Victoria Tirado

Brain imaging and fluid biomarker analysis in young adults at genetic risk for autosomal dominant Alzheimer's disease in the presenilin 1 E280A kindred: a case-control study

BACKGROUND We have previously characterised functional brain abnormalities in young adults at genetic risk for late-onset Alzheimers disease. To gain further knowledge on the preclinical phase of Alzheimers disease, we sought to characterise structural and functional MRI, CSF, and plasma biomarkers in a cohort of young adults carrying a high-penetrance autosomal dominant mutation that causes early-onset Alzheimers disease. METHODS Between January and August, 2010, 18-26-year-old presenilin 1 (PSEN1) E280A mutation carriers and non-carriers from the Colombian Alzheimers Prevention Initiative Registry in Medellín Antioquia, Colombia, had structural MRI, functional MRI during associative memory encoding and novel viewing and control tasks, and cognitive assessments. Consenting participants also had lumbar punctures and venepunctures. Outcome measures were task-dependent hippocampal or parahippocampal activations and precuneus or posterior cingulate deactivations, regional grey matter reductions, CSF Aβ(1-42), total tau and phospho-tau(181) concentrations, and plasma Aβ(1-42) concentrations and Aβ(1-42):Aβ(1-40) ratios. Structural and functional MRI data were compared using automated brain mapping algorithms and search regions related to Alzheimers disease. Cognitive and fluid biomarkers were compared using Mann-Whitney tests. FINDINGS 44 participants were included: 20 PSEN1 E280A mutation carriers and 24 non-carriers. The carrier and non-carrier groups did not differ significantly in their dementia ratings, neuropsychological test scores, or proportion of apolipoprotein E (APOE) ɛ4 carriers. Compared with non-carriers, carriers had greater right hippocampal and parahippocampal activation (p=0·001 and p<0·014, respectively, after correction for multiple comparisons), less precuneus and posterior cingulate deactivation (all p<0·010 after correction), and less grey matter in several parietal regions (all p<0·002 uncorrected and corrected p=0·009 in the right parietal search region). In the 20 participants (ten PSEN1 E280A mutation carriers and ten non-carriers) who had lumbar punctures and venepunctures, mutation carriers had higher CSF Aβ(1-42) concentrations (p=0·008) and plasma Aβ(1-42) concentrations (p=0·01) than non-carriers. INTERPRETATION Young adults at genetic risk for autosomal dominant Alzheimers disease have functional and structural MRI findings and CSF and plasma biomarker findings consistent with Aβ(1-42) overproduction. Although the extent to which the underlying brain changes are either neurodegenerative or developmental remain to be determined, this study shows the earliest known biomarker changes in cognitively normal people at genetic risk for autosomal dominant Alzheimers disease. FUNDING Banner Alzheimers Foundation, Nomis Foundation, Anonymous Foundation, Forget Me Not Initiative, Boston University Department of Psychology, Colciencias, National Institute on Aging, National Institute of Neurological Disorders and Stroke, and the State of Arizona.

Apolipoprotein Eε4 modifies Alzheimer's disease onset in an E280A PS1 kindred

We previously have identified a large kindred from Colombia in which Alzheimers disease (AD) is caused by the E280A presenilin 1 (PS1) mutation. The objective of this study was to examine whether environmental and genetic factors are responsible for variation in the phenotypic expression of the E280A PS1 mutation. We genotyped coding and promoter polymorphisms of the APOE gene in carriers of the E280A PS1 mutation. Kaplan–Meier product‐limit and Cox proportional hazard models were used in the statistical analyses. DNA was available from 114 carriers of the E280A PS1 mutation, including 52 subjects with AD. APOE ε4 allele carriers were more likely to develop AD at an earlier age than subjects without the ε4 allele (hazard ratio, 2.07; 95% confidence interval, 1.07–3.99; p = 0.030). Subjects with low education were more likely to develop AD later than those with higher education (hazard ratio, 0.476; 95% confidence interval, 0.26–0.87). Low educational level was associated with rural residence (p < 0.001). Promoter APOE variants did not influence either the onset or the duration of the disease. This study is the first to our knowledge to demonstrate that genetic and environmental factors influence age of onset in a kindred with a familial AD mutation. Ann Neurol 2003

