Genetic effects on longitudinal cognitive decline during the early stages of Alzheimer's disease

Cognitive decline in early-stage Alzheimer’s disease (AD) may depend on genetic variability. In the Swedish BioFINDER study, we used polygenic scores (PGS) (for AD, intelligence, and educational attainment) to predict longitudinal cognitive change (measured by mini-mental state examination (MMSE) [primary outcome] and other cognitive tests) over a mean of 4.2 years. We included 260 β-amyloid (Aβ) negative cognitively unimpaired (CU) individuals, 121 Aβ-positive CU (preclinical AD), 50 Aβ-negative mild cognitive impairment (MCI) patients, and 127 Aβ-positive MCI patients (prodromal AD). Statistical significance was determined at Bonferroni corrected p value < 0.05. The PGS for intelligence (beta = 0.1, p = 2.9e−02) was protective against decline in MMSE in CU and MCI participants regardless of Aβ status. The polygenic risk score for AD (beta = − 0.12, p = 9.4e−03) was correlated with the rate of change in MMSE and was partially mediated by Aβ-pathology (mediation effect 20%). There was no effect of education PGS on cognitive measures. Genetic variants associated with intelligence mitigate cognitive decline independent of Aβ-pathology, while effects of genetic variants associated with AD are partly mediated by Aβ-pathology

Blood and cerebrospinal fluid neurofilament light differentially detect neurodegeneration in early Alzheimer's disease

Cerebrospinal fluid (CSF) neurofilament light (NfL) concentration has reproducibly been shown to reflect neurodegeneration in brain disorders, including Alzheimer’s disease (AD). NfL concentration in blood correlates with the corresponding CSF levels, but few studies have directly compared the reliability of these 2 markers in sporadic AD. Herein, we measured plasma and CSF concentrations of NfL in 478 cognitively unimpaired (CU) subjects, 227 patients with mild cognitive impairment, and 113 patients with AD dementia. We found that the concentration of NfL in CSF, but not in plasma, was increased in response to Ab pathology in CU subjects. Both CSF and plasma NfL concentrations were increased in patients with mild cognitive impairment and AD dementia. Furthermore, only NfL in CSF was associated with reduced white matter microstructure in CU subjects. Finally, in a transgenic mouse model of AD, CSF NfL increased before serum NfL in response to the development of Ab pathology. In conclusion, NfL in CSF may be a more reliable biomarker of neurodegeneration than NfL in blood in preclinical sporadic AD

Prediction of future Alzheimer's disease dementia using plasma phospho-tau combined with other accessible measures

A combination of plasma phospho-tau (P-tau) and other accessible biomarkers might provide accurate prediction about the risk of developing Alzheimer’s disease (AD) dementia. We examined this in participants with subjective cognitive decline and mild cognitive impairment from the BioFINDER (n = 340) and Alzheimer’s Disease Neuroimaging Initiative (ADNI) (n = 543) studies. Plasma P-tau, plasma Aβ42/Aβ40, plasma neurofilament light, APOE genotype, brief cognitive tests and an AD-specific magnetic resonance imaging measure were examined using progression to AD as outcome. Within 4 years, plasma P-tau217 predicted AD accurately (area under the curve (AUC) = 0.83) in BioFINDER. Combining plasma P-tau217, memory, executive function and APOE produced higher accuracy (AUC = 0.91, P < 0.001). In ADNI, this model had similar AUC (0.90) using plasma P-tau181 instead of P-tau217. The model was implemented online for prediction of the individual probability of progressing to AD. Within 2 and 6 years, similar models had AUCs of 0.90–0.91 in both cohorts. Using cerebrospinal fluid P-tau, Aβ42/Aβ40 and neurofilament light instead of plasma biomarkers did not improve the accuracy significantly. The clinical predictions by memory clinic physicians had significantly lower accuracy (4-year AUC = 0.71). In summary, plasma P-tau, in combination with brief cognitive tests and APOE genotyping, might greatly improve the diagnostic prediction of AD and facilitate recruitment for AD trials

