Preclinical Autosomal Dominant Alzheimer Research Articles

Association of Resilience-Related Life Experiences on Variability on Age of Onset in Dominantly Inherited Alzheimer Disease.

It remains unknown whether the associations between protective lifestyles and sporadic dementia risk reported in observational studies also affect age at symptom onset (AAO) in autosomal dominant Alzheimer disease (ADAD) with predominant genetic influences. We investigated the associations between resilience-related life experiences and interindividual AAO variability in ADAD. We performed a longitudinal and confirmatory analysis of the Dominantly Inherited Alzheimer Network prospective observational cohort (January 2009-June 2018, follow-up duration 2.13 ± 2.22 years), involving clinical, CSF, and lifestyle/behavioral assessments. We performed a 2-pronged comprehensive resilience assessment in each cohort. Cohort 1, incorporating the general resilience definition (cognitive maintenance [Clinical Dementia Rating = 0] despite high pathology), included carriers during the periods of significant CSFp-tau181 variability and grouped into resilience/resistance outcome bins according to the dichotomous pathologic and cognitive statuses, subcategorized by the estimated years from expected symptom onset (EYO). Cohort 2, focused on ADAD-specific genetically determined time frame characterizing the onset predictability, included asymptomatic participants with available preclinical lifestyle data and AAO outcomes and grouped into delayed or earlier AAO relative to the parental AAO. Associations of cognitive, CSFp-tau181, and lifestyle/behavioral predictors with binary outcomes were investigated using logistic regression. Of 320 carriers (age 38.19 ± 10.94 years, female 56.25%), cohort 1 included 218 participants (39.00 ± 9.37 years, 57.34%) and cohort 2 included 28 participants (43.34 ± 7.40 years, 71.43%). In cohort 1, 218 carriers after -20 EYO, when the interindividual variability (SD) of CSFp-tau181 first became more than twice greater in carriers than in noncarriers, were grouped into low-risk control (asymptomatic, low pathology, n = 103), high-resilience (asymptomatic despite high pathology, n = 60), low-resilience (symptomatic despite low pathology, n = 15), and susceptible control (symptomatic, high pathology, n = 40) groups. Multivariable predictors of high resilience, controlling for age and depression, included higher conscientiousness (odds ratio 1.051 [95% CI 1.016-1.086], p = 0.004), openness to experience (1.068 [1.005-1.135], p = 0.03) (vs. susceptible controls), and agreeableness (1.082 [1.015-1.153], p = 0.02) (vs. low resilience). From 1 to 3 years before parental AAO (cohort 2), the multivariable predictor of delayed AAO, controlling for CSFp-tau181, was higher conscientiousness (0.916 [0.845-0.994], p = 0.036). Among the cognitively and socially integrated life experiences associated with resilience, measures of conscientiousness were useful indicators for evaluating resilience and predicting future dementia onset in late preclinical ADAD.

Relationship between physical activity and biomarkers of pathology and neuroinflammation in preclinical autosomal-dominant Alzheimer's disease.

Physical activity (PA) has been linked to reduced Alzheimer's disease (AD) risk. However, less is known about its effects in the AD preclinical stage. We aimed to investigate whether greater PA was associated with lower plasma biomarkers of AD pathology, neural injury, reactive astrocytes, and better cognition in individuals with autosomal-dominant AD due to the presenilin-1 E280A mutation who are virtually guaranteed to develop dementia. Twenty-eight cognitively unimpaired mutation carriers (ages x̄ = 29.28) wore a FitBit Charge-4 for 14 days. We calculated their average steps to measure locomotion, and Training Impulse (TRIMP) to quantify the intensity and duration of PAs using heart rate. Plasma amyloid beta 42/40 ratio, phosphorylated tau 181, neurofilament light chain, and glial fibrillary acidic protein (GFAP) were measured. Cognition was assessed with the Consortium to Establish a Registry for Alzheimer's Disease word list learning and delayed recall, Trail Making Test Part A, and Wechsler Adult Intelligence Scale-version IV Digit Span Backward. We conducted multiple linear regressions controlling for age, sex, body mass index, and education. There were no associations among steps or TRIMP with plasma biomarkers or cognition. Greater TRIMP was related to higher GFAP levels. PA was not associated with cognition or plasma biomarkers. However, greater intensity and duration of PAs were related to higher GFAP. Participants engaged very little in moderate to vigorous PA. Therefore, light PA may not exert a significant protective effect in preclinical AD. Future work with larger samples and longitudinal data is needed to elucidate further the potential impact of PA on AD progression in the preclinical stages. Locomotion (average steps) was not associated with plasma biomarkers or cognition.Greater training load (training impulse) was related to higher glial fibrillary acidic protein levels in mutation carriers.Light physical activity may not suffice to exert a protective effect on Alzheimer's disease.