Associations Between Biomarkers and Age in the Presenilin 1 E280A Autosomal Dominant Alzheimer Disease Kindred A Cross-sectional Study

IMPORTANCE Age-associated changes in brain imaging and fluid biomarkers are characterized and compared in presenilin 1 (PSEN1)E280A mutation carriers and noncarriers from the worlds largest known autosomal dominant Alzheimer disease (AD) kindred. OBJECTIVE To characterize and compare age-associated changes in brain imaging and fluid biomarkers in PSEN1 E280A mutation carriers and noncarriers. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional measures of 18F-florbetapir positron emission tomography, 18F-fludeoxyglucose positron emission tomography, structural magnetic resonance imaging, cerebrospinal fluid (CSF), and plasma biomarkers of AD were assessed from 54 PSEN1 E280A kindred members (age range, 20-59 years). MAIN OUTCOMES AND MEASURES We used brain mapping algorithms to compare regional cerebral metabolic rates for glucose and gray matter volumes in cognitively unimpaired mutation carriers and noncarriers. We used regression analyses to characterize associations between age and the mean cortical to pontine 18F-florbetapir standard uptake value ratios, precuneus cerebral metabolic rates for glucose, hippocampal gray matter volume, CSF Aβ1-42, total tau and phosphorylated tau181, and plasma Aβ measurements. Age at onset of progressive biomarker changes that distinguish carriers from noncarriers was estimated using best-fitting regression models. RESULTS Compared with noncarriers, cognitively unimpaired mutation carriers had significantly lower precuneus cerebral metabolic rates for glucose, smaller hippocampal volume, lower CSF Aβ1-42, higher CSF total tau and phosphorylated tau181, and higher plasma Aβ1-42 measurements. Sequential changes in biomarkers were seen at age 20 years (95% CI, 14-24 years) for CSF Aβ1-42, age 16 years (95% CI, 11-24 years) for the mean cortical 18F-florbetapir standard uptake value ratio, age 15 years (95% CI, 10-24 years) for precuneus cerebral metabolic rate for glucose, age 15 years (95% CI, 7-20 years) for CSF total tau, age 13 years (95% CI, 8-19 years) for phosphorylated tau181, and age 6 years (95% CI, 1-10 years) for hippocampal volume, with cognitive decline up to 6 years before the kindreds estimated median age of 44 years (95% CI, 43-45 years) at mild cognitive impairment diagnosis. No age-associated findings were seen in plasma Aβ1-42 or Aβ1-40. CONCLUSIONS AND RELEVANCE This cross-sectional study provides additional information about the course of different AD biomarkers in the preclinical and clinical stages of autosomal dominant AD.

The Alzheimer's prevention initiative composite cognitive test score: sample size estimates for the evaluation of preclinical Alzheimer's disease treatments in presenilin 1 E280A mutation carriers.

