Precision Medicine: Clarity for the Complexity of Dementia

Abstract

Three key elements to precision medicine are stratification by risk, detection of pathophysiological processes as early as possible (even before clinical presentation), and alignment of mechanism of action of intervention(s) with an individual's molecular driver(s) of disease. Used for decades in the management of some rare diseases and now gaining broad currency in cancer care, a precision medicine approach is beginning to be adapted to cognitive impairment and dementia. This review focuses on the application of precision medicine to address the clinical and biological complexity of two common neurodegenerative causes of dementia: Alzheimer disease and Parkinson disease.

Figure 1

Schematic of traditional and precision medicine approaches. Key elements of precision medicine are classification by risk, surveillance for preclinical disease, and alignment of an expanding repertoire of treatments with the molecular drivers of disease.

Figure 2

Results from 408 brain autopsies in the Adult Changes in Thought (ACT) study as of December 2014. Three cases of dementia were excluded that had neuropathologic diagnosis of frontotemporal lobar degeneration, traumatic brain injury, or extensive laminar necrosis. Summary neuropathology scores for Alzheimer disease (AD; blue bars), vascular brain injury (VBI; red bars), and Lewy body disease (LBD; green bars) for the remaining 405 cases were determined using consensus neuropathologic evaluations, as described previously, and then plotted for each individual stratified by cognitive performance (A–D) or summarized for each cognitive performance group (E). Cognitive performance was determined using the Cognitive Assessment Screening Instrument (CASI), and dementia was diagnosed according to Diagnostic Statistical Manual-IVR criteria. CASI scores ≥91 are in the upper four quintiles of the ACT cohort. The individuals (means ± SD age, M:F ratio) with i) CASI ≥ 91 at last evaluation within 2 years of death are the High Cognitive Performance group (85 ± 7 years, 73:85; A and E); ii) CASI <91 but not diagnosed with dementia at last evaluation within 2 years of death are the Low Cognitive Performance group (87 ± 6 years, 46:44; B and E); iii) dementia at last evaluation within 2 years of death are the Early Dementia group (89 ± 6 years, 26:34; C and E), and iv) dementia at last evaluation >2 years before death are the Late Dementia group (91 ± 6 years, 37:61; D and E). One-way analysis of variance for the data presented in E has P < 0.0001 and Bonferroni-corrected P < 0.05 for all possible paired comparisons.

Figure 3

Stratification by age of Parkinson disease (PD) onset and duration of PD for the 491 individuals who volunteered to join the Pacific Northwest Udall Center (PANUC). Data are the number of PANUC participants diagnosed as PD with mild cognitive impairment (PD-MCI) or PD with dementia (PDD) at their initial evaluation of a total cohort of 619 individuals with PD.

Figure 4

Quantification of Aβ₄₂ and paired helical filament (PHF)-tau in superior and middle temporal gyri (SMTG) or middle frontal gyrus (MFG) from Adult Changes in Thought study brain autopsies. All participants were last evaluated within 2 years of death when they were diagnosed as not meeting criteria for dementia. Cases with neuropathologic changes other than Alzheimer disease were excluded, and we limited our analysis to only those with genotypes APOE ε2/ε3, APOE ε3/ε3, or APOE ε3/ε4. Molecular concentrations were obtained using a method called Histelde (histology and ELISA on a glass slide) and expressed in units of absorbance (Abs) at 405 nm normalized to gray matter (GM) area. Concentrations of Aβ₄₂ did not vary significantly across the two regions (C) and were averaged into a single value for cerebral cortex in correlation analyses. A and B plot average cerebral cortical Aβ₄₂ versus PHF-tau concentrations in SMTG or MFG. There is a highly statistically significant correlation between Aβ₄₂ and PHF-tau concentrations in SMTG (P < 0.0001), and a much weaker correlation in MFG (P < 0.05). C and D plot average concentration of Aβ₄₂ or PHF-tau concentration in SMTG and MFG stratified by APOE genotype. Two-way analysis of variance for Aβ₄₂ concentration had P < 0.0001 for APOE genotype, but was not significant for region or interaction. Two-way analysis of variance for PHF-tau concentration in SMTG had P < 0.01 for APOE genotype, P < 0.0001 for region, and P < 0.01 for interaction. Tukey's multiple comparisons test for PHF-tau concentration showed P < 0.01 for all pair-wise comparisons of APOE genotypes in SMTG but no significant difference among APOE genotypes in MFG. n = 105 (A and B, SMTG); n = 77 (A and B, MFG).