Increased CSF DOPA Decarboxylase Correlates with Lower DaT-SPECT Binding: Analyses in Biopark and PPMI Cohorts.

BACKGROUND: Recent studies identified increased cerebrospinal fluid (CSF) DOPA decarboxylase (DDC) as a promising biomarker for parkinsonian disorders, suggesting a compensation to dying dopaminergic neurons. A correlation with 123I-FP-CIT-SPECT (DaT-SPECT) imaging could shed light on this link. OBJECTIVE: The objective is to assess the relationship between CSF DDC levels and DaT-SPECT binding values. METHODS: A total of 51 and 72 Parkinson's disease (PD) subjects with available DaT-SPECT and CSF DDC levels were selected from the PPMI and Biopark cohorts, respectively. DDC levels were analyzed using proximity extension assay and correlated with DaT-SPECT striatal binding ratios (SBR). All analyses were corrected for age and sex. RESULTS: CSF DDC levels in PD patients correlated negatively with DaT-SPECT SBR in both putamen and caudate nucleus. Additionally, SBR decreased with increased DDC levels over time in PD patients. CONCLUSION: CSF DDC levels negatively correlate with DaT-SPECT SBR in levodopa-treated PD. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Recalibrating the Why and Whom of Animal Models in Parkinson Disease: A Clinician's Perspective.

Animal models have been used to gain pathophysiologic insights into Parkinson's disease (PD) and aid in the translational efforts of interventions with therapeutic potential in human clinical trials. However, no disease-modifying therapy for PD has successfully emerged from model predictions. These translational disappointments warrant a reappraisal of the types of preclinical questions asked of animal models. Besides the limitations of experimental designs, the one-size convergence and oversimplification yielded by a model cannot recapitulate the molecular diversity within and between PD patients. Here, we compare the strengths and pitfalls of different models, review the discrepancies between animal and human data on similar pathologic and molecular mechanisms, assess the potential of organoids as novel modeling tools, and evaluate the types of questions for which models can guide and misguide. We propose that animal models may be of greatest utility in the evaluation of molecular mechanisms, neural pathways, drug toxicity, and safety but can be unreliable or misleading when used to generate pathophysiologic hypotheses or predict therapeutic efficacy for compounds with potential neuroprotective effects in humans. To enhance the translational disease-modification potential, the modeling must reflect the biology not of a diseased population but of subtypes of diseased humans to distinguish What data are relevant and to Whom.

The theoretical problems of "prodrome" and "phenoconversion" in neurodegeneration.

The recognition of and approach to prodromal symptoms, those which manifest before a diagnosis can be ascertained at the bedside, are of increasing interest in neurodegenerative research. A prodrome is conceived of as an early window into a disease, a critical time when putative disease-modifying interventions may be best suited for examination. Several challenges affect research in this area. Prodromal symptoms are highly prevalent in the population, can be nonprogressive for years or decades, and exhibit limited specificity in predicting conversion versus nonconversion into a neurodegenerative category within a time window feasible for most longitudinal clinical studies. In addition, there is a large range of biological alterations subsumed within each prodromal syndrome, forced to converge into the unifying nosology of each neurodegenerative disorder. Initial prodromal subtyping efforts have been developed but given the scarcity of prodrome-to-disease longitudinal studies, it is not yet clear whether any prodromal subtype can be predicted to evolve into the corresponding subtype of manifesting disease - a form of construct validity. As current subtypes generated from one clinical population are not faithfully replicated to others, it is likely that, lacking biological or molecular anchors, prodromal subtypes may only be applicable to the cohorts within which they were developed. Furthermore, as clinical subtypes have not aligned with a consistent pattern of pathology or biology, such might also be the fate of prodromal subtypes. Finally, the threshold defining the change from prodrome to disease for most neurodegenerative disorders remains clinical (e.g., a motor change in gait becoming noticeable to a clinician or measurable with portable technologies), not biological. As such, a prodrome can be viewed as a disease state not yet overt to a clinician. Efforts into identifying biological subtypes of disease, regardless of clinical phenotype or disease stage, may best serve future disease-modifying therapeutic strategies deployed not for a prodromal symptom but for a defined biological derangement as soon as it can be determined to lead to clinical changes, prodromal or not.

Pathology vs pathogenesis: Rationale and pitfalls in the clinicopathology model of neurodegeneration.