OBJECTIVE To identify a cognitive composite that is sensitive to tracking preclinical Alzheimers disease decline to be used as a primary end point in treatment trials. METHOD We capitalized on longitudinal data collected from 1995 to 2010 from cognitively unimpaired presenilin 1 (PSEN1) E280A mutation carriers from the worlds largest known early-onset autosomal dominant Alzheimers disease kindred to identify a composite cognitive test with the greatest statistical power to track preclinical Alzheimers disease decline and estimate the number of carriers age 30 years and older needed to detect a treatment effect in the Alzheimers Prevention Initiatives (API) preclinical Alzheimers disease treatment trial. The mean-to-standard-deviation ratios (MSDRs) of change over time were calculated in a search for the optimal combination of 1 to 7 cognitive tests/subtests drawn from the neuropsychological test battery in cognitively unimpaired mutation carriers during a 2- and 5-year follow-up period (n = 78 and 57), using data from noncarriers (n = 31 and 56) during the same time period to correct for aging and practice effects. Combinations that performed well were then evaluated for robustness across follow-up years, occurrence of selected items within top-performing combinations, and representation of relevant cognitive domains. RESULTS The optimal test combination included Consortium to Establish a Registry for Alzheimers Disease (CERAD) Word List Recall, CERAD Boston Naming Test (high frequency items), Mini-Mental State Examination (MMSE) Orientation to Time, CERAD Constructional Praxis, and Ravens Progressive Matrices (Set A), with an MSDR of 1.62. This composite is more sensitive than using either the CERAD Word List Recall (MSDR = 0.38) or the entire CERAD-Col battery (MSDR = 0.76). A sample size of 75 cognitively normal PSEN1 E280A mutation carriers aged 30 years and older per treatment arm allows for a detectable treatment effect of 29% in a 60-month trial (80% power, P = .05). CONCLUSIONS We have identified a composite cognitive test score representing multiple cognitive domains that, compared to the most sensitive single test item, has improved power to track preclinical Alzheimers disease decline in autosomal dominant Alzheimers disease mutation carriers and to evaluate preclinical Alzheimers disease treatments. This API composite cognitive test score will be used as the primary end point in the first API trial in cognitively unimpaired autosomal dominant Alzheimers disease carriers within 15 years of their estimated age at clinical onset. We have independently confirmed our findings in a separate cohort of cognitively healthy older adults who progressed to the clinical stages of late-onset Alzheimers disease, described in a separate report, and continue to refine the composite in independent cohorts and compared with other analytic approaches.

Brain Imaging and Blood Biomarker Abnormalities in Children With Autosomal Dominant Alzheimer Disease: A Cross-Sectional Study

IMPORTANCE Brain imaging and fluid biomarkers are characterized in children at risk for autosomal dominant Alzheimer disease (ADAD). OBJECTIVE To characterize and compare structural magnetic resonance imaging (MRI), resting-state and task-dependent functional MRI, and plasma amyloid-β (Aβ) measurements in presenilin 1 (PSEN1) E280A mutation-carrying and noncarrying children with ADAD. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional measures of structural and functional MRI and plasma Aβ assays were assessed in 18 PSEN1 E280A carriers and 19 noncarriers aged 9 to 17 years from a Colombian kindred with ADAD. Recruitment and data collection for this study were conducted at the University of Antioquia and the Hospital Pablo Tobon Uribe in Medellín, Colombia, between August 2011 and June 2012. MAIN OUTCOMES AND MEASURES All participants had blood sampling, structural MRI, and functional MRI during associative memory encoding and resting-state and cognitive assessments. Outcome measures included plasma Aβ1-42 concentrations and Aβ1-42:Aβ1-40 ratios, memory encoding-dependent activation changes, resting-state connectivity, and regional gray matter volumes. Structural and functional MRI data were compared using automated brain mapping algorithms and search regions related to AD. RESULTS Similar to findings in adult mutation carriers, in the later preclinical and clinical stages of ADAD, mutation-carrying children were distinguished from control individuals by significantly higher plasma Aβ1-42 levels (mean [SD]: carriers, 18.8 [5.1] pg/mL and noncarriers, 13.1 [3.2] pg/mL; P < .001) and Aβ1-42:Aβ1-40 ratios (mean [SD]: carriers, 0.32 [0.06] and noncarriers, 0.21 [0.03]; P < .001), as well as less memory encoding task-related deactivation in parietal regions (eg, mean [SD] parameter estimates for the right precuneus were -0.590 [0.50] for noncarriers and -0.087 [0.38] for carriers; P < .005 uncorrected). Unlike carriers in the later stages, mutation-carrying children demonstrated increased functional connectivity of the posterior cingulate cortex with medial temporal lobe regions (mean [SD] parameter estimates were 0.038 [0.070] for noncarriers and 0.190 [0.057] for carriers), as well as greater gray matter volumes in temporal regions (eg, left parahippocampus; P < . 049, corrected for multiple comparisons). CONCLUSIONS AND RELEVANCE Children at genetic risk for ADAD have functional and structural brain changes and abnormal levels of plasma Aβ1-42. The extent to which the underlying brain changes are either neurodegenerative or developmental remains to be determined. This study provides additional information about the earliest known biomarker changes associated with ADAD.

