P2‐048: Paradigm shift from Alzheimer‐centric view of brain aging and dementia: Dynamic Polygon Hypothesis

Alzheimer disease (AD), once considered a rare presenile condition, has become almost synonymous with cognitive decline with aging. However, problems posed with a primary focus on “AD” and amyloid-cascade hypothesis have distorted a clear understanding of the heterogeneous mechanisms involved (Fig. 1), necessitating a new way of thinking about brain with aging and dementia. We performed a comprehensive literature review to determine the validity of the amyloid-cascade hypothesis and the notion that AD represents the dominant form of cognitive decline with aging. Our review reveals that at least seven sets of observations are not consistent with the amyloid-cascade hypothesis: 1) Amyloid plaques are not unique to AD and occur in a number of conditions, including normal aging (asymptomatic with AD pathologic diagnosis); 2) Distribution of plaques does not match that of tangles; plaques appear randomly in different cortical areas, whereas tangles first appear in temporal lobes and then progress to frontal lobes; 3) Tangles (not plaques) have a correlation with severity of dementia, yet no genetic link has been discovered for proteins involved in tangles; 4) Cortical areas with the most prominent hypometabolism (precuneus and posterior cingulate) do not contain high loads of plaques or tangles; 5) Antibodies and drugs that reduce the amyloid load have failed to show any benefit for cognitive performance; 6) In animal studies, even the highest loads of plaques and tangles fail to produce neuronal loss; 7) A large number of medical conditions and lifestyle factors that increase or decrease the likelihood of dementia have no impact on amyloid levels. We found considerable confusion in research and clinical practice with regard to diagnosis of dementia and AD. The amyloid-cascade hypothesis is wrong. We propose an alternative framework–the dynamic polygon hypothesis (Fig. 2)–which incorporates the multifactorial aspects of cognitive impairment. It takes into account the contributions of plaques and tangles in parallel to those of obesity, diabetes, head trauma, systemic illness, obstructive sleep apnea, and depression, as well as inflammation, white matter hyperintensities, and strokes of all sizes. We suggest that the words “dementia” and “late-onset AD” be replaced with “mild, intermediate, or severe cognitive impairment.”