Plasma GFAP is an early marker of amyloid-β but not tau pathology in Alzheimer's disease

Although recent clinical trials targeting amyloid-β (Aβ) in Alzheimer's disease (AD) have shown promising results, there is increasing evidence suggesting that understanding alternative disease pathways that interact with Aβ metabolism and amyloid pathology might be important to halt the clinical deterioration. In particular, there is evidence supporting a critical role of astroglial activation and astrocytosis in AD. However, to this date, no studies have assessed whether astrocytosis is independently related to either Aβ or tau pathology, respectively, in vivo. To address this question, we determined the levels of the astrocytic marker glial fibrillary acidic protein (GFAP) in plasma and cerebrospinal fluid (CSF) of 217 Aβ-negative cognitively unimpaired individuals, 71 Aβ-positive cognitively unimpaired individuals, 78 Aβ-positive cognitively impaired individuals, 63 Aβ-negative cognitively impaired individuals and 75 patients with a non-AD neurodegenerative disorder from the Swedish BioFINDER-2 study. Subjects underwent longitudinal Aβ (18F-flutemetamol) and tau (18F-RO948) positron emission tomography (PET) as well as cognitive testing. We found that plasma GFAP concentration was significantly increased in all Aβ-positive groups compared with subjects without Aβ pathology (p < 0.01). In addition, there were significant associations between plasma GFAP with higher Aβ-PET signal in all Aβ-positive groups, but also in cognitively normal individuals with normal Aβ values (p < 0.001), which remained significant after controlling for tau-PET signal. Furthermore, plasma GFAP could predict Aβ-PET positivity with an area under the curve of 0.76, which was greater than the performance achieved by CSF GFAP (0.69) and other glial markers (CSF YKL-40: 0.64, sTREM2: 0.71). Although correlations were also observed between tau-PET and plasma GFAP, these were no longer significant after controlling for Aβ-PET. In contrast to plasma GFAP, CSF GFAP concentration was significantly increased in non-AD patients compared to other groups (p < 0.05) and correlated with Aβ-PET only in Aβ-positive cognitively impaired individuals (p = 0.005). Finally, plasma GFAP was associated with both longitudinal Aβ-PET and cognitive decline, and mediated the effect of Aβ-PET on tau-PET burden, suggesting that astrocytosis secondary to Aβ aggregation might promote tau accumulation. Altogether, these findings indicate that plasma GFAP is an early marker associated with brain Aβ pathology but not tau aggregation, even in cognitively normal individuals with a normal Aβ status. This suggests that plasma GFAP should be incorporated in current hypothetical models of AD pathogenesis and be used as a non-invasive and accessible tool to detect early astrocytosis secondary to Aβ pathology

Tau-PET is superior to phospho-tau when predicting cognitive decline in symptomatic AD patients

Introduction: Biomarkers for the prediction of cognitive decline in patients with amnestic mild cognitive impairment (MCI) and amnestic mild dementia are needed for both clinical practice and clinical trials. Methods: We evaluated the ability of tau-PET (positron emission tomography), cortical atrophy on magnetic resonance imaging (MRI), baseline cognition, apolipoprotein E gene (APOE) status, plasma and cerebrospinal fluid (CSF) levels of phosphorylated tau-217, neurofilament light (NfL), and amyloid beta (Aβ)42/40 ratio (individually and in combination) to predict cognitive decline over 2 years in BioFINDER-2 and Alzheimer's Disease Neuroimaging Initiative (ADNI). Results: Baseline tau-PET and a composite baseline cognitive score were the strongest independent predictors of cognitive decline. Cortical thickness and NfL provided some additional information. Using a predictive algorithm to enrich patient selection in a theoretical clinical trial led to a significantly lower required sample size. Discussion: Models including baseline tau-PET and cognition consistently provided the best prediction of change in cognitive function over 2 years in patients with amnestic MCI or mild dementia

