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[Display omitted] Numerous clinical trials based on a single-cause paradigm have not resulted in efficacious treatments for Alzheimer's disease (AD). Recently, prevention trials that simultaneously intervened on multiple risk factors have shown mixed results, suggesting that careful design is necessary. Moreover, intensive pilot precision medicine (PM) trial results have been promising but may not generalize to a broader population. These observations suggest that a model-based approach to multi-factor precision medicine (PM) is warranted. We systematically developed a system dynamics model (SDM) of AD for PM using data from two longitudinal studies (N=3660). This method involved a model selection procedure in identifying interaction terms between the SDM components and estimating individualized parameters. We used the SDM to explore simulated single- and double-factor interventions on 14 modifiable risk factors. We quantified the potential impact of double-factor interventions over single-factor interventions as 1.5 [95% CI: 1.5–2.6] and of SDM-based PM over a one-size-fits-all approach as 3.5 [3.1, 3.8] ADAS-cog-13 points in 12 years. Although the model remains to be validated, we tentatively conclude that multi-factor PM could come to play an important role in AD prevention. [ABSTRACT FROM AUTHOR]

Structural and functional alterations of the brain in persons genetically at-risk for Alzheimer's disease (AD) are crucial in unravelling AD development. Filippini et al. found that the default mode network (DMN) is already affected in young APOE ε4-carriers, with increased co-activation of the DMN during rest and increased hippocampal task activation. We aimed to replicate the early findings of Filippini et al, using the APOE gene, still the principal AD risk gene, and extended this with a polygenic risk score (PRS) analysis for AD, using the Human Connectome Project dataset (HCP). We included participants from the HCP S1200 dataset (age range: 22-36 years). We studied morphometric features, functional DMN co-activation and functional task activation of recollection performance. Permutation Analysis of Linear Models (PALM) was used to test for group differences between APOE ε4-carriers and non-carriers, and to test the association with PRS. PALM controls for biases induced by the family structure of the HCP sample. Results were family-wise error rate corrected at p < 0.05. Our primary analysis did not replicate the early findings of Filippini et al. (2009). However, compared with non-carriers, APOE ε4-carriers showed increased functional activation during the encoding of subsequently recollected items in areas related to facial recognition (p<0.05, t>756.11). This increased functional activation was also positively associated with PRS (APOE variants included) (p<0.05, t>647.55). Our results are supportive for none to limited genetic effects on brain structure and function in young adults. Taking the methodological considerations of replication studies into account, the true effect of APOE ε4-carriership is likely smaller than indicated in the Filippini paper. However, it still holds that we may not yet be able to detect already present measurable effects decades before a clinical expression of AD. Since the mechanistic pathway of AD is likely to encompass many different factors, further research should be focused on the interactions of genetic risk, biomarkers, aging and lifestyle factors over the life course. Sensitive functional neuroimaging as used here may help disentangling these complex interactions. [ABSTRACT FROM AUTHOR]