Abstract
INTRODUCTION
Evidence linking plasma phosphorylated tau (p‐tau)181 to cognitive decline comes from studies conducted in younger, selected research populations, raising questions about the generalizability of these findings to older adults meeting frailty criteria. The association between plasma p‐tau181 and physical parameters has been sparsely investigated. This study aims to assess the relationship between plasma p‐tau181 levels and the trajectories of cognitive and physical performance in a population of pre‐frail and frail older adults.
METHODS
This is a 2‐year analysis based on longitudinal data from the CogFrail study. Plasma p‐tau181 was measured using the SIMOA method. High p‐tau181 levels were defined by a cut‐off corresponding to the highest tertile of its distribution. Longitudinal changes from baseline in functional/cognitive (Mini‐Mental State Examination [MMSE], Clinical Dementia Rating Sum of Boxes [CDR‐SoB], Activities of Daily Living [ADL]‐Index) and physical outcomes (gait speed, handgrip strength, Short Physical Performance Battery, and chair rise time) according to plasma p‐tau181 status (high vs. low/intermediate levels) were compared using linear mixed‐effects models.
RESULTS
Among the 227 patients with available plasma p‐tau181 concentrations (mean age: 82.1 ± 5.1 years, 63.4% women), 77 (33.9%) were classified as having high plasma p‐tau181 levels. Mean plasma p‐tau181 values were 14.64 (± 3.83) and 29.96 (± 7.63) pg/mL in the low/intermediate and high level groups, respectively. Over 2 years, participants with high p‐tau181 levels showed greater progression in CDR‐SoB (β = +0.43; 95% confidence interval [CI]: +0.24 to +0.63, log transformed), greater decline in MMSE (β = −2.09; 95% CI: −3.17 to −1.02), ADL (β = −0.31; 95% CI: −0.54 to −0.08), and handgrip strength (β = −2.66; 95% CI: −4.10 to −1.23), compared to those with low/intermediate levels.
DISCUSSION
In a population of pre‐frail and frail older adults with cognitive impairment, individuals with elevated plasma p‐tau181 levels showed greater cognitive and physical deterioration over a 2‐year period. Age‐related loss of proteostasis, responsible for amyloidopathy and associated tauopathy, may play a role not only in cognitive but also in physical decline, representing a potential target for preventive and therapeutic interventions.
Keywords: Alzheimer's disease, blood‐based biomarkers, cognitive frailty, dual decline
Highlights
High plasma phosphorylated tau (p‐tau)181 levels were associated with greater global cognitive decline.
Plasma p‐tau181 appears to be a marker of muscle strength decline over time.
Age‐related loss of proteostasis may play a role in dual decline.
1. INTRODUCTION
With the aging population, greater attention has been given to identifying the functions whose impairment is most closely linked to functional decline and loss of independence. 1 In older adults, cognitive and physical decline have historically been considered separately, yet compelling evidence suggests that they are frequently associated. 2 In recent years, there has been a growing interest in identifying potential age‐related pathophysiological pathways underlying cognitive and physical decline, which could serve as targets for preventive and therapeutic interventions.
Disruption of protein homeostasis (proteostasis) is a hallmark of aging, resulting in the accumulation of misfolded or aggregated proteins. 3 Amyloid and tau proteinopathies represent core hallmarks of Alzheimer's disease (AD) pathology. 4 , 5 Although the precise temporal and mechanistic relationships between amyloid beta (Aβ) deposition and tau pathology have yet to be elucidated, the amyloid cascade appears to be involved in tau hyperphosphorylation. 6 , 7 , 8 While Aβ aggregates and tau are found in various peripheral tissues and cells of the human body, including muscles and the peripheral nervous system, 9 their physiological functions and their contribution to physical decline have not been fully elucidated.
Recent technological advancements now allow for the expanded use of fluid biomarkers in peripheral blood, enabling the measurement of different isoforms of phosphorylated tau (p‐tau) in plasma. Plasma p‐tau181 concentrations, which correlate with both amyloid and associated tauopathology, 10 , 11 , 12 have been shown to predict cognitive decline in cognitively unimpaired individuals and across the mild cognitive impairment (MCI)–dementia spectrum. 10 , 13 , 14 , 15 , 16 However, the available evidence is derived from studies involving selected younger research populations, raising questions about the generalizability of these findings to frail and pre‐frail older adults undergoing cognitive evaluation in clinical settings. The current body of evidence linking plasma p‐tau181 levels to physical function remains limited. Cross‐sectional studies have demonstrated associations between elevated plasma p‐tau181 concentrations and slower gait speed, 17 , 18 reduced stride length, 17 , 19 shorter balance duration, and lower total scores on the Short Physical Performance Battery (SPPB). 18 Two longitudinal studies—conducted in a population mainly composed of cognitively unimpaired participants—have identified a significant relationship between plasma p‐tau181 levels and declines in SPPB 20 and handgrip strength. 21 To address these gaps, this study aimed at estimating the associations between p‐tau181 levels and the trajectories of cognitive and physical domains over a 2‐year follow‐up period in a population of frail and pre‐frail older adults with objective cognitive impairment.
