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Introduction The effect of bilingualism on age at onset has yet to be examined within different clinical variants of Alzheimer's disease. Methods We reviewed the research charts of 287 well-characterized participants with either amnestic Alzheimer's dementia or logopenic variant primary progressive aphasia (lvPPA) and identified bilingual speakers based on regular use of two or more languages and/or ability to communicate with native speakers in two or more languages. We evaluated whether bilingual speakers demonstrated a delay in age of symptom onset relative to monolingual speakers while controlling for other variables known to influence cognitive reserve. Results A 5-year delay in age at symptom onset was observed for bilingual relative to monolingual speakers with lvPPA. This delay in onset was not observed in the amnestic Alzheimer's dementia cohort. Discussion Bilingualism may serve as a unique cognitive reserve variable in lvPPA, but not in amnestic Alzheimer's dementia.

Objective To characterize in vivo signatures of pathological diagnosis in a large cohort of patients with primary progressive aphasia (PPA) variants defined by current diagnostic classification. Methods Extensive clinical, cognitive, neuroimaging, and neuropathological data were collected from 69 patients with sporadic PPA, divided into 29 semantic (svPPA), 25 nonfluent (nfvPPA), 11 logopenic (lvPPA), and 4 mixed PPA. Patterns of gray matter (GM) and white matter (WM) atrophy at presentation were assessed and tested as predictors of pathological diagnosis using support vector machine (SVM) algorithms. Results A clinical diagnosis of PPA was associated with frontotemporal lobar degeneration (FTLD) with transactive response DNA-binding protein (TDP) inclusions in 40.5%, FTLD-tau in 40.5%, and Alzheimer disease (AD) pathology in 19% of cases. Each variant was associated with 1 typical pathology; 24 of 29 (83%) svPPA showed FTLD-TDP type C, 22 of 25 (88%) nfvPPA showed FTLD-tau, and all 11 lvPPA had AD. Within FTLD-tau, 4R-tau pathology was commonly associated with nfvPPA, whereas Pick disease was observed in a minority of subjects across all variants except for lvPPA. Compared with pathologically typical cases, svPPA-tau showed significant extrapyramidal signs, greater executive impairment, and severe striatal and frontal GM and WM atrophy. nfvPPA-TDP patients lacked general motor symptoms or significant WM atrophy. Combining GM and WM volumes, SVM analysis showed 92.7% accuracy to distinguish FTLD-tau and FTLD-TDP pathologies across variants. Interpretation Each PPA clinical variant is associated with a typical and most frequent cognitive, neuroimaging, and neuropathological profile. Specific clinical and early anatomical features may suggest rare and atypical pathological diagnosis in vivo. Ann Neurol 2017;81:430–443

Background: Today there are several competing hypotheses trying to provide the explanation of mild cognitive impairment (MCI) and Alzheimer’s disease (AD). The cholinergic hypothesis is derived from the theory of reduced synthesis of the neurotransmitter acetylcholine, while the amyloid hypothesis is based on material analysis of senile plaques or in brain tissue. There are some other theories such as virus, inflammation, and oxidative stress, etc. Apparently those hypotheses have not located the real root of Alzheimer’s disease.Conclusions: In this presentation, the author proposes a rationalized theory of human brain activity mechanism. The theory is derived from basic thermodynamic principles of Gibbs free energy and functional group interactions. By elucidating human memory system and the other brain activity mechanisms, we may come to a better understanding of the pathophysiology of MCI and AD. Since human memory is stored basically as free energy in protein conformation structures, avoidance of energy deficiency may be the key to the problem. By focusing development of products providing optimal energy supply at critical period of life, we may lead to a real alleviation or even reverse the courses of MCI and AD.