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The neuromodulatory subcortical system (NSS) nuclei are critical hubs for survival, hedonic tone, and homeostasis. Tau-associated NSS degeneration occurs early in Alzheimer's disease (AD) pathogenesis, long before the emergence of pathognomonic memory dysfunction and cortical lesions. Accumulating evidence supports the role of NSS dysfunction and degeneration in the behavioral and neuropsychiatric manifestations featured early in AD. Experimental studies even suggest that AD-associated NSS degeneration drives brain neuroinflammatory status and contributes to disease progression, including the exacerbation of cortical lesions. Given the important pathophysiologic and etiologic roles that involve the NSS in early AD stages, there is an urgent need to expand our understanding of the mechanisms underlying NSS vulnerability and more precisely detail the clinical progression of NSS changes in AD. Here, the NSS Professional Interest Area of the International Society to Advance Alzheimer's Research and Treatment highlights knowledge gaps about NSS within AD and provides recommendations for priorities specific to clinical research, biomarker development, modeling, and intervention. HIGHLIGHTS: Neuromodulatory nuclei degenerate in early Alzheimer's disease pathological stages. Alzheimer's pathophysiology is exacerbated by neuromodulatory nuclei degeneration. Neuromodulatory nuclei degeneration drives neuropsychiatric symptoms in dementia. Biomarkers of neuromodulatory integrity would be value-creating for dementia care. Neuromodulatory nuclei present strategic prospects for disease-modifying therapies.

Background: The noradrenergic (NA) system comprises several cortical and subcortical brain areas with differential densities of NA transporters and receptors. A decline in the NA system, together with additional risk factors such as ApoE4‐status, gender, age, vascular changes and years of education may contribute to the development of Alzheimer's disease (AD). The aim of this study was to examine whether brain areas known to be rich in NA receptors and transporters are particularly vulnerable to degeneration in preclinical AD. Method: We examined interindividual differences in volumes of specific brain areas grouped into high and low NA density regions (NA‐high/NA‐low) for healthy controls (HC) and AD relatives (n = 122), individuals with subjective cognitive decline (SCD) (n = 152) and mild cognitive impairment (MCI) (n = 78). Structural equation modeling (SEM) was used to simultaneously examine associations between NA‐high and NA‐low regions across clinical groups. We investigated whether brain volumes in NA‐high and NA‐low areas were differentially related to known AD risk factors (ApoE4 status, CSF amyloid‐ß (Aß) 42/40 and phosphorylated tau (pTau)), and whether these links differed in HC, SCD and MCI. Result: Estimating a two‐factor model with NA‐high and NA‐low revealed a better model fit than estimating one general factor. ApoE4‐carriers were associated with a lower ratio of Aß42/40 (‐0.472***) and a higher level of pTau (0.263***). In the whole sample, a low ratio of Aß42/40 was associated with lower brain volume in NA‐high (0.157***), but not NA‐low areas. pTau showed no significant association to NA‐high or NA‐low areas. The group analysis revealed an increasing association between ApoE4, pTau and Aß42/40 in HC, SCD and MCI. An association between Aß42/40 and NA‐high areas was observed in all groups, whilst for an additional positive association to NA‐low in HC (0.125*), but negative association in SCD (‐0.184*). Finally, the negative association between pTau and Aß42/40 is true for SCD and MCI, but not for HC. Conclusion: SEM can be used to separate brain regions into NA‐high and NA‐low areas. Higher risk status Aß42/40 is linked to lower brain volume in high NA density areas, suggesting a particular vulnerability of brain areas likely more affected by NA decline in AD. [ABSTRACT FROM AUTHOR]