New horizons in the diagnosis and management of Alzheimer's Disease in older adults

Abstract

Alzheimer's Disease (ad) is the most common cause of dementia, and in addition to cognitive decline, it directly contributes to physical frailty, falls, incontinence, institutionalisation and polypharmacy in older adults. Increasing availability of clinically validated biomarkers including cerebrospinal fluid and positron emission tomography to assess both amyloid and tau pathology has led to a reconceptualisation of ad as a clinical-biological diagnosis, rather than one based purely on clinical phenotype. However, co-pathology is frequent in older adults which influence the accuracy of biomarker interpretation. Importantly, some older adults with positive amyloid or tau pathological biomarkers may never experience cognitive impairment or dementia. These strides towards achieving an accurate clinical-biological diagnosis are occurring alongside recent positive phase 3 trial results reporting statistically significant effects of anti-amyloid Disease-Modifying Therapies (DMTs) on disease severity in early ad. However, the real-world clinical benefit of these DMTs is not clear and concerns remain regarding how trial results will translate to real-world clinical populations, potential adverse effects (including amyloid-related imaging abnormalities), which can be severe and healthcare systems readiness to afford and deliver potential DMTs to appropriate populations. Here, we review recent advances in both clinical-biological diagnostic classification and future treatment in older adults living with ad. Advocating for access to both more accurate clinical-biological diagnosis and potential DMTs must be done so in a holistic and gerontologically attuned fashion, with geriatricians advocating for enhanced multi-component and multi-disciplinary care for all older adults with ad. This includes those across the ad severity spectrum including older adults potentially ineligible for emerging DMTs.

Keywords: Alzheimer’s disease; biomarkers; dementia; diagnosis; older people.

Figure 1

Amyloid and Tau processing under physiological conditions and in Alzheimer’s Disease. PSEN 1: Presenilin 1. PSEN 2: Presenilin 2. Aβ: Amyloid beta. BACE-1: Beta- site Amyloid precursor protein Cleaving Enzyme 1. Image adapted from “Cleavage of Amyloid Precursor Protein (APP)” by BioRender.com (2020).

Figure 2

Additional pathophysiological processes known to influence Alzheimer’s Disease pathology in older adults. TDP-43: TAR (transactive response) DNA-binding protein 43. CNS: Central Nervous System. BBB: Blood–Brain Barrier. Image created with BioRender.com.

Figure 3

Diagnostic criteria and disease stages of ad over a chronological continuum. NIA-AA: National Institute of Aging and Alzheimer’s Association. CSF: Cerebro-spinal Fluid. Aβ42: amyloid-beta 42. Aβ-PET: amyloid-beta positron emission tomography. Image created with BioRender.com.

Figure 4

Brain Health Clinic assessments and recommended clinical assessment tools. IPAQ: International Physical Activity Questionnaire. TFT: Thyroid Function Test. RLB: Renal, Liver, Bone laboratory profile. BP: Blood Pressure. BMI: Body Mass Index. TIA: Transient Ischaemic Attack. IHD: Ischaemic Heart Disease. DM: Diabetes Mellitus. LIBRA: Lifestyle For Brain Health Index. HADS: Hospital Anxiety and Depression Scale. PSQI: Pittsburgh Sleep Quality Index. Image created with BioRender.com.