An important concept that has not been sufficiently represented in research into neurodegenerative diseases1–7 is the role of the neurovascular unit. The neurovascular unit comprises neurons and non-neuronal cells such as vascular cells (endothelia, pericytes and vascular smooth muscle cells) and glia (astrocytes, microglia and oligodendroglia), which could have major roles in disease pathogenesis. These non-neuronal cells form the anatomical, biochemical and immune blood-brain barriers (BBBs) of the CNS and maintain the chemical and cellular composition of the neuronal ‘milieu’, which is required for proper functioning of neuronal synapses and circuits and for remodeling, angiogenesis and neurogenesis. A key concern is how we should study neurodegenerative disorders using animal models3. Genetically engineered models of human neurodegenerative disorders in Drosophila melanogaster and Caenorhabditis elegans have been useful for dissecting basic disease mechanisms and screening compounds. However, in addition to having much simpler nervous systems, non-mammalian species have cerebrovascular and immune systems that differ substantially from those of humans. For instance, the BBB in insects is between the hemolymph and glial cells, and worms do not have a cardiovascular system or BBB. So, genetic models of human diseases in non-mammalian species might not replicate the spectrum of disease pathology found in mammals.

For most neurodegenerative disorders, early steps in the disease cascade are unclear1, and biomarkers have yet to be identified5. It is therefore not clear to what extent genetic manipulation of targets that probably belong to a downstream cascade in the disease process, such as β-amyloid (Aβ) and tau in Alzheimer’s disease, will help us to develop new therapies for early stage disease or delay disease onset. For example, triple transgenic mice that express human amyloid precursor protein with the Swedish mutation, mutant presenilin-1 and mutant human tau develop accumulations of Aβ in the brain and phosphorylated tau in some neurons8, as in Alzheimer’s disease, but do not show neuronal cell death as robust as that seen in the human disease9. It is possible that further study of the comorbidity factors that are associated with Alzheimer’s disease, such as the overlap with vascular dementia, brain hypoperfusion, hypertension, silent ministrokes, diabetes, atherosclerosis, hypercoagulant blood profile, cardiac disease and so on, will generate better correlates of human disease dementia phenotypes than the current transgenic models. Alternatively, new animal models should be developed that are based on currently undiscovered early molecular and cellular targets. Diminished cerebrovascular function, including reduced blood flow, breakdown of the BBB, or both, has been associated with or