Untangling the Plaque Mess in Neurological Disorders: “Oh, What a Tangled Web we Weave, When First We Practice to Deceive!”

In 1906, Alois Alzheimer first reported a connection between dementia and plaques after postmortem examination of the brain and medical records of a patient with strange behavioral symptoms. Dementia is a progressive, irreversible brain disease that slowly destroys cognitive skills and memory function. Alzheimer’s disease (AD) is the most common form of dementia accounting for more than half the cases of dementia. AD and dementia are heterogenous diseases and exhibit a high degree of variations in clinical manifestation and symptoms. While this phenotypic variability is recognized by clinicians, researchers, and epidemiologists, no effort is made to subcategorize these neurological diseases, their management, and/or treatments.

Age is the single biggest risk factor for AD. While the average duration of AD is 8 years, people can live for over two decades with this disease. The etiology, symptoms presentation, risk factors, development, and progression of most neurological diseases, including dementia and AD differs between women and men. While the incidence of AD appears to be greater in women, there is no evidence of sex or race effect. Since women on an average live longer than men, there are more women with AD. Reporting bias likely skews the numbers. In most societies, women play a key role in running day-to-day life for the household and even small decline in cognitive skills and memory function will be noticed and impact normal functioning of that household, whereas a similar cognitive decline in men may simply be attributed to old age. Another key sex difference is that the disease progression is faster in men and slower in women. A systematic review of all clinical trials performed so far for AD found that none of the trials/studies reported or analyzed data accounting for biological sex or age as variables on the safety, efficacy, and tolerability of therapeutic interventions.

Brain imaging studies, especially those that compare brain images between AD patients and healthy controls for diagnosis of dementia and AD seldom consider age in data analysis. For example, when age is accounted for before statistical tests are applied for data analysis, substantial differences between young AD…