Retrogenesis: A Model of Dementia Progression in Alzheimer's Disease Related to Neuroplasticity

Rubial-Alvarez et al. [1] analyzed 181 children (ages 4 to 12 years) and 148 adults, ranging from normal to severe dementia (approximate ages 65 to 95 years), using the Mini-Mental State Exam [2], an intelligence test, the Global Deterioration Scale [3], and an activities of daily living measure, in order to test the “retrogenesis model” of Alzheimer’s disease (AD) [4]. The Rubial-Alvarez et al. analysis supports the concept that the general pattern of childhood development is approximately recapitulated in reverse order by the pattern of deterioration associated with the continuum of AD progression from normal adult cognition through “mild cognitive impairment” and the stages of dementia to the most profound, complete state. The specific comparisons indicate that normal adult function is fairly well approximated by a 12 year old individual, while mild dementia is comparable to the level of function of a 5 to 6 year old child, and moderate dementia is similar to the function of a 4 year old. However, there were some expectable deviations from the retrogenesis model, particularly in activities of daily living. It has been well established that cognitive and functional deterioration in AD follows a generally uniform course [5]. While the retrogenesis model is compelling and useful, there are several points that should be carefully addressed in the examination of this model, including heuristic and neuropathological issues. ∗Correspondence to: J. Wesson Ashford, M.D., Ph.D., Stanford/VA Aging Clinical Research Center, VA Palo Alto Health Care System, Palo Alto, CA, USA. E-mail: ashford@stanford.edu. First, the pattern of dementia deterioration does not precisely mirror the pattern of childhood development. Needless-to-say, children have excellent memories and learn age appropriate material quickly, while dementia itself begins selectively as a memory problem [6, 7]. Further, the specific ordinal pattern loss of items and functions during the course of the dementia associated with AD [8] is most closely related to the progressive deterioration of memory function (e.g., inability to remember what groceries need to be purchased or what objects are called, rather than being unable to organize a shopping trip or being unable to pronounce specific words). A specific “item-analysis” along the developmental continuum would highlight the divergences between the courses of childhood development and dementia. Further, a “time-index” analysis of the ADtype dementia progression [7, 9, 10] would provide direct contrast of the temporal patterns of development and dementia, which are only roughly comparable in this study. The issue of great relevance regarding the retrogenesis model for AD pathology is the potential for understanding the neuronal vulnerability underlying AD. While the explanation of retrogenesis as a consequence of reversal of developmental myelination patterns [11] is interesting, the similarity is not close enough to be accepted as relevant. Further, with the definition by Brun & Englund of the pathological pattern of AD as affecting the posterior temporal and inferior parietal lobes [12] and the pathological analysis of Braak & Braak [13] showing the initiation