Soluble P-tau217 reflects amyloid and tau pathology and mediates the association of amyloid with tau

Alzheimer\u27s disease is characterized by β-amyloid plaques and tau tangles. Plasma levels of phospho-tau217 (P-tau217) accurately differentiate Alzheimer\u27s disease dementia from other dementias, but it is unclear to what degree this reflects β-amyloid plaque accumulation, tau tangle accumulation, or both. In a cohort with post-mortem neuropathological data (N = 88), both plaque and tangle density contributed independently to higher P-tau217, but P-tau217 was not elevated in patients with non-Alzheimer\u27s disease tauopathies (N = 9). Several findings were replicated in a cohort with PET imaging ( BioFINDER-2 , N = 426), where β-amyloid and tau PET were independently associated with P-tau217. P-tau217 concentrations correlated with β-amyloid PET (but not tau PET) in early disease stages and with both β-amyloid and (more strongly) tau PET in late disease stages. Finally, P-tau217 mediated the association between β-amyloid and tau in both cohorts, especially for tau outside of the medial temporal lobe. These findings support the hypothesis that plasma P-tau217 concentration is increased by both β-amyloid plaques and tau tangles and is congruent with the hypothesis that P-tau is involved in β-amyloid-dependent formation of neocortical tau tangles

Tau PET correlates with different Alzheimer's disease-related features compared to CSF and plasma p-tau biomarkers

PET, CSF and plasma biomarkers of tau pathology may be differentially associated with Alzheimer's disease (AD)-related demographic, cognitive, genetic and neuroimaging markers. We examined 771 participants with normal cognition, mild cognitive impairment or dementia from BioFINDER-2 (n = 400) and ADNI (n = 371). All had tau-PET ([18F]RO948 in BioFINDER-2, [18F]flortaucipir in ADNI) and CSF p-tau181 biomarkers available. Plasma p-tau181 and plasma/CSF p-tau217 were available in BioFINDER-2 only. Concordance between PET, CSF and plasma tau biomarkers ranged between 66 and 95%. Across the whole group, ridge regression models showed that increased CSF and plasma p-tau181 and p-tau217 levels were independently of tau PET associated with higher age, and APOEɛ4-carriership and Aβ-positivity, while increased tau-PET signal in the temporal cortex was associated with worse cognitive performance and reduced cortical thickness. We conclude that biofluid and neuroimaging markers of tau pathology convey partly independent information, with CSF and plasma p-tau181 and p-tau217 levels being more tightly linked with early markers of AD (especially Aβ-pathology), while tau-PET shows the strongest associations with cognitive and neurodegenerative markers of disease progression

CSF biomarkers of neuroinflammation and cerebrovascular dysfunction in early Alzheimer disease

OBJECTIVE: To measure CSF levels of biomarkers reflecting microglia and astrocytes activation, neuroinflammation, and cerebrovascular changes and study their associations with the core biomarkers of Alzheimer disease (AD) pathology (β-amyloid [Aβ] and tau), structural imaging correlates, and clinical disease progression over time. METHODS: The study included cognitively unimpaired elderly (n = 508), patients with mild cognitive impairment (MCI, n = 256), and patients with AD dementia (n = 57) from the longitudinal Swedish BioFINDER cohort. CSF samples were analyzed for YKL-40, interleukin (IL)-6, IL-7, IL-8, IL-15, IP-10, monocyte chemoattractant protein 1, intercellular adhesion molecule 1 (ICAM-1), vascular adhesion molecule 1 (VCAM-1), placental growth factor, and fms-related tyrosine kinase 1 (Flt-1). MRI data were available from 677 study participants. Longitudinal clinical assessments were conducted in control individuals and patients with MCI (mean follow-up 3 years, range 1-6 years). RESULTS: CSF levels of YKL-40, ICAM-1, VCAM-1, IL-15, and Flt-1 were increased during the preclinical, prodromal, and dementia stages of AD. High levels of these biomarkers were associated with increased CSF levels of total tau, with the associations, especially for YKL-40, being stronger in Aβ-positive individuals. The results were similar for associations between phosphorylated tau and YKL-40, ICAM-1, and VCAM-1. High levels of the biomarkers were also associated with cortical thinning (primarily in the precuneus and superior parietal regions) and with subsequent cognitive deterioration in patients without dementia as measured with Mini-Mental State Examination (YKL-40) and Clinical Dementia Rating Sum of Boxes (YKL-40, ICAM-1, VCAM-1 and IL-15). Finally, higher levels of CSF YKL-40, ICAM-1, and Flt-1 increased risk of development of AD dementia in patients without dementia. CONCLUSIONS: Neuroinflammation and cerebrovascular dysfunction are early events occurring already at presymptomatic stages of AD and contribute to disease progression

