neurofilament light (NfL) is a promising biomarker of early neurodegeneration in Alzheimer's disease (AD). We examined whether plasma NfL was associated with in vivo amyloid beta and tau, and cognitive performance in non-demented presenilin-1 (PSEN1) E280A mutation carriers. METHODS: Twenty-five mutation carriers and 19 non-carriers (age range: 28 to 49 years) were included in this study. Participants underwent 11C Pittsburgh compound B (PiB)-PET (positron emission tomography), flortaucipir-PET, blood sampling, and cognitive testing. RESULTS: Mutation carriers exhibited higher plasma NfL levels than non-carriers. In carriers, higher NfL levels were related to greater regional tau burden and worse cognition, but not amyloid beta load. When we adjusted for age, a proxy of disease progression, elevated plasma NfL levels were only correlated with worse memory recall. CONCLUSIONS: Findings support an association between plasma NfL, cognition, and tau pathology in non-demented individuals at genetic risk for developing AD dementia. Plasma NfL may be useful for selecting individuals at increased risk and tracking disease progression in AD

White matter hyperintensities are a prominent feature of autosomal dominant Alzheimer’s disease that emerge prior to dementia

Background To promote the development of effective therapies, there is an important need to characterize the full spectrum of neuropathological changes associated with Alzheimer’s disease. In line with this need, this study examined white matter abnormalities in individuals with early-onset autosomal dominant Alzheimer’s disease, in relation to age and symptom severity. Methods This is a cross-sectional analysis of data collected in members of a large kindred with a PSEN1 E280A mutation. Participants were recruited between September 2011 and July 2012 from the Colombian Alzheimer’s Prevention Initiative registry. The studied cohort comprised 50 participants aged between 20 and 55 years, including 20 cognitively unimpaired mutation carriers, 9 cognitively impaired mutation carriers, and 21 non-carriers. Participants completed an MRI, a lumbar puncture for cerebrospinal fluid collection, a florbetapir PET scan, and neurological and neuropsychological examinations. The volume of white matter hyperintensities (WMH) was compared between cognitively unimpaired carriers, cognitively impaired carriers, and non-carriers. Relationships between WMH, age, and cognitive performance were further examined in mutation carriers. Results The mean (SD) age of participants was 35.8 (9.6) years and 64% were women. Cardiovascular risk factors were uncommon and did not differ across groups. Cognitively impaired carriers [median, 6.37; interquartile range (IQR), 9.15] had an increased volume of WMH compared to both cognitively unimpaired carriers [median, 0.85; IQR, 0.79] and non-carriers [median, 1.07; IQR, 0.71]. In mutation carriers, the volume of WMH strongly correlated with cognition and age, with evidence for an accelerated rate of changes after the age of 43 years, 1 year earlier than the estimated median age of symptom onset. In multivariable regression models including cortical amyloid retention, superior parietal lobe cortical thickness, and cerebrospinal fluid phospho-tau, the volume of WMH was the only biomarker independently and significantly contributing to the total explained variance in cognitive performance. Conclusions The volume of WMH is increased among individuals with symptomatic autosomal-dominant Alzheimer’s disease, begins to increase prior to clinical symptom onset, and is an independent determinant of cognitive performance in this group. These findings suggest that WMH are a key component of autosomal-dominant Alzheimer’s disease that is closely related to the progression of clinical symptoms

Waning locus coeruleus integrity precedes cortical tau accrual in preclinical autosomal dominant Alzheimer's disease

Introduction Autopsy studies recognize the locus coeruleus (LC) as one of the first sites accumulating tau in Alzheimer's disease (AD). Recent AD work related in vivo LC magnetic resonance imaging (MRI) integrity to tau and cognitive decline; however, relationships of LC integrity to age, tau, and cognition in autosomal dominant AD (ADAD) remain unexplored. Methods We associated LC integrity (3T-MRI) with estimated years of onset, cortical amyloid beta, regional tau (positron emission tomography [PET]) and memory (Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Word-List-Learning) among 27 carriers and 27 non-carriers of the presenilin-1 (PSEN1) E280A mutation. Longitudinal changes between LC integrity and tau were evaluated in 10 carriers. Results LC integrity started to decline at age 32 in carriers, 12 years before clinical onset, and 20 years earlier than in sporadic AD. LC integrity was negatively associated with cortical tau, independent of amyloid beta, and predicted precuneus tau increases. LC integrity was positively associated with memory. Discussion These findings support LC integrity as marker of disease progression in preclinical ADAD

Sex Differences in Cognitive Abilities among Children with the Autosomal Dominant Alzheimer Disease Presenilin 1 E280A Variant from a Colombian Cohort