RESEARCH IN CONTEXT
Systematic review: The authors conducted a PubMed review. Several studies have found that plasma phosphorylated tau (p‐tau)181 predicts cognitive decline in cognitively unimpaired individuals and across the mild cognitive impairment–dementia spectrum, mostly in younger, selected populations. These findings may not generalize to frail older adults. Only two longitudinal studies have examined the relationship between p‐tau181 and physical parameters, reporting an association with handgrip strength and decline in Short Physical Performance Battery.
Interpretation: Our findings highlight the prognostic role of plasma p‐tau181, a biomarker of amyloidopathy and associated tauopathy, in predicting the trajectory of both cognitive and physical performances among older adults in clinical settings.
Future directions: The age‐related loss of proteostasis, contributing to amyloidopathy and tauopathy, may underlie both cognitive and physical decline, thereby representing a potential target for preventive and therapeutic interventions.
2. METHODS
2.1. Study population
This analysis uses data from the CogFrail observational trial (NCT03129269). The study protocol has been detailed previously. 22 In brief, 317 cognitively impaired participants were enrolled between 2017 and 2020 at the Frailty Day Hospital 23 and the Memory Clinic of Toulouse University Hospital after a geriatric consultation or during daily hospitalization as part of routine clinical practice. Patients were included if they met all of the following criteria: (1) being aged ≥ 70 years, (2) presenting at least one criterion of physical frailty (according to the Fried phenotype), 24 (3) exhibiting objective cognitive impairment compatible with a Clinical Dementia Rating Scale Global Score (CDR‐GS) score of 0.5 (MCI) or 1 (mild dementia), 25 , 26 (4) having a Mini‐Mental State Examination (MMSE) score ≥ 20, 27 (5) being affiliated with the French health‐care system, and (6) being accompanied by a study partner available by phone or in person during visits. The main exclusion criteria were (1) a severe or unstable medical condition that could potentially interfere with the study procedures, (2) impairment in basic daily living activities (index of Activities of Daily Living [ADL] score < 4), 28 and (3) being under legal supervision or guardianship. The primary aim of the CogFrail study was to quantify the prevalence of brain amyloidopathy in this population. The study protocol received approval from the institutional research committee (CPP SOOM II; registration number RC31/16/8753). All participants provided written informed consent. The CogFrail cohort did not include any robust (non‐frail) individuals. Physical frailty was assessed using the Fried phenotype. 24 The Fried frailty phenotype includes the following criteria: (1) unintentional weight loss (> 4.5 kg over the past year), (2) self‐reported exhaustion, (3) reduced handgrip strength, (4) slow gait speed, and (5) low levels of physical activity. Individuals were classified as pre‐frail if they met one or two criteria, and as frail if they met three or more criteria. For the present study, we excluded participants without plasma p‐tau181 measurements, resulting in a final sample of 227 older adults. Sample sizes for each outcome are specified in Figure 1.
FIGURE 1.
Participant flowchart. ADL, activities of daily living; CDR‐SoB, Clinical Dementia Rating–Sum of Boxes; CNT, Category Naming Test; COWAT, Controlled Oral Word Association Test; FCSRT, Free and Cued Selective Reminding Test; MMSE, Mini‐Mental State Examination; p‐tau, phosphorylated tau; TMT‐A, Trail Making Test Part A; TMT‐B, Trail Making Test Part B; WAIS‐R, Wechsler Adult Intelligence Scale–Revised.
2.2. Study procedures
Participants underwent a comprehensive geriatric assessment, including medical (comorbidities and treatments), neuropsychological, and physical evaluations at baseline and annually over a 2‐year follow‐up period. Additionally, two intermediate consultations (at 6 and 18 months) were conducted to collect data on medical events and treatment changes, along with brief assessments of cognition (MMSE) and autonomy (ADL). Blood samples were collected at each annual visit and at the 6‐month visit for biomarker analysis.
