J Neuropathol Exp Neurol. 2014 Apr;73(4):295-304. doi: 10.1097/NEN.0000000000000052.

Mild cognitive impairment and asymptomatic Alzheimer disease subjects: equivalent β-amyloid and tau loads with divergent cognitive outcomes.

Iacono D, Resnick SM, O’Brien R, Zonderman AB, An Y, Pletnikova O, Rudow G, Crain B, Troncoso JC.

From the Departments of Pathology (DI, OP, GR, BC, JT), and Neurology (RO, JT), Johns Hopkins University School of Medicine; and Laboratory of Personality and Cognition, Intramural Research Program, National Institute on Aging, National Institutes of Health (SMR, ABZ, YA), Baltimore, Maryland; and Neuropathology Research, Biomedical Research Institute of New Jersey, Cedar Knolls, New Jersey (DI).



Older adults with intact cognition before death and substantial Alzheimer disease (AD) lesions at autopsy have been termed “asymptomatic AD subjects” (ASYMAD). We previously reported hypertrophy of neuronal cell bodies, nuclei, and nucleoli in the CA1 of the hippocampus (CA1), anterior cingulate gyrus, posterior cingulate gyrus, and primary visual cortex of ASYMAD versus age-matched Control and mild cognitive impairment (MCI) subjects. However, it was unclear whether the neuronal hypertrophy could be attributed to differences in the severity of AD pathology. Here, we performed quantitative analyses of the severity of β-amyloid (Aβ) and phosphorylated tau (tau) loads in the brains of ASYMAD, Control, MCI, and AD subjects (n = 15 per group) from the Baltimore Longitudinal Study of Aging. Tissue sections from CA1, anterior cingulate gyrus, posterior cingulate gyrus, and primary visual cortex were immunostained for Aβ and tau; the respective loads were assessed using unbiased stereology by measuring the fractional areas of immunoreactivity for each protein in each region. The ASYMAD and MCI groups did not differ in Aβ and tau loads. These data confirm that ASYMAD and MCI subjects have comparable loads of insoluble Aβ and tau in regions vulnerable to AD pathology despite divergent cognitive outcomes. These findings imply that cognitive impairment in AD may be caused or modulated by factors other than insoluble forms of Aβ and tau.

PMID: 24607960



Our data demonstrate, for the first time using unbiased protocols and stereological tools, that some individuals assessed as cognitively normal shortly before death (i.e., 1 year or less), reveal at autopsy, cerebral amounts of insoluble β-amyloid and hyperphosphorylated tau lesions (i.e. β-amyloid neuritic-plaques and neurofibrillary tangles (NFT), which are histopathologic hallmarks of Alzheimer’s disease (AD), equivalent to those found in Mild Cognitive Impairment (MCI) subjects, as well as even in some definite AD cases. These subjects have been termed asymptomatic Alzheimer’s disease (ASYMAD) subjects (1). Our quantitative findings, although novel, are actually in-line with previous series of clinicopathologic studies, beginning from the initial and historical observations by Tomlinson more than 4 decades ago (2), and others (3,4,5), that could be summarized as follows: “neuritic plaques and neurofibrillary tangles are not always or necessarily associated with a clinical picture of dementia, in particular AD”. So far, it is not possible to affirm in a definitive manner that either β-amyloid or tau pathology are indeed the very initial or direct cause of AD, that is, are those primary biochemical disorders able to initiate pathologic processes ending into neuronal degeneration characterizing people with a clinical diagnosis of AD.

Furthermore, the only three genetic mutations recognized so far, which are associated with rare familial cases of AD (6), can actually only justify a minimal portion of the total AD cases (altogether these familial AD cases are estimated to represent only a 5% of the total AD population worldwide). Moreover, ApoE4 allele, the major genetic risk factor for AD (7), seems only to accelerate or amplify, do not cause, the accumulation of β-amyloid (and tau) in specific and more vulnerable cerebral regions. In fact, the other two alleles of ApoE gene, ApoE3 and ApoE2 alleles, do not exclude the formation, for example, of β-amyloid neuritic-plaques or tau-NFTs.

So, the initial cause, or more probably, the multiple initial causes, of AD remain to be precisely individuated.

The now pluridecennial, and animated, debate between “baptist” and “tauist” parties, respectively supporting alternatively the amyloid- and tau-hypothesis as “primum movens” of AD, is still very open, with pros and cons, as well as clinical trial failures, on one side and the other (8, 9, 10). In addition, the most recent NIA pathologic criteria for AD (11) recommended evaluating AD neuropathologic changes at brain autopsy, independently from a clinical documented presence of dementia. This proposed disconnection between clinical and pathologic features seemed to be an implicit understated proposal to re-evaluate and re-consider our perspectives on the possible “direct” causes of AD.

Clearly, when talking about the human central nervous system, a myriad of factors, genetic and non-genetic, must be taken in account. The simplistic approach linking a very frequent accumulation of an amyloidaceous protein (β-amyloid), jointly to an almost universal presence of NFT pathology (in the same anatomical regions than AD cases) in aged human brains, cannot be kept any longer, and poses new serious questions on the etiology and primary pathogenetic mechanisms of AD (12). Moreover, it is not by chance that the nearly universal presence of NFT pathology (in the hippocampus for example, as in other “AD-associated” anatomical regions, such as: temporal, parietal, occipital cortex, etc.) in human aged-brains has been recently proposed to be termed “primary age-related tauopathy” (PART) (13). Is this, perhaps, because there are two parallel NFT-producing mechanisms: one more ”aspecific” and “generally linked” to the aging process (the PART), and the other expression of a specific AD-related pathogenetic mechanism? So far, there are no evidences showing biochemical, structural, or anatomical predilection differences between PART and AD-related NFT pathology. Are also these considerations in support for a general re-thinking on AD, and human aging in general?

We would like to emphasize that “the measurement” in AD (14), that is, a reliable measurement of the global, and possibly regional-specific, synaptic loss, is still lacking. For historical, and practical reasons, measuring levels of synaptic loss, although ideal, has never been translated in operational efforts aiming to perform it in a feasible way, either in vivo or in postmortem AD cases, as in other dementias, or in other type of neurodegenerative disorders in general. In the meantime that the AD puzzle gets composed, “the measurement”, that is, a reliable measurement of the synaptic loss, could “disentangle” AD (and other sporadic dementias/neurodegenerative diseases) from those series of “hypothesized” and “specific” pathologic biomarkers of the disease, and offer a more linear correlation between cognition and neuronal/synaptic loss (14), independently from any specific cause. At the same time, synaptic loss measurements could be a very important way to stimulate the creation of new therapeutic approaches finalized to the “synaptic wellness” and its maintenance, obtained, for example, through the combined effects of “synaptic” pharmacological and non-pharmacological treatments for AD, as for other sporadic dementias, and in general, for any sporadic neurodegenerative disorders.

Iacono _D Supplement FIGURE 1


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For more information on the study please contact:

Diego Iacono, M.D. Ph.D.

Associate Professor, Department of Neurology, Icahn School of Medicine at Mount Sinai, NY

Lead Researcher, Atlantic Health System, AHS, NJ

Director, Neuropathology Research, Biomedical Research Institute of New Jersey, BRInj

140 E. Hanover Ave.

Cedar Knolls, NJ 07927

Website: http://brinj.org

Emails:   diego.iacono@atlantichealth.org; iacono@brinj.org; diego.iacono@mssm.edu


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