. Amyloid β Deposition and Suspected Non-Alzheimer Pathophysiology and Cognitive Decline Patterns for 12 Years in Oldest Old Participants Without Dementia. JAMA Neurol. 2018 Jan 1;75(1):88-96. PubMed.


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  1. Zhao and colleagues studied neurocognitive outcomes over ~12 years for 175 persons stratified by baseline PiB-PET (Aβ) status and structural MRI (operationalized by hippocampal volume, HV). The research participants were a subgroup of the Ginkgo Evaluation of Memory (GEM) study, who were enrolled in the subsequent Ginkgo Evaluation of Memory Study (GEMS) Imaging Substudy. This was an elderly and predominantly Caucasian population, with mean age at imaging of 86.0 yrs.

    In this study, the authors classified the persons according to the baseline presence or absence of Ab biomarker positivity by PiB-PET scan (AB+/–), and decreased HV on MRI scans (ND+/–).   They found that persons in each group (AB+/ND+, AB+/ND–, AB–/ND+, and AB–/ND–) had somewhat distinct “typical” cognitive outcomes. Perhaps as to be expected, the “classic AD” AB+/ND+ persons had the worst outcomes in terms of cognitive trajectories, but the AB–/ND+ (suspected non-Alzheimer’s pathology, or SNAP) profile also experienced, with time, a substantial decline in a number of domains, including visual memory.

    There are many strengths to this study, including the outstanding clinical research team, the long follow-up with longitudinal visits featuring an extensive battery of neurocognitive assessments, and the topical relevance of these findings to clinicians and researchers interested in dementia.

    This study adds to a growing appreciation of the importance of non-AD pathophysiology in patients who otherwise may meet the clinical criteria for MCI and subsequently for “Probable AD” according to the McKhann criteria. Notably, a large proportion of the research subjects (20 percent) had the AB–/ND+ biomarker profile that indicates the presence of SNAP, i.e., neurodegenerative disease with no AD. Since the allele frequency of ApoE4 positivity (19 percent) in this sample was around 50 percent higher than the general Caucasian population (almost always higher in research volunteers recruited to study AD!), a study of a more representative epidemiologic sample could find even greater relative impact of SNAP versus pure AD.

    Some of the limitations were as stated trenchantly in the article: "Because the imaging lagged behind the initial cognitive assessment, biomarker status at initial intake was unknown. In addition, ND was operationalized only by HV, simplifying the complexity of ND biomarkers. Finally, the participants were relatively highly educated and mostly of white European descent; the findings may not generalize to other populations."

    In addition, it would be great to know the neuropathologic endpoints (i.e., detailed autopsy results) on as many of the patients as possible. Even lacking those data, we know that many of the AB–/ND+ patients probably had some combinations of hippocampal sclerosis/cerebral age-related TDP-43 pathology with sclerosis (CARTS), primary age-related tauopathy (PART), aging-related tau astrogliopathy (ARTAG), α-synucleinopathy, brain arteriolosclerosis, and/or other cerebrovascular pathologies.  Among the >50 percent of the persons included in this study who had the AD-specific pathophysiologic biomarker (AB+), we can also assume that a great many of these persons also had some combination of these pathologies as well. Whereas they may not constitute “SNAP” according to current definitions, their non-AD brain diseases are definitely relevant to the patients, clinicians, and clinical trials.

    View all comments by Peter Nelson

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