A therapeutic approach for senile dementias: neuroangiogenesis

Alzheimer's disease (AD) and related senile dementias (SDs) represent a growing medical and economic crisis in this country. Apart from cautioning persons about risk factors, no practical, effective therapy is currently available. Much of the recent research in AD has been based on the amyloid cascade theory. Another approach assumes a vascular basis for SDs. This paper presents evidence from a score of studies that cerebral capillary density (CCD) declines during old age in animals and people as well as in AD. Neuroangiogenic (NAG) factors initiate and maintain capillaries in the brain. Thus a waning level of these factors and the ensuing declining CCD would lead to local areas of reduced oxygen and glucose and result in impaired synaptic and neuronal function. The NAG hypothesis developed here proposes that the age-linked decline in CCD is a terminal condition in SDs, including many cases of AD. This age-linked decline is independent of any other of the various pathologies proposed as causing AD and listed in Table 1. Waning NAG factors would render the SDs a deficiency condition, somewhat like falling androgen levels in aging males. A logical corollary of this hypothesis is that chronic replacement therapy with recombinant forms of NAG factors may arrest the age-linked decline in CCD and prevent further loss of memory and mental deterioration. A transnasal route of therapy seems the most practical one for general use in the large aging populations.