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Age changes during follow-up, so the generator matrix $Q(s)$ changes with time. The transition matrix must solve ${\partial }_{t_2}P(t_1,t_2)=P(t_1,t_2)Q(t_2)$, with $P(t_1,t_1)=I$. It is generally not the matrix exponential of one constant matrix; even $\exp (\int Q(s)ds)$ is not generally valid because the matrices at different times need not commute.

For example, write the age-dependent onset rate as $\lambda (s)$ and keep progression rate $\nu$ constant. ThenEven when the integrated onset rate is elementary, this remaining integral need not have an elementary closed form. Special cases can have closed forms; time dependence does not by itself prove universal impossibility.

For a tractable likelihood function, freeze age at its left-endpoint value, or a midpoint value, on each observation interval $[t_j,t_{j+1})$. The genetic covariate is already constant. This piecewise-constant covariate approximation gives a constant matrix $Q_j$ on each interval and a product of closed-form interval probabilities:Here $x_j$ is the observed state at $t_j$, and the likelihood function is conditional on the initial state. The approximation improves when intervals are short relative to the variation in the age effect.