In neurodegenerative disorders, the term pathology is often implicitly referred to as pathogenesis. Pathology has been conceived as a window into the pathogenesis of neurodegenerative disorders. This clinicopathologic framework posits that what can be identified and quantified in postmortem brain tissue can explain both premortem clinical manifestations and the cause of death, a forensic approach to understanding neurodegeneration. As the century-old clinicopathology framework has yielded little correlation between pathology and clinical features or neuronal loss, the relationship between proteins and degeneration is ripe for revisitation. There are indeed two synchronous consequences of protein aggregation in neurodegeneration: the loss of the soluble/normal proteins on one; the accrual of the insoluble/abnormal fraction of these proteins on the other. The omission of the first part in the protein aggregation process is an artifact of the early autopsy studies: soluble, normal proteins have disappeared, with only the remaining insoluble fraction amenable to quantification. We here review the collective evidence from human data suggesting that protein aggregates, known collectively as pathology, are the consequence of many biological, toxic, and infectious exposures, but may not explain alone the cause or pathogenesis of neurodegenerative disorders.

Subtyping monogenic disorders: Huntington disease.

Huntington disease is a highly disabling neurodegenerative disease characterized by psychiatric, cognitive, and motor deficits. The causal genetic mutation in huntingtin (Htt, also known as IT15), located on chromosome 4p16.3, leads to an expansion of a triplet coding for polyglutamine. The expansion is invariably associated with the disease when >39 repeats. Htt encodes for the protein huntingtin (HTT), which carries out many essential biological functions in the cell, in particular in the nervous system. The precise mechanism of toxicity is not known. Based on a one-gene-one-disease framework, the prevailing hypothesis ascribes toxicity to the universal aggregation of HTT. However, the aggregation process into mutant huntingtin (mHTT) is associated with a reduction of the levels of wild-type HTT. A loss of wild-type HTT may plausibly be pathogenic, contributing to the disease onset and progressive neurodegeneration. Moreover, many other biological pathways are altered in Huntington disease, such as in the autophagic system, mitochondria, and essential proteins beyond HTT, potentially explaining biological and clinical differences among affected individuals. As one gene does not mean one disease, future efforts at identifying specific Huntington subtypes are important to design biologically tailored therapeutic approaches that correct the corresponding biological pathways-rather than continuing to exclusively target the common denominator of HTT aggregation for elimination.

The shift to a proteinopenia paradigm in neurodegeneration.

The toxic proteinopathy paradigm has defined neurodegenerative disorders for over a century. This gain-of-function (GOF) framework posited that proteins become toxic when turned into amyloids (pathology), predicting that lowering its levels would translate into clinical benefits. Genetic observations used to support a GOF framework are equally compatible with a loss-of-function (LOF) framework, as the soluble pool of proteins rendered unstable by these mutations (e.g., APP in Alzheimer's disease, SNCA in Parkinson's disease) aggregate, becoming depleted. In this review, we highlight misconceptions that have prevented LOF from gaining currency. Some of these misconceptions include no phenotype in knock-out animals (there is neurodegenerative phenotype in knock-out animals) and high levels of proteins in patients (patients have lower levels of the proteins involved in neurodegeneration than healthy age-matched controls). We also expose the internal contradictions within the GOF framework, namely that (1) pathology can have both pathogenic and protective roles; (2) the neuropathology gold standard for diagnosis can be present in normal individuals and absent in those affected; (3) oligomers are the toxic species even if they are ephemeral and decrease over time. We therefore advocate for a paradigm shift from proteinopathy (GOF) to proteinopenia (LOF) based on the universal depletion of soluble functional proteins in neurodegenerative diseases (low amyloid-ß 42 in Alzheimer's disease, low α-synuclein in Parkinson's disease, and low tau in progressive supranuclear palsy) and supported by the confluence of biologic, thermodynamic, and evolutionary principles with proteins having evolved to perform a function, not to become toxic, and where protein depletion is consequential. Such shift to a Proteinopenia paradigm is necessary to examining the safety and efficacy of protein replacement strategies instead of perpetuating a therapeutic paradigm with further antiprotein permutations.

High Soluble Amyloid-ß42 Predicts Normal Cognition in Amyloid-Positive Individuals with Alzheimer's Disease-Causing Mutations.