Importance: We previously reported that children with the autosomal dominant Alzheimer disease (ADAD) presenilin 1 (PSEN1) E280A variant had early life plasma biomarker findings consistent with amyloid β overproduction. However, the cognitive functioning of children with this variant has not been characterized vs those without the variant. Objective: To test whether cognitive functioning of children with and without the PSEN1 E280A variant in the same ADAD cohort differed by genetic status (ie, PSEN1 variant) and sex. Design, Setting, and Participants: This cohort study was conducted among 1354 children (including 265 children with the variant) aged 6 to 16 years recruited from the Alzheimer Prevention Initiative Colombia Registry. Participants from the city of Medellín and surrounding suburban areas traveled to the University of Antioquia to undergo all procedures. Participants were administered a Spanish version of the Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV) to measure general cognitive functioning. Data were analyzed from July through November 2020. Main Outcomes and Measures: Univariate general linear models were used to characterize differences on WISC-IV cognitive performance by genetic status, sex, and the interaction of genetic status with sex. Urbanity, socioeconomic status, and education were entered as covariates. Results: Among 1354 children with ADAD (695 [51.3%] girls; mean [SD] age, 11.64 [2.64] years), there were 265 children with the variant (19.6%) and 1089 children without the variant (80.4%). Children with and without the variant did not differ by demographic variables or performance on WISC-IV indices. Irrespective of genetic status, boys had statistically significantly decreased mean scores on indices for working memory (90.27 [95% CI, 89.21-91.34] vs 92.99 [95% CI, 91.98-93.99]; mean difference = -2.72; P <.001), perceptual reasoning (91.56 [95% CI, 90.47-92.65] vs. 93.27 [95% CI, 91.23-94.30]; mean difference = -1.71; P =.03), and verbal comprehension (88.69 [95% CI, 87.54-89.84] vs. 90.81 [95% CI, 89.73-91.90]; mean difference = -2.12; P =.009) compared with girls. In the interaction between sex and genetic status, boys with the variant had worse mean working memory index performance (88.78 [95% CI, 86.86-90.70]) than girls with the variant (93.75 [95% CI, 91.95-95.55]; mean difference = -4.97; P =.001), as well as boys (91.77 [95% CI, 90.85-92.70]; mean difference = -2.99; P =.04) and girls (92.22 [95% CI, 91.32-93.13]; mean difference = -3.44; P =.009) without the variant. Conclusions and Relevance: This study found that boys with the PSEN1 variant had decreased working memory abilities compared with girls with the variant and boys and girls without the variant, suggesting a sex-specific genetic risk in early life cognitive performance among individuals with the PSEN1 variant. This increased risk of future cognitive difficulties among boys with the variant may have important downstream implications for learning and academic achievement and could be associated with sex differences seen in adulthood on episodic memory measures.. © 2021 American Medical Association. All rights reserved.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Cortical thickness across the lifespan in a Colombian cohort with autosomal-dominant Alzheimer's disease: A cross-sectional study

Introduction Cortical thinning is a marker of neurodegeneration in Alzheimer's disease (AD). We investigated the age-related trajectory of cortical thickness across the lifespan (9-59 years) in a Colombian kindred with autosomal dominant AD (ADAD). Methods Two hundred eleven participants (105 presenilin-1 [PSEN1] E280A mutation carriers, 16 with cognitive impairment; 106 non-carriers) underwent magnetic resonance imaging. A piecewise linear regression identified change-points in the age-related trajectory of cortical thickness in carriers and non-carriers. Results Unimpaired carriers exhibited elevated cortical thickness compared to non-carriers, and thickness more negatively correlated with age and cognition in carriers relative to non-carriers. We found increased cortical thickness in child carriers, after which thickness steadied compared to non-carriers prior to a rapid reduction in the decade leading up to the expected age at cognitive impairment in carriers. Discussion Findings suggest that cortical thickness may fluctuate across the ADAD lifespan, from early-life increased thickness to atrophy proximal to clinical onset

Plasma neurofilament light chain in the presenilin 1 E280A autosomal dominant Alzheimer's disease kindred: a cross-sectional and longitudinal cohort study

Background: Neurofilament light chain (NfL) is a promising biomarker of active axonal injury and neuronal degeneration. We aimed to characterise cross-sectional and longitudinal plasma NfL measurements and determine the age at which NfL concentrations begin to differentiate between carriers of the presenilin 1 (PSEN1) E280A (Glu280Ala) mutation and age-matched non-carriers from the Colombian autosomal dominant Alzheimer's disease kindred. / Methods: In this cross-sectional and longitudinal cohort study, members of the familial Alzheimer's disease Colombian kindred aged 8–75 years with no other neurological or health conditions were recruited from the Alzheimer's Prevention Initiative Registry at the University of Antioquia (Medellín, Colombia) between Aug 1, 1995, and Dec 15, 2018. We used a single molecule array immunoassay and log-transformed data to examine the relationship between plasma NfL concentrations and age, and establish the earliest age at which NfL concentrations begin to diverge between mutation carriers and non-carriers. / Findings: We enrolled a cohort of 1070 PSEN1 E280A mutation carriers and 1074 non-carriers with baseline assessments; of these participants, longitudinal measures (with a mean follow-up of 6 years) were available for 242 mutation carriers and 262 non-carriers. Plasma NfL measurements increased with age in both groups (p<0·0001), and began to differentiate carriers from non-carriers when aged 22 years (22 years before the estimated median age at mild cognitive impairment onset of 44 years), although the ability of plasma NfL to discriminate between carriers and non-carriers only reached high sensitivity close to the age of clinical onset. / Interpretation: Our findings further support the promise of plasma NfL as a biomarker of active neurodegeneration in the detection and tracking of Alzheimer's disease and the evaluation of disease-modifying therapies

