Cerebrospinal fluid tau and ptau
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            increase with cortical amyloid deposition in cognitively normal individuals: Implications for future clinical trials of Alzheimer's disease

Background: Subjective cognitive decline (SCD) might occur at the early stages of dementia. Individuals with SCD have an increased risk of subsequent objective cognitive decline and greater rates of progression to dementia. Objective: We aimed to explore the associations between SCD and cerebrospinal fluid (CSF) biomarkers of Alzheimer’s disease (AD) pathology in cognitively normal individuals. Methods: A total of 1,099 cognitively normal elders with available data on CSF biomarkers of AD pathology (Aβ 42, P-tau, and T-tau) were included in our analysis. Linear regression was used to examine the associations of SCD status and SCD severity with CSF biomarkers. Additionally, a review was conducted to discuss the associations between SCD and CSF biomarkers of AD pathology. Results: After adjustments for covariates, SCD and SCD severity showed significant associations with CSF Aβ 42 (SCD: β= –0.0003, p = 0.0263; SCD severity: β= –0.0004, p = 0.0046), CSF T-tau/Aβ 42 ratio (SCD: β= 0.1080, p = 0.1080; SCD severity: β= 0.1129, p = 0.0009) and CSF P-tau/Aβ 42 ratio (SCD: β= 0.0167, p = 0.0103; SCD severity: β= 0.0193, p = 0.0006) rather than T-tau and P-tau compared with cognitively normal individuals. In the review, a total of 28 studies were finally included after reviewing 174 articles. CSF Aβ 42 was lower in SCD than cognitively normal (CN) individuals, but higher than those with objective cognitive decline. However, CSF tau pathology showed no difference between SCD and CN. Conclusion: The results indicated that pathophysiological changes in CSF Aβ pathology occurred in individuals with SCD, which provide new insights into early intervention of AD.

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O1-01-06: Longitudinal changes in cerebrospinal fluid biomarkers of Alzheimer's disease during middle-age in cognitively normal individuals with a positive family history

Alzheimer s & Dementia ◽

10.1016/j.jalz.2012.05.207 ◽

2012 ◽

Vol 8 (4S_Part_2) ◽

pp. P86-P86

Author(s):

Courtney L. Sutphen ◽

Aarti R. Shah ◽

Matthew Amos ◽

Andrei G. Vlassenko ◽

Tammie L.S. Benzinger ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Family History ◽

Middle Age ◽

Positive Family History ◽

Cognitively Normal ◽

Longitudinal Changes ◽

Cerebrospinal Fluid Biomarkers ◽

Normal Individuals

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On the design of early-phase Alzheimer’s disease clinical trials with cerebrospinal fluid tau outcomes

Clinical Trials ◽

10.1177/17407745211034497 ◽

2021 ◽

pp. 174077452110344

Author(s):

Michelle M Nuño ◽

Joshua D Grill ◽

Daniel L Gillen ◽

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Clinical Trials ◽

Cerebrospinal Fluid ◽

Phosphorylated Tau ◽

Inclusion Criteria ◽

Eligibility Criteria ◽

Total Tau ◽

Prodromal Alzheimer’S Disease ◽

Study Power

Background/Aims: The focus of Alzheimer’s disease studies has shifted to earlier disease stages, including mild cognitive impairment. Biomarker inclusion criteria are often incorporated into mild cognitive impairment clinical trials to identify individuals with “prodromal Alzheimer’s disease” to ensure appropriate drug targets and enrich for participants likely to develop Alzheimer’s disease dementia. The use of these eligibility criteria may affect study power. Methods: We investigated outcome variability and study power in the setting of proof-of-concept prodromal Alzheimer’s disease trials that incorporate cerebrospinal fluid levels of total tau (t-tau) and phosphorylated (p-tau) as primary outcomes and how differing biomarker inclusion criteria affect power. We used data from the Alzheimer’s Disease Neuroimaging Initiative to model trial scenarios and to estimate the variance and within-subject correlation of total and phosphorylated tau. These estimates were then used to investigate the differences in study power for trials considering these two surrogate outcomes. Results: Patient characteristics were similar for all eligibility criteria. The lowest outcome variance and highest within-subject correlation were obtained when phosphorylated tau was used as an eligibility criterion, compared to amyloid beta or total tau, regardless of whether total tau or phosphorylated tau were used as primary outcomes. Power increased when eligibility criteria were broadened to allow for enrollment of subjects with either low amyloid beta or high phosphorylated tau. Conclusion: Specific biomarker inclusion criteria may impact statistical power in trials using total tau or phosphorylated tau as the primary outcome. In concert with other important considerations such as treatment target and population of clinical interest, these results may have implications to the integrity and efficiency of prodromal Alzheimer’s disease trial designs.

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