BACKGROUND: In amyloid-positive individuals at risk for Alzheimer's disease (AD), high soluble 42-amino acid amyloid-ß (Aß42) levels are associated with normal cognition. It is unknown if this relationship applies longitudinally in a genetic cohort. OBJECTIVE: To test the hypothesis that high Aß42 preserves normal cognition in amyloid-positive individuals with Alzheimer's disease (AD)-causing mutations (APP, PSEN1, or PSEN2) to a greater extent than lower levels of brain amyloid, cerebrospinal fluid (CSF) phosphorylated tau (p-tau), or total tau (t-tau). METHODS: Cognitive progression was defined as any increase in Clinical Dementia Rating (CDR = 0, normal cognition; 0.5, very mild dementia; 1, mild dementia) over 3 years. Amyloid-positivity was defined as a standard uptake value ratio (SUVR) ≥1.42 by Pittsburgh compound-B positron emission tomography (PiB-PET). We used modified Poisson regression models to estimate relative risk (RR), adjusted for age at onset, sex, education, APOE4 status, and duration of follow-up. The results were confirmed with multiple sensitivity analyses, including Cox regression. RESULTS: Of 232 mutation carriers, 108 were PiB-PET-positive at baseline, with 43 (39.8%) meeting criteria for progression after 3.3±2.0 years. Soluble Aß42 levels were higher among CDR non-progressors than CDR progressors. Higher Aß42 predicted a lower risk of progression (adjusted RR, 0.36; 95% confidence interval [CI], 0.19-0.67; p = 0.002) better than lower SUVR (RR, 0.81; 95% CI, 0.68-0.96; p = 0.018). CSF Aß42 levels predicting lower risk of progression increased with higher SUVR levels. CONCLUSION: High CSF Aß42 levels predict normal cognition in amyloid-positive individuals with AD-causing genetic mutations.

Glycosphingolipid Changes in Plasma in Parkinson's Disease Independent of Glucosylceramide Levels.

BACKGROUND: Alteration in glycosphingolipids (GSLs) in Parkinson's disease (PD) still needs to be determined. OBJECTIVES: We evaluated if PD subjects show abnormal GSLs levels compared to healthy controls (HC) and if GSLs correlate with clinical features. METHODS: We analyzed GSLs and glucosylceramide (GlcCer) in plasma using two normal-phase high-performance liquid chromatography assays; clinico-demographic data were extracted. RESULTS: Eighty PD subjects and 25 HCs were analyzed. Levels of GlcCer, GD1b, Gb4, GalNAcGA1, and b-series were higher in PD patients than in HCs; total GSLs, GT1b, GM1a, GM3, GM2, and a-series levels were lower in PD patients than in HCs. Changes in GSLs were present in PD subjects, with GlcCer levels similar to those in HCs. The results were similar after excluding certain GBA1 mutation carriers. Movement Disorder Society Unified Parkinson's Disease Rating Scale, Part III, correlated with Gb4 and Montreal Cognitive Assessment with GD1b levels. CONCLUSIONS: Multiple GSL abnormalities in plasma were detected in patients with and without GlcCer changes, indicating a broader shift in lipid homeostasis. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.

Are smartphones and machine learning enough to diagnose tremor?

BACKGROUND: Patients with essential tremor (ET), Parkinson's disease (PD) and dystonic tremor (DT) can be difficult to classify and often share similar characteristics. OBJECTIVES: To use ubiquitous smartphone accelerometers with and without clinical features to automate tremor classification using supervised machine learning, and to use unsupervised learning to evaluate if natural clusterings of patients correspond to assigned clinical diagnoses. METHODS: A supervised machine learning classifier was trained to classify 78 tremor patients using leave-one-out cross-validation to estimate performance on unseen accelerometer data. An independent cohort of 27 patients were also studied. Next, we focused on a subset of 48 patients with both smartphone-based tremor measurements and detailed clinical assessment metrics and compared two separate machine learning classifiers trained on these data. RESULTS: The classifier yielded a total accuracy of 74.4% and F1-score of 0.74 for a trinary classification with an area under the curve of 0.904, average F1-score of 0.94, specificity of 97% and sensitivity of 84% in classifying PD from ET or DT. The algorithm classified ET from non-ET with 88% accuracy, but only classified DT from non-DT with 29% accuracy. A poorer performance was found in the independent cohort. Classifiers trained on accelerometer and clinical data respectively obtained similar results. CONCLUSIONS: Machine learning classifiers achieved a high accuracy of PD, however moderate accuracy of ET, and poor accuracy of DT classification. This underscores the difficulty of using AI to classify some tremors due to lack of specificity in clinical and neuropathological features, reinforcing that they may represent overlapping syndromes.

Droxidopa reduces postural sway in Parkinson disease patients with orthostatic hypotension.