Longitudinal amyloid and tau accumulation in autosomal dominant Alzheimer's disease: findings from the Colombia-Boston (COLBOS) biomarker study

Background: Neuroimaging studies of autosomal dominant Alzheimer's disease (ADAD) enable characterization of the trajectories of cerebral amyloid-beta (A beta) and tau accumulation in the decades prior to clinical symptom onset. Longitudinal rates of regional tau accumulation measured with positron emission tomography (PET) and their relationship with other biomarker and cognitive changes remain to be fully characterized in ADAD.Methods: Fourteen ADAD mutation carriers (Presenilin-1 E280A) and 15 age-matched non-carriers from the Colombian kindred underwent 2-3 sessions of A beta (11C-Pittsburgh compound B) and tau (18F-flortaucipir) PET, structural magnetic resonance imaging, and neuropsychological evaluation over a 2-4-year follow-up period. Annualized rates of change for imaging and cognitive variables were compared between carriers and non-carriers, and relationships among baseline measurements and rates of change were assessed within carriers.Results: Longitudinal measurements were consistent with a sequence of ADAD-related changes beginning with A beta accumulation (16 years prior to expected symptom onset, EYO), followed by entorhinal cortex (EC) tau (9 EYO), neocortical tau (6 EYO), hippocampal atrophy (6 EYO), and cognitive decline (4 EYO). Rates of tau accumulation among carriers were most rapid in parietal neocortex (similar to 9%/year). EC tau PET signal at baseline was a significant predictor of subsequent neocortical tau accumulation and cognitive decline within carriers.Conclusions: Our results are consistent with the sequence of biological changes in ADAD implied by cross-sectional studies and highlight the importance of EC tau as an early biomarker and a potential link between A beta burden and neocortical tau accumulation in ADAD

PET evidence of preclinical cerebellar amyloid plaque deposition in autosomal dominant Alzheimer's disease-causing Presenilin-1 E280A mutation carriers

Background: In contrast to sporadic Alzheimer's disease, autosomal dominant Alzheimer's disease (ADAD) is associated with greater neuropathological evidence of cerebellar amyloid plaque (Aβ) deposition. In this study, we used positron emission tomography (PET) measurements of fibrillar Aβ burden to characterize the presence and age at onset of cerebellar Aβ deposition in cognitively unimpaired (CU) Presenilin-1 (PSEN1) E280A mutation carriers from the world's largest extended family with ADAD. Methods: 18F florbetapir and 11C Pittsburgh compound B (PiB) PET data from two independent studies – API ADAD Colombia Trial (NCT01998841) and Colombia-Boston (COLBOS) longitudinal biomarker study were included. The tracers were selected independently by the respective sponsors prior to the start of each study and used exclusively throughout. Template-based cerebellar Aβ-SUVR (standard-uptake value ratios) using a known-to-be-spared pons reference region (cerebellar SUVR_pons), to a) compare 28–56-year-old CU carriers and non-carriers; b) estimate the age at which cerebellar SUVR_pons began to differ significantly in carrier and non-carrier groups; and c) characterize in carriers associations with age, cortical SUVR_pons, delayed recall memory, and API ADAD composite score. Results: Florbetapir and PiB cerebellar SUVR_pons were significantly higher in carriers than non-carriers (p &lt; 0.0001). Cerebellar SUVR_pons began to distinguish carriers from non-carriers at age 34, 10 years before the carriers’ estimated age at mild cognitive impairment onset. Florbetapir and PiB cerebellar SUVR_pons in carriers were positively correlated with age (r = 0.44 &amp; 0.69, p &lt; 0.001), cortical SUVR_pons (r = 0.55 &amp; 0.69, p &lt; 0.001), and negatively correlated with delayed recall memory (r = −0.21 &amp; −0.50, p &lt; 0.05, unadjusted for cortical SUVR_pons) and API ADAD composite (r = −0.25, p &lt; 0.01, unadjusted for cortical SUVR_pons in florbetapir API ADAD cohort). Conclusion: This PET study provides evidence of cerebellar Aβ plaque deposition in CU carriers starting about a decade before the clinical onset of ADAD. Additional studies are needed to clarify the impact of using a cerebellar versus pons reference region on the power to detect and track ADAD changes, even in preclinical stages of this disorder. © 2021 The Author(s)Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]