With the increase of human lifespan and refinement of diagnostic techniques dementia, and Alzheimer’s disease (AD) in particular, have become a multi-decade process with a complex pathogenesis. The prognosis of AD patients, especially in late stages, may be strongly influenced by factors that go far beyond the well-recognized cascades (tau deposition, amyloid plaques). In this context, AD and Frailty, a multidimensional process of the elderly, inevitably overlap. Not surprisingly, the routine biomarkers collectable in the cerebrospinal fluid, while highly relevant in allowing specific diagnoses, becoming limiting when used to define severity and rate of progression of cognitive impairment. In reviewing merits and pitfalls of routine cerebrospinal fluid profile for AD, this manuscript will examine the state-of-theart related to a parallel field, the extrapyramidal disorders. For synucleinopathies, we will discuss the possibility to detect factors directly involved in earliest disease pathology (alpha-synuclein, tau-proteins) together with indexes of disease progression (i.e. dopamine-metabolite ratio and loss of blood-brain barrier integrity). This approach might guarantee the capability of monitoring putative disease-modifying strategies. However, we will show the likelihood that nonconventional approaches already proposed for Frail subjects (such as exercise-mediated neuro-protection) might prove to be a useful aid for an ageing brain already impaired by AD alterations. A crucial test for these hypotheses would be to apply this sort of interventional, and not merely pharmacological, therapy to homogeneous patient cohorts.