33 Associations Between Long-Term Forgetting and Slow Wave Activity in Autosomal-Dominant Alzheimer’s Disease: Findings from the Colombia-Boston (COLBOS) Biomarker Study

Objective:Sleep contributes to memory retention and recall. Alzheimer’s disease (AD) patients experience decreased slow wave activity (SWA) during sleep. This decrease in SWA is associated with impaired memory consolidation (Lee et al., 2020). Long-term forgetting (LTF) over days or weeks has been linked to memory consolidation deficits and has been suggested as an early marker of AD that could be useful for identifying at-risk individuals for preclinical AD trials (Weston et al., 2018). Here, we examined associations between LTF and SWA in a sample of Presenilin-1 (PSEN1) E280A mutation carriers with autosomal dominant Alzheimer’s disease and non-carrier family members. Carriers of this mutation usually develop dementia in their forties (Fuller et al., 2019).Participants and Methods:Fourteen cognitively unimpaired PSEN1-E280A mutation carriers and sixteen age-matched non-carriers (mean age: 34.2 years) from the Colombia-Boston (COLBOS) biomarker study were included. Participants completed an overnight polysomnogram (PSG) and memory testing (NEUROPSI Word List) at 3-time points: 1) the night before PSG: immediate recall (Day1-ImmRecall) and a 20-minute delayed recall (Day1-DelayedRecall), 2) recall the following day (Day2-recall), and 3) recall one week later (Day7-recall). SWA was measured as the ratio 0. 6-1Hz/0.6-4Hz in frontopolar and frontotemporal regions and was calculated for sleep stages N2+N3 (slow wave sleep) based on an automated staging algorithm. Each participant’s LTF was calculated as the percent retention between Day 1 immediate recall and Day 7 recall (Butler, 2009). Mann-Whitney U tests were used to compare differences in recall, SWA, and LTF between groups. Spearman’s correlation was used to examine the associations between memory recall at different time points and SWA, as well as between LTF and SWA.Results:On Day 1, carriers had lower performance in immediate recall (p=0.02), compared to non-carriers, but there were no group differences in the 20-minute delayed recall. Carriers also recalled fewer words on Day 2 (p=0.03) and Day 7 (p=0.009) and had greater LTF (p=0.03). There were no group differences in SWA. In our overall sample, worse performance on word list delayed recall on Day 1, Day 2, and Day 7 was associated with less SWA across both frontotemporal (Day1: p=0.04, Day2: p=0.02, Day7: p=0.02) and frontopolar (all Ps<0.01) regions. In carriers, only worse performance on Day 1 delayed recall was associated with lower SWA in the frontopolar region (r= 0.535; p=0.049). Memory recall on other days was not associated with SWA in any brain regions. Additionally, greater LTF was associated with less SWA across both frontopolar (r= 0.507; p=0.005) and frontotemporal regions (r= 0.463 p= 0.01).Conclusions:Preliminary findings suggest that long-term forgetting is associated with less slow- wave activity in preclinical autosomal dominant Alzheimer’s disease. These results also suggest that SWA may be related to pre-sleep learning and subsequent overnight memory consolidation processes. LTF testing may be useful in selecting individuals for preclinical AD trials. Future research on the impact of slow wave activity on LTF may be useful in identifying ways to enhance short- and long-term memory consolidation in individuals at greater risk for dementia.

Depressive symptoms and hippocampal volume in autosomal dominant Alzheimer's disease.

Depressive symptoms are among early behavioral changes in Alzheimer's disease (AD); however, the relationship between neurodegeneration and depressive symptoms remains inconclusive. To better understand this relationship in preclinical AD, we examined hippocampal volume and depressive symptoms in cognitively unimpaired carriers of the presenilin-1 (PSEN1) E280A mutation for autosomal dominant AD. A total of 27 PSEN1 mutation carriers and 26 non-carrier family members were included. Linear regression was used to test the relationship between hippocampal volume and 15-item Geriatric Depression Scale. Carriers and non-carriers did not differ in depressive symptoms or hippocampal volume. Within carriers, lower hippocampal volume was associated with greater depressive symptoms, which remained significant after adjusting for age and cognition. This relationship was not significant in non-carriers. Hippocampal neurodegeneration may underlie depressive symptoms in preclinical autosomal dominant AD. These findings provide support for the utility of targeting depressive symptoms in AD prevention. We compared unimpaired autosomal dominant Alzheimer's disease (AD) mutation carriers and non-carriers. Carriers and non-carriers did not differ in severity of depressive symptoms. In carriers, hippocampal volume was inversely associated with depressive symptoms. Depressive symptoms may be a useful target in AD prevention.

