Dataset Information

ATN profiles among cognitively normal individuals and longitudinal cognitive outcomes.

ABSTRACT: OBJECTIVE:To examine the long-term cognitive trajectories of individuals with normal cognition at baseline and distinct amyloid/tau/neurodegeneration (ATN) profiles. METHODS:Pooling data across 4 cohort studies, 814 cognitively normal participants (mean baseline age = 59.6 years) were classified into 8 ATN groups using baseline CSF levels of β-amyloid 1-42 as a measure of amyloid (A), phosphorylated tau 181 as a measure of tau (T), and total tau as a measure of neurodegeneration (N). Cognitive performance was measured using a previously validated global factor score and with the Mini-Mental State Examination. We compared the cognitive trajectories across groups using growth curve models (mean follow-up time = 7 years). RESULTS:Using different model formulations and cut points for determining biomarker abnormality, only the group with abnormal levels of amyloid, tau, and neurodegeneration (A+T+N+) showed consistently greater cognitive decline than the group with normal levels of all biomarkers (A-T-N-). Replicating prior findings using the 2011 National Institute on Aging-Alzheimer's Association/suspected non-Alzheimer disease pathophysiology schema, only individuals with abnormal levels of both amyloid and phosphorylated tau 181 or total tau (stage 2) showed greater cognitive decline than those with normal biomarker levels (stage 0). CONCLUSION:The results are consistent with the hypothesis that both elevated brain amyloid and neurofibrillary tangles are necessary to observe accelerated neurodegeneration, which in turn leads to cognitive decline.

SUBMITTER: Soldan A

PROVIDER: S-EPMC6448449 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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ATN profiles among cognitively normal individuals and longitudinal cognitive outcomes.

Soldan Anja A Pettigrew Corinne C Fagan Anne M AM Schindler Suzanne E SE Moghekar Abhay A Fowler Christopher C Li Qiao-Xin QX Collins Steven J SJ Carlsson Cynthia C Asthana Sanjay S Masters Colin L CL Johnson Sterling S Morris John C JC Albert Marilyn M Gross Alden L AL

Neurology 20190306 14

<h4>Objective</h4>To examine the long-term cognitive trajectories of individuals with normal cognition at baseline and distinct amyloid/tau/neurodegeneration (ATN) profiles.<h4>Methods</h4>Pooling data across 4 cohort studies, 814 cognitively normal participants (mean baseline age = 59.6 years) were classified into 8 ATN groups using baseline CSF levels of β-amyloid 1-42 as a measure of amyloid (A), phosphorylated tau 181 as a measure of tau (T), and total tau as a measure of neurodegeneration ( ...[more]

PMID: 30842300

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Project description:BackgroundIndividuals on the preclinical Alzheimer's continuum, particularly those with both amyloid and tau positivity (A + T +), display a rapid cognitive decline and elevated disease progression risk. However, limited studies exist on brain atrophy trajectories within this continuum over extended periods.MethodsThis study involved 367 ADNI participants grouped based on combinations of amyloid and tau statuses determined through cerebrospinal fluid tests. Using longitudinal MRI scans, brain atrophy was determined according to the whole brain, lateral ventricle, and hippocampal volumes and cortical thickness in AD-signature regions. Cognitive performance was evaluated with the Preclinical Alzheimer's Cognitive Composite (PACC). A generalized linear mixed-effects model was used to examine group × time interactions for these measures. In addition, progression risks to mild cognitive impairment (MCI) or dementia were compared among the groups using Cox proportional hazards models.ResultsA total of 367 participants (48 A + T + , 86 A + T - , 63 A - T + , and 170 A - T - ; mean age 73.8 years, mean follow-up 5.1 years, and 47.4% men) were included. For the lateral ventricle and PACC score, the A + T - and A + T + groups demonstrated statistically significantly greater volume expansion and cognitive decline over time than the A - T - group (lateral ventricle: β = 0.757 cm3/year [95% confidence interval 0.463 to 1.050], P < .001 for A + T - , and β = 0.889 cm3/year [0.523 to 1.255], P < .001 for A + T + ; PACC: β = - 0.19 /year [- 0.36 to - 0.02], P = .029 for A + T - , and β = - 0.59 /year [- 0.80 to - 0.37], P < .001 for A + T +). Notably, the A + T + group exhibited additional brain atrophy including the whole brain (β = - 2.782 cm3/year [- 4.060 to - 1.504], P < .001), hippocampus (β = - 0.057 cm3/year [- 0.085 to - 0.029], P < .001), and AD-signature regions (β = - 0.02 mm/year [- 0.03 to - 0.01], P < .001). Cox proportional hazards models suggested an increased risk of progressing to MCI or dementia in the A + T + group versus the A - T - group (adjusted hazard ratio = 3.35 [1.76 to 6.39]).ConclusionsIn cognitively normal individuals, A + T + compounds brain atrophy and cognitive deterioration, amplifying the likelihood of disease progression. Therapeutic interventions targeting A + T + individuals could be pivotal in curbing brain atrophy, cognitive decline, and disease progression.

Project description:BackgroundBoth Alzheimer's disease (AD) genetic risk factors and indices of cognitive reserve (CR) influence risk of cognitive decline, but it remains unclear whether they interact. This study examined whether a CR index score modifies the relationship between AD genetic risk factors and long-term cognitive trajectories in a large sample of individuals with normal cognition.MethodsAnalyses used data from the Preclinical AD Consortium, including harmonized data from 5 longitudinal cohort studies. Participants were cognitively normal at baseline (M baseline age = 64 years, 59% female) and underwent 10 years of follow-up, on average. AD genetic risk was measured by (i) apolipoprotein-E (APOE) genetic status (APOE-ε2 and APOE-ε4 vs. APOE-ε3; N = 1819) and (ii) AD polygenic risk scores (AD-PRS; N = 1175). A CR index was calculated by combining years of education and literacy scores. Longitudinal cognitive performance was measured by harmonized factor scores for global cognition, episodic memory, and executive function.ResultsIn mixed-effects models, higher CR index scores were associated with better baseline cognitive performance for all cognitive outcomes. APOE-ε4 genotype and AD-PRS that included the APOE region (AD-PRSAPOE) were associated with declines in all cognitive domains, whereas AD-PRS that excluded the APOE region (AD-PRSw/oAPOE) was associated with declines in executive function and global cognition, but not memory. There were significant 3-way CR index score × APOE-ε4 × time interactions for the global (p = 0.04, effect size = 0.16) and memory scores (p = 0.01, effect size = 0.22), indicating the negative effect of APOE-ε4 genotype on global and episodic memory score change was attenuated among individuals with higher CR index scores. In contrast, levels of CR did not attenuate APOE-ε4-related declines in executive function or declines associated with higher AD-PRS. APOE-ε2 genotype was unrelated to cognition.ConclusionsThese results suggest that APOE-ε4 and non-APOE-ε4 AD polygenic risk are independently associated with global cognitive and executive function declines among individuals with normal cognition at baseline, but only APOE-ε4 is associated with declines in episodic memory. Importantly, higher levels of CR may mitigate APOE-ε4-related declines in some cognitive domains. Future research is needed to address study limitations, including generalizability due to cohort demographic characteristics.

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ATN profiles among cognitively normal individuals and longitudinal cognitive outcomes.

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ATN profiles among cognitively normal individuals and longitudinal cognitive outcomes.

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