Cognitive Decline in a Colombian Kindred With Autosomal Dominant Alzheimer Disease: A Retrospective Cohort Study

IMPORTANCE Data from an autosomal dominant Alzheimer disease (ADAD) kindred were used to track the longitudinal trajectory of cognitive decline associated with preclinical ADAD and explore factors that may modify the rate of cognitive decline. OBJECTIVES To evaluate the onset and rate of cognitive decline during preclinical ADAD and the effect of socioeconomic, vascular, and genetic factors on the cognitive decline. DESIGN, SETTING, AND PARTICIPANTS We performed a retrospective cohort study from January 1, 1995, through June 31, 2012, of individuals from Antioquia, Colombia, who tested positive for the ADAD-associated PSEN1 E280A mutation. Data analysis was performed from August 20, 2014, through November 30, 2015. A mixed-effects model was used to estimate annual rates of change in cognitive test scores and to mark the onset of cognitive decline. MAIN OUTCOMES AND MEASURES Memory, language, praxis, and total scores from the Consortium to Establish a Registry for Alzheimer Disease test battery. Chronologic age was used as a time scale in the models. We explore the effects of sex; educational level; socioeconomic status; residence area; occupation type; marital status; history of hypertension, diabetes mellitus, and dyslipidemia; tobacco and alcohol use; and APOE ε4 on the rates of cognitive decline. RESULTS A total of 493 carriers met the inclusion criteria and were analyzed. A total of 256 carriers had 2 or more assessments. At the time of the initial assessment, participants had a mean (SD) age of 33.4 (11.7) years and a mean (SD) educational level of 7.2 (4.2) years. They were predominantly female (270 [54.8%]), married (293 [59.4%]), and of low socioeconomic status (322 [65.3%]). Word list recall scores provided the earliest indicator of preclinical cognitive decline at 32 years of age, 12 and 17 years before the kindreds respective median ages at mild cognitive impairment and dementia onset. After the change point, carriers had a statistically significant cognitive decline with a loss of 0.24 (95% CI, -0.26 to -0.22) points per year for the word list recall test and 2.13 (95% CI, -2.29 to -1.96) points per year for total scores. Carriers with high educational levels had an increase of approximately 36% in the rate of cognitive decline after the change point when compared with those with low educational levels (-2.89 vs -2.13 points per year, respectively). Onset of cognitive decline was delayed by 3 years in individuals with higher educational levels compared with those with lower educational levels. Those with higher educational level, middle/high socioeconomic status, history of diabetes and hypertension, and tobacco and alcohol use had a steeper cognitive decline after onset. CONCLUSIONS AND RELEVANCE Preclinical cognitive decline was evident in PSEN1 E280A mutation carriers 12 years before the onset of clinical impairment. Educational level may be a protective factor against the onset of cognitive impairment.

Diagnostic accuracy of CERAD total score in a Colombian cohort with mild cognitive impairment and Alzheimer's disease affected by E280A mutation on presenilin-1 gene.

BACKGROUND This study aimed to determine Consortium to Establish a Registry for Alzheimers Disease (CERAD) Neuropsychological Assessment Battery total score diagnostic accuracy in the diagnosis of mild cognitive impairment (MCI) and dementia in familial Alzheimers disease (FAD) with E280A mutation on presenilin-1 gene (PSEN1). METHODS A cross-sectional study was conducted in a cohort of PSEN1 E280A carriers and non-carriers assessed between January 1995 and February 2013. During the first neuropsychological assessment, 76 were having dementia, 46 had MCI, and 1,576 were asymptomatic. CERAD cut-off points were established for MCI and dementia using a Receiver Operating Characteristics (ROC) analysis, and were further analyzed according to education level in two groups: low education level (eight years or less), and high education level (over eight years). RESULTS The area under curve-ROC CERAD total score for dementia was 0.994 (95% CI = 0.989-0.999), and that for MCI was 0.862 (95% CI = 0.816-0.908). The dementia diagnosis cut-off point for the low education group was 54, (98.4% sensitivity, 92.6% specificity), and that for the high education group was 67 (100% sensitivity, 94.1% specificity). The MCI diagnosis cut-off point for the low education group was 66 (91.2% sensitivity, 56.4% specificity), and that for the high education group was 72 (91.7% sensitivity, 76.3% specificity). CONCLUSIONS The CERAD total score is a useful screening tool for dementia and MCI in a population at risk of FAD.