Amyloid-β and tau pathologies relate to distinctive brain dysconnectomics in preclinical autosomal-dominant Alzheimer’s disease

The human brain is composed of functional networks that have a modular topology, where brain regions are organized into communities that form internally dense (segregated) and externally sparse (integrated) subnetworks that underlie higher-order cognitive functioning. It is hypothesized that amyloid-β and tau pathology in preclinical Alzheimer’s disease (AD) spread through functional networks, disrupting neural communication that results in cognitive dysfunction. We used high-resolution (voxel-level) graph-based network analyses to test whether in vivo amyloid-β and tau burden was associated with the segregation and integration of brain functional connections, and episodic memory, in cognitively unimpaired Presenilin-1 E280A carriers who are expected to develop early-onset AD dementia in ∼13 y on average. Compared to noncarriers, mutation carriers exhibited less functional segregation and integration in posterior default-mode network (DMN) regions, particularly the precuneus, and in the retrospenial cortex, which has been shown to link medial temporal regions and cortical regions of the DMN. Mutation carriers also showed greater functional segregation and integration in regions connected to the salience network, including the striatum and thalamus. Greater tau burden was associated with lower segregated and integrated functional connectivity of DMN regions, particularly the precuneus and medial prefrontal cortex. In turn, greater tau pathology was related to higher segregated and integrated functional connectivity in the retrospenial cortex and the anterior cingulate cortex, a hub of the salience network. These findings enlighten our understanding of how AD-related pathology distinctly alters the brain’s functional architecture in the preclinical stage, possibly contributing to pathology propagation and ultimately resulting in dementia.

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

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. 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. 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. These findings support LC integrity as marker of disease progression in preclinical ADAD.

Amygdala tau pathology in preclinical autosomal dominant Alzheimer’s disease

AbstractBackgroundThe amygdala has been found to be pathologically affected in early stages of Alzheimer’s disease (AD), with particular amygdala subnuclei being especially vulnerable. We used in vivo positron emission tomography (PET) imaging to examine whether amygdala tau accumulation could be observed in cognitively unimpaired PSEN‐1 mutation carriers who carry an autosomal‐dominant mutation in the Presenilin‐1 (PSEN‐1) gene and are determined to develop dementia in their early 50s. We further aimed to investigate associations between amygdala tau, age, amyloid deposition, and cognition in mutation carriers and non‐carrier family members.MethodA total of 29 PSEN‐1 mutation carriers (M age = 37.4 +/‐ 5.8 years) and 35 age‐matched non‐carriers (M age = 35.9 +/‐ 5.8 years) were recruited from the Colombia‐Boston (COLBOS) Longitudinal Biomarker Study, which follows Colombian families with autosomal‐dominant AD. Participants underwent PET, using Pittsburgh Compound B to measure mean cortical amyloid‐β and Flortaucipir for regional tau, and episodic memory testing (CERAD Word List Learning). Amygdala subnuclei were automatically segmented with FreeSurfer7. Spearman correlations were used to examine associations among amygdala tau, age, mean amyloid‐β, and memory performance.ResultCompared to non‐carriers, cognitively unimpaired mutation carriers had greater tau accumulation in the amygdala (p<0.001). Unimpaired carriers had greater tau burden in amygdala compared to neocortical regions (vs. inferior temporal: t=2.3, p=0.03), suggesting early involvement of amygdala tau. Among amygdala subnuclei, basal and accessory basal nuclei had greater tau burden compared to the other subregions (vs. lateral nucleus: t=5.5, p<0.0001) in unimpaired carriers. Greater amygdala tau burden was associated with older age (r=0.649, p<0.0001), greater mean cortical amyloid (r=0.597, p=0.001) and worse memory performance (r=‐0.433, p= 0.019) in carriers. No significant associations were observed in the non‐carrier group.ConclusionAmygdala tau burden is associated with greater age, cortical amyloid burden, and worse memory in preclinical autosomal dominant Alzheimer’s disease. These results suggest that amygdala tau accumulation is evident in preclinical Alzheimer’s disease. Future studies should determine if amygdala tau (including subnuclei) can be used as an early indicator of Alzheimer’s disease progression. Longitudinal studies are needed to examine the associations between amygdala tau and onset of neuropsychiatric and behavioral symptoms.