We evaluate the effect of droxidopa on gait and balance measures in nine patients with Parkinson's disease and neurogenic orthostatic hypotension. Computerized gait/balance analysis showed a significant effect of droxidopa in reducing postural sway. Future studies may determine if such effect translates into improvement in postural reflexes and falls.

Proteins Do Not Replicate, They Precipitate: Phase Transition and Loss of Function Toxicity in Amyloid Pathologies.

Protein aggregation into amyloid fibrils affects many proteins in a variety of diseases, including neurodegenerative disorders, diabetes, and cancer. Physicochemically, amyloid formation is a phase transition process, where soluble proteins are transformed into solid fibrils with the characteristic cross-ß conformation responsible for their fibrillar morphology. This phase transition proceeds via an initial, rate-limiting nucleation step followed by rapid growth. Several well-defined nucleation pathways exist, including homogenous nucleation (HON), which proceeds spontaneously; heterogeneous nucleation (HEN), which is catalyzed by surfaces; and seeding via preformed nuclei. It has been hypothesized that amyloid aggregation represents a protein-only (nucleic-acid free) replication mechanism that involves transmission of structural information via conformational templating (the prion hypothesis). While the prion hypothesis still lacks mechanistic support, it is also incompatible with the fact that proteins can be induced to form amyloids in the absence of a proteinaceous species acting as a conformational template as in the case of HEN, which can be induced by lipid membranes (including viral envelopes) or polysaccharides. Additionally, while amyloids can be formed from any protein sequence and via different nucleation pathways, they invariably adopt the universal cross-ß conformation; suggesting that such conformational change is a spontaneous folding event that is thermodynamically favorable under the conditions of supersaturation and phase transition and not a templated replication process. Finally, as the high stability of amyloids renders them relatively inert, toxicity in some amyloid pathologies might be more dependent on the loss of function from protein sequestration in the amyloid state rather than direct toxicity from the amyloid plaques themselves.

Movement disorders associated with neuronal antibodies: a data-driven approach.

BACKGROUND: Movement disorders can be associated with anti-neuronal antibodies. METHODS: We conducted a systematic review of cases with documented anti-neuronal antibodies in serum and/or cerebrospinal fluid published in PubMed before April 1, 2020. Only patients with at least one movement disorder were included. We used random forests for variable selection and recursive partitioning and regression trees for the creation of a data-driven decision algorithm, integrated with expert's clinical feedback. RESULTS: Three hundred and seventy-seven studies met eligibility criteria, totaling 844 patients and 13 antibodies: amphiphysin, GAD, GlyR, mGluR1, ANNA-2/Ri, Yo/PCA-1, Caspr2, NMDAR, LGI-1, CRMP5/CV2, ANNA-1/Hu, IgLON5, and DPPX. Stiffness/rigidity/spasm spectrum symptoms were more frequently associated with amphiphysin, GAD, and GlyR; ataxia with mGluR1, ANNA-2/Ri, Yo/PCA-1, Caspr2, and ANNA-1/Hu; dyskinesia with NMDAR and paroxysmal movement with LGI1; chorea/choreoathetosis with CRMP5/CV2, IgLON5, and NMDAR; myoclonus with GlyR and DPPX; tremors with ANNA2/Ri and anti-DPPX; and parkinsonism with IgLON5 and NMDAR. Data-driven classification analysis determined the following diagnostic predictions (with probability selection): psychiatric symptoms and dyskinesia predicted NMDAR (71% and 87%, respectively); stiffness/rigidity/spasm and ataxia, GAD (67% and 47%, respectively); ataxia and opsoclonus, ANNA-2/Ri (68%); chorea/choreoathetosis, CRMP5/CV2 (41%). These symptoms remained the top predictors in random forests analysis. The integration with an expert opinion analysis refined the precision of the approach. Breast and lung tumors were the most common tumors. On neuroimaging, cerebellar involvement was associated with GAD and Yo/PCA-1; temporal involvement with Caspr2, LGI-1, ANNA-1/Hu. CONCLUSION: Selected movement disorders are associated with specific anti-neuronal antibodies. The combination of data-driven and expert opinion approach to the diagnosis may assist early management efforts.

Low soluble amyloid-ß 42 is associated with smaller brain volume in Parkinson's disease.

