76 Recent biochemical studies found extensive overlap with only subtle quantitative differencies between Aβ levels, peptide profiles, solubility, and oligomeric assemblies in PA and AD brains, suggesting that PA represents an initial

prodromal stage of AD and that these individuals would eventually develop clinical symptoms, if they lived long enough, or an inherent individual resistance to the toxic effects of Aβ.77 Recent studies suggest that two Compound C independent processes (synapse-mediated and ApoE-mediated) may contribute Inhibitors,research,lifescience,medical to region-specific Aβ accumulation in nondemented individuals, and may influence the mechanisms of the regional vulnerability to Aβ accumulation, which is prevented by ApoE.78 A coding mutation (A673T) in the APP gene that reduces the P-cleavage of APP may protect against AD and also against cognitive decline in the elderly without AD.79 Older persons with ARQ197 molecular weight overall normal cognitive

function and preclinical AD changes by brain autopsy usually have lower scores on cognitive function Inhibitors,research,lifescience,medical tests, particularly episodic and working memory.24,54 Aβ biomarker studies also confirmed the relations between preclinical AD and Inhibitors,research,lifescience,medical cognition,80,81 and a clinicopathologic study indicated that elders with AD changes but without overt dementia are more likely to have memory complaints.82 The definition of nondemented subjects with AD pathology raises important questions regarding the cognitive Inhibitors,research,lifescience,medical profile of these people who are relatively protected from the devastating effects of AD-related lesions. A default hypothesis for AD is that it is a part of a “normal aging process,” such that plaques and tangles are secondary to aging or that the primary aging effect is on synapses and neurons independent of Inhibitors,research,lifescience,medical these morphological AD markers. AD is indeed a disease that accompanies human aging, but it is not an inevitable consequence of it.83,84 However, the suggestion that plaques and tangles may “cause” this disorder is oversimplified or even wrong, since accumulating evidence suggests that AD pathology represents effect rather than cause

or at least a host response to injury, equaling adaptive Dacomitinib or neuroprotective reactions.85 Many studies emphasize multiple additional pathologies in nondemented elders, in particular cerebrovascular lesions (CVLs), eg, small or large cerebral infarctions, lacunes, WMLs, in 22 up to almost 100%. 36,49,51-53 Evaluation of 336 cognitively normal (CN) seniors from four studies revealed moderately to frequent neuritic plaque density in 47%; of these 6% also had Braak stages V or VI; medullary, nigral, and cortical Lewy bodies in 15%, 8%, and 4%, respectively; cerebral microinfarcts in 33% and high-level cerebral microinfarcts in 10%. The burden of brain lesions and comorbidities varied widely within each study but was similar across studies.86 Among 418 nondemented participants of the Religious Order study (mean age 88.5±5.