Cross-Sectional and Longitudinal Comparisons of Biomarkers and Cognition Among Asymptomatic Middle-Aged Individuals with a Parental History of Either Autosomal Dominant or Late Onset Alzheimer Disease

Background: The comparison of autosomal dominant Alzheimer disease (ADAD) and late-onset Alzheimer disease (LOAD) is almost perfectly confounded by age, leading to a major challenge in the interpretation of results. We aim to compare biomarkers from the cerebrospinal fluid (CSF) and neuroimaging (magnetic resonance imaging (MRI); amyloid Positron Emission Tomography (PET)) between age-matched asymptomatic individuals at-risk for ADAD or LOAD. Methods: Cross-sectional and longitudinal biomarker and cognitive data from asymptomatic participants of 42 to 65 years in the Dominantly Inherited Alzheimer Network (DIAN) and the Washington University Adult Children Study (ACS) of LOAD were analyzed across 4 groups: DIAN mutation carriers (MC, n=33) and non-carriers (NON-MC, n=58), and ACS participants with a positive (FH+, n=176) and negative family history (FH-, n=120) of LOAD. Findings: Baseline age had the strongest effect on β-amyloid load (via Pittsburgh Compound B (PIB) PET) in DIAN MC, and was significantly associated with cortical thickness for all except for DIAN NON-MC. At the mean baseline age, DIAN MC had the lowest levels of CSF Aβ42, the highest levels of CSF total Tau, phosphorylated Tau (pTau181), and PIB PET uptake. Longitudinally, DIAN NON-MC showed no significant changes in any markers, whereas DIAN MC showed significant changes in all but CSF markers. ACS FH+ and FH- both showed significant changes in CSF Aβ42 and PIB uptake. DIAN MC had similar rate of increase in PIB PET uptake to ACS FH+, drastically faster rate of decline in hippocampal volume than others, and was the only group showing significant cognitive decline. Interpretation: Preclinical ADAD and LOAD appear to share many biomarker signatures, but significant differences between preclinical ADAD and ACS FH+ were found at baseline, and on the longitudinal changes in hippocampal volume and cognition, likely due to the later preclinical stage of ADAD at the similar ages. Funding: This study was supported by National Institute on Aging (NIA) grant R01 AG053550 (Dr. Xiong) and NIA grants P50 AG005681, P01AG026276, and P01 AG0399131 (Dr. Morris), and UF1AG032438 (Dr. Bateman). Image processing was supported in part by the Neuroimaging Informatics and Analysis Center (1P30NS098577) and R01 EB009352 (Benzinger). Data collection and sharing for this project was partly supported by The Dominantly Inherited Alzheimer’s Network (DIAN, UF1AG032438) funded by the National Institute on Aging (NIA), the German Center for Neurodegenerative Diseases (DZNE), Raul Carrea Institute for Neurological Research (FLENI), Partial support by Japan Agency for Medical Research and Development (AMED) JP21dk0207049 (Dr. Ikeuchi), and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) Declaration of Interest: All the authors declare no competing interest. Ethical Approval: The WU Human Research Protection Office approved both the ACS and the DIAN, the Institutional Review Boards/Independent Ethics Committees approved the DIAN protocol at all DIAN sites, and all participants gave written informed consent.

Sex differences in neurodegeneration and memory performance in preclinical autosomal dominant Alzheimer’s disease: Baseline findings from the API ADAD trial

AbstractBackgroundGrowing evidence suggests that females have greater biological risk for Alzheimer’s disease (AD). As levels of AD pathology increase, females show greater tau accumulation, faster hippocampal volume loss, and faster cognitive decline than males. We sought to investigate sex differences in individuals with preclinical autosomal dominant AD (ADAD), who are destined to develop early‐onset dementia and have minimal age‐related confounds known to vary by sex (e.g., mortality, cardiovascular disease, or menopause). We plan to examine the role of sex in the associations among markers of pathology, neurodegeneration, and cognition leveraging baseline data from the Alzheimer’s Prevention Initiative (API) ADAD Colombia Trial.MethodsWe analyzed baseline data from 242 cognitively unimpaired 30‐53 year‐old prevention trial participants, including 167 PSEN1 E280A mutation carriers and 75 non‐carrier family members. Clinical ratings, CERAD word list delayed recall, hippocampal grey matter volume, florbetapir cortical‐to‐pontine standard‐uptake value ratios (SUVR), and precuneus 18F‐fludeoxyglucose (FDG) positron emission tomography were included in the analyses. T‐tests and multiple regressions models controlling for age, PSEN1 mutation status and amyloid burden were conducted.ResultsAcross groups, females had greater hippocampal volumes (p=.05) and better delayed recall (p=.005) than males. Female carriers were younger than male carriers (p=.04). Females continued to have better delayed recall after adjusting for glucose metabolism in the precuneus (Sex: β=.562, p=.023), and showed a trend towards significance after adjusting for hippocampal volumes (Sex: β=.462, p=.059). In carriers only, as age increased, males had lower hippocampal volumes than females (Slope difference: p ≤ .05), while no differences were found in amyloid levels or metabolism. There was no sex difference in the relationship between amyloid accumulation, hippocampal volumes (Sex: β=.000, p=.094), and metabolism (Sex: β=‐.004, p=.815).ConclusionFindings suggest that cognitively unimpaired female mutation carriers may have greater cognitive resilience to AD‐related neurodegeneration compared to male mutation carriers. Further investigation of sex‐specific differences in AD‐related clinical and pathological markers is key to inform AD detection, prevention, and development of treatments.

