The Association of Multimorbidity With Preclinical AD Stages and SNAP in Cognitively Unimpaired Persons

Abstract

Multimorbidity was associated with biomarker combinations that included neurodegeneration with or without elevated amyloid deposition (ie, A-N+, A+N+). The associations should be validated in longitudinal studies.

Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report

“…More recent clinical studies have demonstrated biomarker evidence of ‘suspected non-Alzheimer’s disease pathophysiology’ (SNAP) causing amnestic type cognitive impairment with substantial hippocampal atrophy but lacking detectable amyloid-β amyloidosis (Caroli et al , 2015; Burnham et al , 2016; Jack et al , 2016, 2017; Abner et al , 2017; Wisse et al , 2018). For example, the evaluation of 1535 participants in the Mayo Clinic Study of Aging showed significantly greater prevalence of SNAP compared with preclinical Alzheimer’s disease, and multimorbidity was increased in SNAP (odds ratio 2.16) (Vassilaki et al , 2018). LATE is probably an important contributor in this group of subjects (see below).…”

Comorbidity Trajectories Associated With Alzheimer’s Disease: A Matched Case-Control Study in a United States Claims Database

“…Certain chronic medical conditions, including type 2 diabetes (T2DM), hypertension, coronary artery disease, and depression, are established risk factors for cognitive decline (Artero et al, 2008;Vicini Chilovi et al, 2009;Li et al, 2012;Roberts and Knopman, 2013;Imtiaz et al, 2014;Johnson et al, 2015;Vassilaki et al, 2015;Fan et al, 2017). These conditions are also common in multimorbidity (defined as at least two comorbid conditions) in older adults, which may also be associated with biomarkers of the preclinical AD stages (Sperling et al, 2011;Jack et al, 2014;Sperling et al, 2014) and suspected non-amyloid pathophysiology (Jack et al, 2016;Vassilaki et al, 2019), even before clinically detectable cognitive decline becomes apparent. Not only is there an increase in the prevalence of comorbidities among patients at risk of AD, but multimorbidity, a distinctive hallmark of aging and potentially a clinical marker of accelerated aging (Fabbri et al, 2015), is also associated with increased risk of cognitive impairment (Palmer et al, 2007;Vassilaki et al, 2015;Santiago and Potashkin, 2021).…”

Functional Decline in Alzheimer's Disease: A Continuum

“…As expected, only a small minority of patients with MCI and an even smaller subgroup of cognitively unimpaired persons exhibited abnormal scores on these scales, although abnormal scores have been associated with higher odds of being A+ and even higher chances of being N+. Therefore, not only subtle cognitive impairment appears to be in accordance with the asymptomatic stage of AD, but also subtle functional impairment at predementia stages . This would result in a slight modification of the biomarker model previously proposed from members of this group as shown in Figure .…”

“…During the course of AD, the extent of impairment in both cognitive abilities and in activities of daily living (ADLs), also referred to as functional abilities, is used to define the clinical syndrome. The article in this issue of JAGS by Dr. Vassilaki and colleagues of the Mayo Clinic in Rochester, Minnesota, provides further evidence that there is no sharp demarcation of presence vs absence of impaired ADLs between the different clinical stages of AD, but rather a continuum of gradually increasing ADL impairment during the course of the disease.…”

“…Biomarker model of the Alzheimer's continuum. Black arrows indicate that subtle impairment of functional abilities may begin before the mild cognitive impairment (MCI) stage, and thus the corresponding curve now reflects this update. Aβ = beta amyloid; CSF = cerebrospinal fluid; FDG = 2‐fluor‐2‐desoxy‐D‐glucose; MRI = magnetic resonance imaging; PET = positron emission tomography; pTau = phosphorylated tau; tTau = total tau.…”