Subjective memory complaints in preclinical autosomal dominant Alzheimer disease

Objective: To cross-sectionally study subjective memory complaints (SMC) in autosomal dominant Alzheimer disease (ADAD). Methods: We examined self-reported and study partner–based SMC in 52 young, cognitively unimpaired individuals from a Colombian kindred with early-onset ADAD. Twenty-six carried the PSEN-1 E280A mutation, averaging 7 years of age younger than the kindreds expected clinical onset. Twenty-six were age-matched noncarriers. Participants also underwent structural MRI and cognitive testing. Results: Self-reported SMC were greater in carriers than noncarriers (p = 0.02). Study partner–based SMC did not differ between groups (p = 0.21), but in carriers increased with age (r = 0.66, p < 0.001) and decreased with hippocampal volume (r = −0.35, p = 0.08). Conclusions: Cognitively unimpaired PSEN-1 carriers have elevated SMC. Self-reported SMC may be a relatively early indicator of preclinical AD, while partner- reported SMC increases later in preclinical AD, closer to clinical onset.

Relationships between baseline biomarkers and subsequent cognitive decline in cognitively unimpaired PSEN1 E280A mutation carriers from the colombian kindred with autosomal dominant Alzheimer’s disease

VFT Normal 11 10 0.031* 6 15 0.151 12 9 0.070 Mildly impaired 5 11 2 14 7 9 Moderately impaired 4 21 2 23 6 19 mBNT Normal 14 16 0.063 8 22 0.058 15 15 0.323 Mildly impaired 3 13 2 14 5 11 Moderately impaired 3 13 0 16 5 11 MMSEKC Normal 1 2 0.056 0 3 0.002* 3 0 0.014* Mildly impaired 6 3 5 4 6 3 Moderately impaired 13 37 5 45 16 34 WLMT Normal 9 11 0.088 6 14 0.103 10 10 0.451 Mildly impaired 6 8 2 14 6 8 Moderately impaired 5 23 2 26 9 19 CPT Normal 15 25 0.111 9 31 0.167 19 21 0.295 Mildly impaired 5 9 1 13 4 10 Moderately impaired 0 8 0 8 2 6 WLRT Normal 7 2 0.005* 4 5 0.042* 6 3 0.215 Mildly impaired 2 10 1 11 4 8 Moderately impaired 11 30 5 36 15 26 WLRcT Normal 11 9 0.021* 7 13 0.014* 10 10 0.301 Mildly impaired 4 9 0 13 3 10 Moderately impaired 5 24 3 26 12 17 CRT Normal 6 4 0.116 4 6 0.051 6 4 0.333 Mildly impaired 2 7 2 7 4 5 Moderately impaired 12 31 4 39 15 28

Factores asociados con el declive cognitivo en población menor de 65 años. Una revisión sistemática

INTRODUCTION Cognitive decline could begin 20 years before the diagnosis of dementia. Besides age, several factors related to medical, socioeconomic, and behavioral and genetic condition may be associated with cognitive decline. The aim of this systematic review was to summarize evidence on the risk and protective factors for cognitive decline in people under 65 years old. METHODS A systematic review was conducted using a search strategy in MEDLINE and Embase, including longitudinal studies to analyze the effect of protective or risk factors on cognitive decline in a population under 65 years old. RESULTS A total of 22 studies were included in this review. Factors such as diabetes, hyperinsulinemia, overweight or obesity, metabolic syndrome, education, physical activity, cognitive stimulation, marital status and diet, could be related to cognitive decline before 65 years of age. CONCLUSIONS Cardiovascular risk factors and lifestyle conditions may be associated with cognitive decline before 65 years of age. However, the quality of the evidence was low.