Depressive symptoms are associated with hippocampal neurodegeneration in preclinical autosomal dominant Alzheimer’s disease

AbstractBackgroundIncreasing evidence suggests that depressive symptoms may be among early behavioral changes in Alzheimer’s Disease (AD). However, the neurobiology of these symptoms in the preclinical stages of AD remains unclear, particularly in relation to markers of neurodegeneration. Studying depression in individuals who carry mutations for autosomal dominant AD (ADAD) is a compelling way to characterize depressive symptoms in preclinical AD, as virtually all ADAD mutation carriers develop dementia and have a well‐characterized trajectory from pre‐symptomatic to clinical disease stages.MethodWe evaluated cross‐sectional associations between the 15‐item Geriatric Depression Scale (GDS) and neurodegeneration of the hippocampus, one of the most vulnerable brain regions in ADAD and depression, in 27 cognitively unimpaired PSEN1 E280A mutation carriers and 26 matched non‐carrier family members of a Colombian kindred with ADAD. Global cognition was measured by the Mini‐Mental State Examination (MMSE); hippocampal volume was assessed by structural MRI. A general linear model with dependent variable GDS, predictor hippocampal volume, and covariates, age, sex, MMSE, and intracranial volume (ICV), was employed.Result PSEN1 E280A carriers and non‐carriers did not differ in GDS (carriers:2.2±2.6, non‐carriers:2.9±3.5; p=0.64), sex (carriers:70% females, non‐carriers:88% females; p=0.24), age (carriers:35.9±8.2 years, non‐carriers:37.0±6.5; p=0.56), ICV (carriers:1.4 x106 ±1.1 x 105 mm3, non‐carriers:1.4 x 106 ±1.3 x 105 mm3; p=0.16), or hippocampal volume (carriers: 3867±569 mm3, non‐carriers: 4090±371 mm3; p=0.20). Compared to non‐carriers, carriers had lower MMSE scores (carriers: 28.3±2.9, non‐carriers: 29.7±0.5; p=0.03). In carriers, GDS was negatively associated with hippocampal volume (β= ‐0.71, t= ‐2.6, p=0.02), but not with age, sex, MMSE, or ICV. This association between GDS and hippocampal volume was not observed in non‐carriers (β= ‐0.26, t= ‐1.2, p=0.25).ConclusionDepressive symptoms in cognitively‐unimpaired carriers of an ADAD mutation are significantly associated with early hippocampal neurodegeneration, years before the estimated onset of dementia. This provides some of the first evidence of a region‐specific neurodegenerative basis of depressive symptoms in preclinical ADAD. Future longitudinal investigation is needed to characterize the temporal sequence of depressive symptoms in relation to markers of brain pathology and cognitive decline in AD. Findings may have implications for early interventions to reduce depressive symptoms in individuals who have AD risk factors.

Reduced thalamic volume is associated with early brain pathology in preclinical autosomal dominant Alzheimer’s disease

AbstractBackgroundSleep‐wake dysregulation may increase the risk of developing Alzheimer’s Disease (AD). In turn, AD pathology in sleep/wake regulatory brain regions may exacerbate sleep disturbances. It is unclear whether sleep dysregulation occurs before or after the onset of clinical symptoms in AD. In this study, we aimed to investigate whether the volume of brain regions known to regulate sleep/wake cycles (thalamus, brainstem sub‐regions) was different between carriers and non‐carriers of autosomal dominant AD (ADAD); and whether volume of such brain regions is associated with markers of brain pathology (amyloid and tau) and memory performance.MethodsA total of 36 non‐demented Presenilin‐1 mutation carriers and 32 age‐matched non‐carrier family members (mean age=36.3, SD=6.1) from the Colombia‐Boston (COLBOS) study underwent memory testing, and MRI and PET scanning. The CERAD word list delayed recall was used to assess memory; FreeSurfer was used to analyze bilateral volumes of the thalamus and sub‐regions of the brainstem (medulla, pons, superior cerebellar peduncle, midbrain); Pittsburgh compound‐B and flortaucipir (FTP) were used to assess cortical amyloid and entorhinal tau levels, respectively. Non‐parametric tests were used to assess group differences and correlations between brain volume, brain pathology, and memory.ResultsNo MRI volumetric differences were found between groups. In carriers, reduced thalamic volume was associated with greater mean cortical amyloid (r= ‐0.48, p=0.006) and entorhinal tau (r= ‐0.46, p=0.008). Reduced thalamic volume was also associated with worse memory performance (r= 0.38, p=0.03). When controlling for age, which is a proxy for clinical progression in this population, these associations were no longer significant. No associations were observed between memory, pathology, and any of the brainstem sub‐regions .ConclusionFindings suggest that brain regions important for sleep‐wake regulation do not show early signs of degeneration in preclinical ADAD. The association between reduced thalamic volume with both cortical amyloid and entorhinal tau supports previous work suggesting that thalamic structures are affected early in the preclinical stage of ADAD. Future research should focus on the functional abnormalities and AD‐related pathology in specific thalamic nuclei during preclinical ADAD, and their potential associations with sleep physiological features, such as thalamic spindles.