2.3. Plasma p‐tau 181 measurement
Two hundred twenty‐seven patients benefited from the assessment of plasma p‐tau181 concentration. Blood samples were collected at the 6‐month visit, stored in edetic acid tubes at −80°C, and analyzed using an in‐house single molecule array (Simoa) method. This technique uses the AT270 antibody (specific to the threonine 181 phosphorylation site) and the Tau12 antibody (which targets the N‐terminal epitope 6‐18 of the human tau protein). 14 The analyses were carried out by the Clinical Neurochemistry Laboratory at the University of Gothenburg (Mölndal, Sweden). All measurements were performed using an HD‐X Analyzer (Quanterix) in a single‐batch analysis. Given the lack of established manufacturer cut‐offs for positive plasma p‐tau181 levels in our population, we applied in this analysis a threshold corresponding to the highest tertile of its distribution (21.5 pg/mL), as previously used in the literature, 29 , 30 , 31 , 32 to indicate high plasma p‐tau181 levels.
2.4. Cognitive and autonomy assessment
Global cognitive performance was evaluated using the Clinical Dementia Rating Scale—Sum of Boxes (CDR‐SoB; range 0–18, with higher scores indicating worse performance) at baseline and during annual visits. The MMSE (range 0–30, with higher scores indicating better performance) was performed at baseline, during annual visits, and at intermediate consultations. A standardized neuropsychological test battery was administered by a neuropsychologist to assess performance in three cognitive domains (memory, attention, and executive function) at baseline and during annual visits. Memory was evaluated with the Free and Cued Selective Reminding Test (FCSRT). 33 Attention was assessed with the Trail Making Test Part A (TMT‐A) 34 and the Digit Symbol Substitution Subtest of the Wechsler Adult Intelligence Scale‐Revised (DSSS WAIS‐R). 35 Executive function was evaluated with the Trail Making Test Part B (TMT‐B), 36 the Controlled Oral Word Association Test (COWAT; p, 2 minutes), and Category Naming Test fluencies (CNT; animals, 2 minutes). 37 Autonomy in activities of daily living was assessed using the ADL index at each annual visit and intermediate consultation. Four of these cognitive tests (MMSE orientation items, category fluency, free and total recall from the FCSRT, and the DSST from the WAIS‐R) were used to create a “composite cognitive score.” 38 The composite score was calculated as the average of four Z scores. Each component's Z score (standardized using baseline means and standard deviations) was summed, and the total was then divided by four.
2.5. Physical assessment
Global physical performance was assessed using the SPPB (range 0–12, with higher values indicating better performances), which includes a 4‐meter usual gait speed test (measured in meters per second), a five‐repetition chair rise test (measured in seconds), and a balance assessment featuring three levels of increasing difficulty. 39 The total SPPB score, along with two of its components (gait speed, chair rise time), was considered an isolated measure for analysis. Handgrip strength (measured in the dominant hand, in kilograms) was also evaluated as an additional physical performance parameter. 40
2.6. Statistical analyses
Descriptive statistics were presented as mean (standard deviation [SD]) for continuous variables and as frequencies (percentages) for categorical variables. Baseline characteristics according to plasma p‐tau181 status (high vs. low/intermediate levels) were compared using two‐sample t tests or Kruskal–Wallis tests if the distribution is not Gaussian for continuous variables and by the χ 2 test or Fisher exact test if we had expected values < 5 for categorical variables. Longitudinal changes from baseline in cognitive/functional (MMSE, CDR‐SoB, ADL index, and neuropsychological test battery) and physical outcomes (SPPB, gait speed, handgrip strength, and chair rise time) according to plasma p‐tau181 status (high vs. low/intermediate levels) were compared using linear mixed models with random subject effects (intercept and slope). All models were run unadjusted and adjusted for age, sex, education level (on an ordinal scale: primary school certificate or less, secondary education diploma, high school diploma, and university degree), body mass index (BMI; kg/m2), Charlson comorbidity index 41 (CCI, range 0–37, with higher scores indicating greater multimorbidity burden), and estimated glomerular filtration rate (eGFR; reduced if < 60 mL/minute), as well as their interactions with time. To investigate whether the association between plasma p‐tau181 levels and physical outcomes was influenced by cognitive decline, a second model was run for the physical measures. This model was adjusted for the same variables as previously (age, sex, education level, BMI, CCI, and eGFR), with the addition of a binary variable “cognitive decline.” Based on the literature, 42 cognitive decline was defined as an increase in the CDR‐GS score between baseline and the 2‐year follow‐up (no decline = CDR‐GS stable between baseline and 2 years; cognitive decline = participants moving from 0.5 to 1, or from 1 to > 1). The rationale for adjusting for eGFR is grounded in evidence indicating that kidney function significantly affects p‐tau species levels, 29 In the absence of a normal distribution, outcome values were transformed using a logarithmic transformation. A P value < 0.05 was considered the threshold for statistical significance. Data were analyzed using Statistical Analysis Software (SAS) version 9.4.