INTRODUCTION: We sought to examine whether levels of soluble alpha-synuclein (α-syn), amyloid-beta (Aß42), phosphorylated tau (p-tau), and total tau (t-tau), as measured in cerebrospinal fluid (CSF), are associated with changes in brain volume in Parkinson's disease. METHODS: We assessed the 4-year change in total brain volume (n = 99) and baseline CSF α-syn, Aß42, p-tau, and t-tau of Parkinson Progression Markers Initiative participants. We used linear mixed models to assess the longitudinal effect of baseline CSF biomarkers on total and regional brain volume and thickness as well as linear regression for cross-sectional analyses at baseline and year 2. All models were adjusted for age and gender; brain volume models also adjusted for baseline intracranial volume. Bonferroni correction was applied. RESULTS: The 4-year change in total brain volume was -21.2 mm3 (95% confidence interval, -26.1, -16.3). There were no significant associations between the 4-year change in total brain volume and baseline levels of any CSF biomarker (all p-values > 0.05). On cross-sectional analyses, CSF Aß42 was linearly associated with total brain volume at baseline (R2 = 0.60, p = 0.0004) and at year 2 (R2 = 0.66, p < 0.0001), with CSF Aß42 < 1100 pg/ml, the threshold for brain amyloid pathology, associated with smaller total brain volume at baseline (p = 0.0010) and at year 2 (p = 0.0002). CSF α-syn was linearly associated with total brain volume at baseline (R2 = 0.58, p = 0.0044) but not at year 2 (R2 = 0.58, p = 0.1342). CONCLUSION: Reduction in soluble Aß42 is associated with lower total brain volume in Parkinson's disease.

Biphasic (Subtherapeutic) Levodopa-Induced Respiratory Dysfunction in Parkinson Disease.

OBJECTIVE: To evaluate 3 cases illustrating a rarely recognized phenotype of Parkinson disease (PD), namely, biphasic levodopa-induced respiratory dysfunction manifesting as dyspnea. METHODS: To appreciate the nature of the fluctuations of respiratory function in response to levodopa, we measured changes in respiratory muscle control before and after the best therapeutic response to levodopa in 3 PD patients with fluctuating dyspnea. RESULTS: Episodes of breathlessness were accompanied by shallow tachypnea and reduced respiratory muscle control, as measured by maximal expiratory pressure, peak cough flow, and forced expiratory volume in 1 second. CONCLUSIONS: The spectrum of respiratory dysfunction in PD includes a biphasic reduced respiratory muscle control accompanying periods when the effect of levodopa is subtherapeutic. This biphasic levodopa-related complication represents a rarely recognized nonmotor phenomenon in PD. Management requires increasing the levodopa dose, shortening the interdose interval, or implementing a program of continuous dopaminergic stimulation.

High cerebrospinal amyloid-ß 42 is associated with normal cognition in individuals with brain amyloidosis.

BACKGROUND: Brain amyloidosis does not invariably predict dementia. We hypothesized that high soluble 42-amino acid ß amyloid (Aß42) peptide levels are associated with normal cognition and hippocampal volume despite increasing brain amyloidosis. METHODS: This cross-sectional study of 598 amyloid-positive participants in the Alzheimer's Disease Neuroimaging Initiative cohort examined whether levels of soluble Aß42 are higher in amyloid-positive normal cognition (NC) individuals compared to mild cognitive impairment (MCI) and Alzheimer's disease (AD) and whether this relationship applies to neuropsychological assessments and hippocampal volume measured within the same year. All subjects were evaluated between June 2010 and February 2019. Brain amyloid positivity was defined as positron emission tomography-based standard uptake value ratio (SUVR) ≥1.08 for [18] F-florbetaben or 1.11 for [18]F-florbetapir, with higher SUVR indicating more brain amyloidosis. Analyses were adjusted for age, sex, education, APOE4, p-tau, t-tau, and centiloids levels. FINDINGS: Higher soluble Aß42 levels were observed in NC (864.00 pg/ml) than in MCI (768.60 pg/ml) or AD (617.46 pg/ml), with the relationship between NC, MCI, and AD maintained across all amyloid tertiles. In adjusted analysis, there was a larger absolute effect size of soluble Aß42 than SUVR for NC (0.82 vs. 0.40) and MCI (0.60 vs. 0.26) versus AD. Each standard deviation increase in Aß42 was associated with greater odds of NC than AD (adjusted odds ratio, 6.26; p < 0.001) or MCI (1.42; p = 0.006). Higher soluble Aß42 levels were also associated with better neuropsychological function and larger hippocampal volume. INTERPRETATION: Normal cognition and hippocampal volume are associated with preservation of high soluble Aß42 levels despite increasing brain amyloidosis. FUNDING: Please refer to the Funding section at the end of the article.

