The unique neuropathological vulnerability of the human brain to aging

Alzheimer's disease (AD)-related neurofibrillary tangles (NFT), argyrophilic grain disease (AGD), aging-related tau astrogliopathy (ARTAG), limbic predominant TDP-43 proteinopathy (LATE), and amygdala-predominant Lewy body disease (LBD) are proteinopathies that, together with hippocampal sclerosis, progressively appear in the elderly affecting from 50% to 99% of individuals aged 80 years, depending on the disease. These disorders usually converge on the same subject and associate with additive cognitive impairment. Abnormal Tau, TDP-43, and α-synuclein pathologies progress following a pattern consistent with an active cell-to-cell transmission and abnormal protein processing in the host cell. However, cell vulnerability and transmission pathways are specific for each disorder, albeit abnormal proteins may co-localize in particular neurons. All these alterations are unique or highly prevalent in humans. They all affect, at first, the archicortex and paleocortex to extend at later stages to the neocortex and other regions of the telencephalon. These observations show that the phylogenetically oldest areas of the human cerebral cortex and amygdala are not designed to cope with the lifespan of actual humans. New strategies aimed at reducing the functional overload of the human telencephalon, including optimization of dream repair mechanisms and implementation of artificial circuit devices to surrogate specific brain functions, appear promising.