The Latin American Spanish version of the Face-Name Associative Memory Exam is sensitive to cognitive and pathological changes in preclinical autosomal dominant Alzheimer\u2019s disease

BackgroundTo determine whether performance on the Latin American Spanish version of the Face-Name Associative Memory Exam (LAS-FNAME) can differentiate between cognitively intact carriers of an autosomal dominant Alzheimer’s disease mutation (E280A) in Presenilin-1, who are genetically determined to develop early-onset dementia, from matched non-carriers. We also sought to examine whether LAS-FNAME performance is associated with amyloid-β and regional tau burden in mutation carriers.MethodsA total of 35 cognitively intact mutation carriers (age range 26–41), 19 symptomatic carriers, and 48 matched non-carriers (age range 27–44) completed a neuropsychological assessment including the LAS-FNAME. A subset of participants (31 carriers [12 symptomatic] and 35 non-carriers) traveled from Colombia to Boston to undergo positron emission tomography (PET) using Pittsburgh compound B to measure mean cortical amyloid-β and flortaucipir for regional tau. ANOVA analyses and Spearman correlations were used to examine group differences and relationships among LAS-FNAME performance and amyloid-β and tau accumulation.ResultsCompared to non-carriers, cognitively intact mutation carriers had lower scores on the LAS-FNAME Total Scores (p = .040). Across all carriers (including symptomatic carriers), higher levels of amyloid-β (r = − .436, p = .018) and regional tau in the entorhinal (r = − .394, p = .031) and inferior temporal cortex (r = − .563, p = .001) were associated with lower LAS-FNAME Total Scores.ConclusionsPerformance on the LAS-FNAME differentiated between cognitively intact mutation carriers from non-carriers and was associated with greater amyloid and tau burden when examining all carriers. Findings suggest that the LAS-FNAME is sensitive to early clinical and pathological changes and can potentially help track disease progression in Spanish-speaking individuals.

A-05 The Latin American Spanish Version of the Face-Name Associative Memory Exam is Sensitive to Cognitive and Pathological Changes in Preclinical Autosomal Dominant Alzheimer’s Disease

Abstract Objective To determine whether performance on the Latin American Spanish version of the Face-Name Associative Memory Exam (LAS-FNAME) can differentiate between cognitively intact carriers of an autosomal dominant Alzheimer’s disease mutation (E280A) in Presenilin-1, who are destined to develop early-onset dementia, from matched non-carriers. We also sought to examine whether LAS-FNAME performance is associated with amyloid-β and regional tau burden in mutation carriers. Methods 35 cognitively intact mutation carriers (age range 26–41), 48 matched non-carriers (aged 27 to 44), and 19 symptomatic carriers (13 with subjective cognitive concerns, 6 with mild cognitive impairment [MCI]) completed the LAS-FNAME. A subset of participants (31 carriers [12 symptomatic] and 35 non-carriers) traveled from Colombia to Boston to undergo positron emission tomography (PET) using Pittsburgh compound B to measure mean cortical amyloid-β and Flortaucipir for regional tau tangles. ANOVA analyses and Spearman correlations were used to examine group differences and relationships among LAS-FNAME performance, Aβ and tau accumulation. Results Compared to non-carriers, cognitively intact carriers had lower scores on the LAS-FNAME total scores (p = .040). Across all carriers (including symptomatic carriers), higher levels of amyloid-β (r = −.436, p = .018) and regional tau in the entorhinal (r = −.394, p = .031) and inferior temporal cortex (r = −.563, p = .001) were associated with lower LAS-FNAME total scores (see Figure). Conclusions Performance on the LAS-FNAME differentiated between cognitively intact mutation carriers from non-carriers, and was associated with greater amyloid and tau burden when examining all carriers. Findings suggest that the LAS-FNAME is sensitive to early clinical and pathological changes and can potentially help track disease progression in Spanish-speaking individuals.

