Coath, William Oliver; (2025) Characterising Pre-Symptomatic Trajectories of Alzheimer’s Disease Pathology Using Amyloid-Beta and Tau PET in the 1946 British Birth Cohort. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Amyloid-beta (Aβ) and hyperphosphorylated tau are cardinal pathologies of AD, detectable in vivo through positron emission tomography (PET) years before symptom onset. Identifying the onset of pathology and rates of presymptomatic change are vital for informing trials aimed at disease prevention. In this thesis, I aimed to utilise PET imaging to characterise the emergence of Aβ and tau pathologies in individuals enrolled in Insight 46, the neuroimaging sub-study of the 1946 British birth cohort. I performed a systematic evaluation of Aβ-PET standard uptake value ratio (SUVR) processing approaches at baseline (age 69-72 years). The different methods classified between 16-25% as Aβ positive. The ability of cerebellum referenced SUVRs to detect Aβ increased with partial volume correction. I applied the Centiloid standardisation in this PET/MR dataset and found that SUVRs could be transformed to Centiloids, however, differences remained after transformation. Data driven positivity cutpoints fell between 12-23 Centiloids (CL). In a longitudinal evaluation, reliable accumulation was found to be 3-4 CL/year. A novel longitudinal processing pipeline added benefit in some scenarios. I then estimated individual age at Aβ positivity (Aβ age). I found that median Aβ-free survival for APOE ε4 carriers reached at age ∼71 years. APOE ε4 non-carriers were ∼11 years behind. Lastly, investigated [18F]MK-6240 tau-PET at age ∼77 years in the context of Aβ duration (chronological age - Aβ age). Changepoints in the relationship between tau-PET and Aβ duration were detected ∼2 years following estimated Aβ-PET positivity in early regions. After ∼11-13 years of Aβ-PET positivity, changepoints were found in later regions. As we move into the era of AD prevention trials, understanding the timing of Aβ and tau will be crucial. The first decade of Aβ positivity is emerging as an important period, where intervention before widespread tau holds promise for slowing or even halting clinical decline.

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