The VDR FokI (rs2228570) polymorphism is involved in Parkinson's disease.

The etiology of Parkinson's disease (PD) is presumably multifactorial and likely involves interactions between genetic and environmental factors, as well as mitochondrial dysfunction, oxidative stress and inflammation. Among environmental factors, Vitamin D was reported to associate with the risk of PD. Vitamin D activity is mediated by its binding to the vitamin D Receptor (VDR), a transcriptional factor for almost 3% of human genes. We genotyped for ApaI, BsmI, TaqI, FokI and rs1989969 VDR single nucleotide polymorphisms (SNPs) a cohort of 406 PD and 800 healthy controls (HC) and found a strong association between the FokI (rs2228570) VDR SNP and PD. Thus, the TT genotype and the T allele resulted associated with PD in the overall analyzed PD population. Gender-based stratification of data indicated that results were maintained for FokI TT genotype and T allele in male PD patients, whereas the FokI T allele alone was confirmed as a risk factor for PD in females. Co-segregation analyses indicated the TaqI ApaI FokI rs1989969 GCTG as a "risk" haplotype for PD. In a subgroup of patients and controls neural Vitamin D and VDR concentration was analyzed in extravesicles (NDEVs) isolated from peripheral blood: no differences emerged between PD and HC. NDEVs results will need to be validated in ampler cohort but we can speculate that, if at neuronal level the amounts of Vitamin D and of VDR are comparable, than the bioavailability of vitamin D and the efficacy of the vitamin D/VDR axis is differentially modulated in PD by VDR SNPs.

Neither a Novel Tau Proteinopathy nor an Expansion of a Phenotype: Reappraising Clinicopathology-Based Nosology.

The gold standard for classification of neurodegenerative diseases is postmortem histopathology; however, the diagnostic odyssey of this case challenges such a clinicopathologic model. We evaluated a 60-year-old woman with a 7-year history of a progressive dystonia-ataxia syndrome with supranuclear gaze palsy, suspected to represent Niemann-Pick disease Type C. Postmortem evaluation unexpectedly demonstrated neurodegeneration with 4-repeat tau deposition in a distribution diagnostic of progressive supranuclear palsy (PSP). Whole-exome sequencing revealed a new heterozygous variant in TGM6, associated with spinocerebellar ataxia type 35 (SCA35). This novel TGM6 variant reduced transglutaminase activity in vitro, suggesting it was pathogenic. This case could be interpreted as expanding: (1) the PSP phenotype to include a spinocerebellar variant; (2) SCA35 as a tau proteinopathy; or (3) TGM6 as a novel genetic variant underlying a SCA35 phenotype with PSP pathology. None of these interpretations seem adequate. We instead hypothesize that impairment in the crosslinking of tau by the TGM6-encoded transglutaminase enzyme may compromise tau functionally and structurally, leading to its aggregation in a pattern currently classified as PSP. The lessons from this case study encourage a reassessment of our clinicopathology-based nosology.

Soluble Amyloid-ß Consumption in Alzheimer's Disease.

Brain proteins function in their soluble, native conformation and cease to function when transformed into insoluble aggregates, also known as amyloids. Biophysically, the soluble-to-insoluble phase transformation represents a process of polymerization, similar to crystallization, dependent on such extrinsic factors as concentration, pH, and a nucleation surface. The resulting cross-ß conformation of the insoluble amyloid is markedly stable, making it an unlikely source of toxicity. The spread of brain amyloidosis can be fully explained by mechanisms of spontaneous or catalyzed polymerization and phase transformation instead of active replication, which is an enzyme- and energy-requiring process dependent on a specific nucleic acid code for the transfer of biological information with high fidelity. Early neuronal toxicity in Alzheimer's disease may therefore be mediated to a greater extent by a reduction in the pool of soluble, normal-functioning protein than its accumulation in the polymerized state. This alternative loss-of-function hypothesis of pathogenicity can be examined by assessing the clinical and neuroimaging effects of administering non-aggregating peptide analogs to replace soluble amyloid-ß levels above the threshold below which neuronal toxicity may occur. Correcting the depletion of soluble amyloid-ß, however, would only exemplify 'rescue medicine.' Precision medicine will necessitate identifying the pathogenic factors catalyzing the protein aggregation in each affected individual. Only then can we stratify patients for etiology-specific treatments and launch precision medicine for Alzheimer's disease and other neurodegenerative disorders.