Intrusions in episodic memory in preclinical autosomal dominant Alzheimer’s disease: Contributions of education and occupation to optimal recall (1897)

Intrusions in episodic memory in preclinical autosomal dominant Alzheimer’s disease: Contributions of education and occupation to optimal recall (1897)

Staging biomarkers in preclinical autosomal dominant Alzheimer's disease by estimated years to symptom onset

IntroductionStaging preclinical Alzheimer disease (AD) by the expected years to symptom onset (EYO) in autosomal dominant AD (ADAD) through biomarker correlations is important. MethodsWe estimated the correlation matrix between EYO/cognition and imaging/CSF biomarkers, and searched for the EYO cutoff where a change in the correlations occurred before and after the cutoff among the asymptomatic mutation carriers of ADAD. We then estimated the longitudinal rate of change for biomarkers/cognition within each preclinical stage defined by the EYO. ResultsBased on the change in the correlations, the preclinical ADAD was divided by EYOs −7 and −13 years. Mutation carriers demonstrated a temporal ordering of biomarker/cognition changes across the three preclinical stages. DiscussionDuration of each preclinical stage can be estimated in ADAD, facilitating better planning of prevention trials with the EYO cutoffs under the recently released FDA guidance. The generalization of these results to sporadic AD warrants further investigation.

1H MRS spectroscopy in preclinical autosomal dominant Alzheimer disease.

1H magnetic resonance spectroscopy (MRS) can reveal changes in brain biochemistry in vivo in humans and has been applied to late onset Alzheimer disease (AD). Carriers of mutations for autosomal dominant Alzheimer disease (ADAD) may show changes in levels of metabolites prior to the onset of clinical symptoms. Proton MR spectra were acquired at 1.5T for 16 cognitively asymptomatic or mildly symptomatic mutation carriers (CDR < 1) and 11 non-carriers as part of a comprehensive cross-sectional study of preclinical ADAD. Levels of N-acetyl-aspartate+N-acetyl-aspartyl-glutamate (NAA), glutamate/glutamine (Glx), creatine/phosphocreate (Cr), choline (Cho), and myo-inositol (mI) in the left and right anterior cingulate and midline posterior cingulate and precuneus were compared between mutation carriers (MCs) and non-carriers (NCs) using multivariate analysis of variance with age as a covariate. Among MCs, correlations between metabolite levels and time until expected age of dementia diagnosis were calculated. MCs had significantly lower levels of NAA and Glx in the left pregenual anterior cingulate cortex, and lower levels of NAA and higher levels of mI and Cho in the precuneus compared to NCs. Increased levels of mI were seen in these regions in association with increased proximity to expected age of dementia onset. MRS shows effects of ADAD similar to those seen in late onset AD even during the preclinical period including lower levels of NAA and higher levels of mI. These indices of neuronal and glial dysfunction might serve as surrogate outcome measures in prevention studies of putative disease-modifying agents.

Early striatal amyloid deposition distinguishes Down syndrome and autosomal dominant Alzheimer's disease from late-onset amyloid deposition

IntroductionThe objective of this study was to evaluate amyloid β (Aβ) deposition patterns in different groups of cerebral β amyloidosis: (1) nondemented with amyloid precursor protein overproduction (Down syndrome); (2) nondemented with abnormal processing of amyloid precursor protein (preclinical autosomal dominant Alzheimer disease); (3) presumed alteration in Aβ clearance with clinical symptoms (late-onset AD); and (4) presumed alterations in Aβ clearance (preclinical AD). MethodsWe performed whole-brain voxelwise comparison of cerebral Aβ between 23 Down syndrome, 10 preclinical autosomal dominant Alzheimer disease, 17 late-onset AD, and 16 preclinical AD subjects, using Pittsburgh Compound B–positron emission tomography. ResultsWe found both Down syndrome and preclinical autosomal dominant Alzheimer disease shared a distinct pattern of increased bilateral striatal and thalamic Aβ deposition compared to late-onset AD and preclinical AD. ConclusionDisorders associated with early-life alterations in amyloid precursor protein production or processing are associated with a distinct pattern of early striatal fibrillary Aβ deposition before significant cognitive impairment. A better understanding of this unique pattern could identify important mechanisms of Aβ deposition and possibly important targets for early intervention.