Earliest accumulation of beta-amyloid occurs within the default-mode network and concurrently affects brain connectivity

It is not known exactly where amyloid-β (Aβ) fibrils begin to accumulate in individuals with Alzheimer’s disease (AD). Recently, we showed that abnormal levels of Aβ42 in cerebrospinal fluid (CSF) can be detected before abnormal amyloid can be detected using PET in individuals with preclinical AD. Using these approaches, here we identify the earliest preclinical AD stage in subjects from the ADNI and BioFINDER cohorts. We show that Aβ accumulation preferentially starts in the precuneus, medial orbitofrontal, and posterior cingulate cortices, i.e., several of the core regions of the default mode network (DMN). This early pattern of Aβ accumulation is already evident in individuals with normal Aβ42 in the CSF and normal amyloid PET who subsequently convert to having abnormal CSF Aβ42. The earliest Aβ accumulation is further associated with hypoconnectivity within the DMN and between the DMN and the frontoparietal network, but not with brain atrophy or glucose hypometabolism. Our results suggest that Aβ fibrils start to accumulate predominantly within certain parts of the DMN in preclinical AD and already then affect brain connectivity

Brain myoinositol as a potential marker of amyloid-related pathology: A longitudinal study

Objective To investigate the association between longitudinal changes in proton magnetic resonance spectroscopy (MRS) metabolites and amyloid pathology in individuals without dementia, and to explore the relationship between MRS and cognitive decline. Methods In this longitudinal multiple time point study (a subset of the Swedish BioFINDER), we included cognitively healthy participants, individuals with subjective cognitive decline, and individuals with mild cognitive impairment. MRS was acquired serially in 294 participants (670 individual spectra) from the posterior cingulate/precuneus. Using mixed-effects models, we assessed the association between MRS and baseline β-amyloid (Aβ), and between MRS and the longitudinal Mini-Mental State Examination, accounting for APOE, age, and sex. Results While baseline MRS metabolites were similar in Aβ positive (Aβ+) and negative (Aβ−) individuals, in the Aβ+ group, the estimated rate of change was +1.9%/y for myo-inositol (mI)/creatine (Cr) and −2.0%/y for N-acetylaspartate (NAA)/mI. In the Aβ− group, mI/Cr and NAA/mI yearly change was −0.05% and +1.2%; however, this was not significant across time points. The mild cognitive impairment Aβ+ group showed the steepest MRS changes, with an estimated rate of +2.93%/y (p = 0.07) for mI/Cr and −3.55%/y (p < 0.01) for NAA/mI. Furthermore, in the entire cohort, we found that Aβ+ individuals with low baseline NAA/mI had a significantly higher rate of cognitive decline than Aβ+ individuals with high baseline NAA/mI. Conclusion We demonstrate that the longitudinal change in mI/Cr and NAA/mI is associated with underlying amyloid pathology. MRS may be a useful noninvasive marker of Aβ-related processes over time. In addition, we show that in Aβ+ individuals, baseline NAA/mI may predict the rate of future cognitive decline