From 1901 to 2022, how far are we from truly understanding the pathogenesis of age-related dementia?

From the first described AD case in 1901 to the current year 2022, understanding the pathogenesis of Alzheimer's disease (AD) and dementia has undergone a long and tortuous journey. Many mechanisms of AD etiology have been proposed and studied. However, current medications and FDA-approved treatments cannot cure AD and AD-related dementias (AD/ADRD). Recently, brain hypoperfusion associated with neurovascular dysfunction was recognized as one of the causal factors in the development of AD dementia. Arteriosclerotic changes were observed in the first AD case. A recent study reported that the functional hyperemic response to whisker stimulation was reduced in 9-12 months old atherosclerotic mice. Interestingly, they found that evoked hemodynamic responses were not altered in age-matched AD mice or AD mice with superimposed atherosclerosis using 2D-optical imaging spectroscopy in chronic studies. However, functional hyperemia was impaired in AD mice using the same approach in an acute study. It is essential to scrutinize the available data critically since different genetic backgrounds, ages, sexes of studied animal models, and different approaches used for the same function even structural examination may provide opposite information. We certainly are closer to truly understanding the pathogenesis of dementia. We expect positive results from using aducanumab (Aduhelm®) as the first FDA-approved anti-amyloid monoclonal antibody as a treatment for AD/ADRD. We hope to identify and develop new drugs targeting other potential contributing mechanisms such as the cerebral vascular pathways.