Impairment of memory generalization in preclinical autosomal dominant Alzheimer's disease mutation carriers

Fast, inexpensive, and noninvasive identification of Alzheimer's disease (AD) before clinical symptoms emerge would augment our ability to intervene early in the disease. Individuals with fully penetrant genetic mutations causing autosomal dominant Alzheimer's disease (ADAD) are essentially certain to develop the disease, providing a unique opportunity to examine biomarkers during the preclinical stage. Using a generalization task that has previously shown to be sensitive to medial temporal lobe pathology, we compared preclinical individuals carrying ADAD mutations to noncarrying kin to determine whether generalization (the ability to transfer previous learning to novel but familiar recombinations) is vulnerable early, before overt cognitive decline. As predicted, results revealed that preclinical ADAD mutation carriers made significantly more errors during generalization than noncarrying kin, despite no differences between groups during learning or retention. This impairment correlated with the left hippocampal volume, particularly in mutation carriers. Such identification of generalization deficits in early ADAD may provide an easily implementable and potentially linguistically and culturally neutral way to identify and track cognition in ADAD.

Does BDNF Val66Met contribute to preclinical Alzheimer's disease?

This scientific commentary refers to ‘ BDNF Val66Met moderates memory impairment, hippocampal function and tau in preclinical autosomal dominant Alzheimer’s disease’, by Lim et al. (doi:10.1093/brain/aww200) . Brain-derived neurotrophic factor (BDNF) is a protein of 247 amino acids (NP_001137277) that is encoded on chromosome 11p13 in humans. During its biogenesis, the protein traverses through the endoplasmic reticulum and Golgi apparatus before it is stored in dense core vesicles. Following its activity-dependent release into the synaptic cleft, BDNF can bind to several receptors, including TrkB and p75. The activation of these and other cell surface receptors by an intricate balance of BDNF expression products, involving various BDNF splice isoforms and post-translational products, affects brain physiology and neural plasticity through a context-dependent promotion of long-term potentiation or depression. In addition, neurotrophic signalling elicited by BDNF modulates the architecture of the brain by influencing the stability of dendritic spines and promoting neurogenesis (Martinowich et al. , 2007). In this issue of Brain , Lim and co-workers show that a common BDNF polymorphism modulates Alzheimer-related endophenotypes in individuals with mutations in the APP , PSEN1 or PSEN2 genes (Lim et al. , 2016). Several coding variations have been reported in the human BDNF gene. The most studied BDNF variation, Val66Met (rs6265), maps to the pro-domain that is absent in mature BDNF (Fig. 1) and results in a 30% reduction in BDNF secretion, most likely by partially impairing its packaging into dense core vesicles. The Met66 allele is common in human populations (e.g. ∼30% heterozygotes and ∼4% homozygotes in datasets of European origin). Following early reports proposing that the Val66Met polymorphism confers risk of sporadic Alzheimer’s disease (Ventriglia et al. , 2002), the presence of this allele has been linked to a wide range of conditions from psychiatric and personality disorders, including …

BDNF Val66Met moderates memory impairment, hippocampal function and tau in preclinical autosomal dominant Alzheimer's disease.

SEE ROGAEVA AND SCHMITT-ULMS DOI101093/AWW201 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is implicated in synaptic excitation and neuronal integrity, and has previously been shown to moderate amyloid-β-related memory decline and hippocampal atrophy in preclinical sporadic Alzheimer's disease. However, the effect of BDNF in autosomal dominant Alzheimer's disease is unknown. We aimed to determine the effect of BDNF Val66Met on cognitive function, hippocampal function, tau and amyloid-β in preclinical autosomal dominant Alzheimer's disease. We explored effects of apolipoprotein E (APOE) ε4 on these relationships. The Dominantly Inherited Alzheimer Network conducted clinical, neuropsychological, genetic, biomarker and neuroimaging measures at baseline in 131 mutation non-carriers and 143 preclinical autosomal dominant Alzheimer's disease mutation carriers on average 12 years before clinical symptom onset. BDNF genotype data were obtained for mutation carriers (95 Val66 homozygotes, 48 Met66 carriers). Among preclinical mutation carriers, Met66 carriers had worse memory performance, lower hippocampal glucose metabolism and increased levels of cerebrospinal fluid tau and phosphorylated tau (p-tau) than Val66 homozygotes. Cortical amyloid-β and cerebrospinal fluid amyloid-β42 levels were significantly different from non-carriers but did not differ between preclinical mutation carrier Val66 homozygotes and Met66 carriers. There was an effect of APOE on amyloid-β levels, but not cognitive function, glucose metabolism or tau. As in sporadic Alzheimer's disease, the deleterious effects of amyloid-β on memory, hippocampal function, and tau in preclinical autosomal dominant Alzheimer's disease mutation carriers are greater in Met66 carriers. To date, this is the only genetic factor found to moderate downstream effects of amyloid-β in autosomal dominant Alzheimer's disease.