Clinical Manifestations.

Abstract

Early and reliable detection of Alzheimer's disease (AD) is fundamental in an era with novel disease modifying treatments on the market. Late in life emerging neuropsychiatric symptoms (NPS) (e.g., apathy, anxiety, depression) have been reported prevalent among cognitively unimpaired (CU) older adults, as well as among patients with Mild Cognitive Impairment (MCI). Findings have indicated that NPS can emerge prior to MCI in ∼50% of cases that subsequently develop a neurocognitive disorder (NCD). Additionally, ∼30% of AD patients have been reported to have received a primary psychiatric diagnosis before their final NCD diagnosis. Combined, these studies point to NPS as important early clinical manifestations of AD. NPS have furthermore been related to several clinically negative outcomes, such as reduced quality of life, increased caregiver burden and earlier institutionalization. Some reports even indicate that NPS can be stronger related to these outcomes than cognition. Importantly, several studies have demonstrated NPS to be predictive of future cognitive decline, dementia, or AD. For example, anxiety in non-demented subjects has consistently been shown to interact with beta-amyloid yielding accelerated cognitive decline. NPS are further demonstrated related to AD neuropathological changes including beta-amyloid, tau, and neurodegeneration. For instance, beta-amyloid in initially CU elderly has been demonstrated associated with steeper development of NPS over time. Intriguingly, an earlier study has reported the overall burden of NPS to precede memory deficits in its association with early tau deposition in amyloid-beta positive CU subjects, results supportive of NPS as early markers of dementing biochemical processes. Despite this growing evidence of being both prevalent and early prognostic markers, as well as associated with AD pathology, NPS are only given diminutive consideration in contemporary clinical AD diagnostic criteria. Perhaps so since the added value of NPS in such criteria has rarely been investigated. Consequently, CU subjects with a positive NPS and biomarker status face the risk of not being eligible for a disease modifying treatment since they formally do not fulfill diagnostic criteria for AD. Hence, studies exploring the added value of NPS in clinical diagnostic criteria for AD are prompted.