3. RESULTS
A total of 227 patients were included in this analysis (mean age 82.1 ± 5.1 years, with 154 individuals [67.8%] aged ≥ 80 years; 63.4% were women). High p‐tau181 levels were defined using a cut‐off corresponding to the highest tertile of its distribution (21.5 pg/mL). According to this threshold, 77 individuals (33.9%) were classified as having high plasma p‐tau181 levels. Baseline participant characteristics according to p‐tau181 status are presented in Table 1. At baseline, no significant differences were observed between participants with high p‐tau181 levels and those with low or intermediate levels regarding demographic characteristics and most cognitive and physical parameters. However, handgrip strength was significantly higher in individuals with elevated p‐tau181 levels (21.1 ± 7.2 vs. 18.2 ± 7.4 kg; P = 0.0046). In contrast, the FCSRT global score (maximum 96; calculated as 2 × free recall + cued recall) was significantly lower in individuals with elevated p‐tau181 levels compared to those with low or intermediate levels (48.81 ± 13.11 vs. 53.73 ± 13.69; P = 0.0224). No significant differences in the main comorbidities were found between the groups (Table S1 in supporting information).
TABLE 1.
Baseline participant characteristics according to p‐tau181 status.
|
Total sample (N = 227) |
High plasma p‐tau181 levels (≥ 21.5 pg/mL) (N = 77) |
Low/Intermediate plasma p‐tau181 levels (<21.5 pg/mL) (N = 150) |
P value | |
|---|---|---|---|---|
| Age(y) | 82.06 (5.13) | 82.81 (4.78) | 81.67 (5.28) | 0.1158 a |
| Sex | 0.0888 b | |||
| Female | 144 (63.44%) | 43 (55.84%) | 101 (67.33%) | |
| Male | 83 (36.56%) | 34 (44.16%) | 49 (32.67%) | |
| Level of education | 0.3365 b | |||
| No diploma or primary school | 74 (32.74%) | 21 (27.27%) | 53 (35.57%) | |
| Secondary education | 59 (26.11%) | 18 (23.38%) | 41 (27.52%) | |
| High school | 48 (21.24%) | 19 (24.68%) | 29 (19.46%) | |
| University degree | 45 (19.91%) | 19 (24.68%) | 26 (17.45%) | |
| Frailty status | 0.7251 b | |||
| Pre‐frail | 129 (56.83%) | 45 (58.44%) | 84 (56.00%) | |
| Frail | 98 (43.17%) | 32 (41.56%) | 66 (44.00%) | |
| BMI (kg/m2) | 26.84 (4.81) | 26.58 (4.67) | 26.97 (4.90) | 0.5607 1 |
| Charlson Comorbidity Index | 1.68 (1.74) | 1.94 (2.05) | 1.55 (1.55) | 0.4245 d |
| e‐GFR < 60 mL/min | 69 (30.40%) | 32 (41.56%) | 37 (24.67%) | 0.0088 b |
| CDR‐GS | 0.7622 b | |||
| 0.5 | 191 (84.14%) | 64 (83.12%) | 127 (84.67%) | |
| 1 | 36 (15.86%) | 13 (16.88%) | 23 (15.33%) | |
| CDR‐SoB | 2.64 (1.61) | 2.53 (1.68) | 2.69 (1.58) | 0.3009 d |
| MMSE | 24.54 (2.80) | 24.42 (2.91) | 24.61 (2.75) | 0.6977 d |
| ADL Index | 5.64 (0.48) | 5.73 (0.37) | 5.60 (0.52) | 0.0941 d |
| ADL | 0.1637 b | |||
| <6 | 106 (46.70%) | 31 (40.26%) | 75 (50.00%) | |
| 6 | 121 (53.30%) | 46 (59.74%) | 75 (50.00%) | |
| Chair rise time(s) | 14.39 (5.30) | 14.46 (5.47) | 14.35 (5.24) | 0.8922 4 |
| Gait speed(m/s) | 0.81 (0.21) | 0.81 (0.22) | 0.81 (0.20) | 0.9196 a |
| Grip strength(kg) | 19.18 (7.49) | 21.13 (7.23) | 18.17 (7.44) | 0.0046 a |
| SPPB | 8.50 (2.81) | 8.22 (2.97) | 8.65 (2.73) | 0.3376 d |
| TMT‐A(s) | 65.68 (30.02) | 67.51 (30.54) | 64.72 (29.81) | 0.4798 d |
| TMT‐B(s) | 171.38 (77.77) | 177.85 (80.04) | 168.51 (77.03) | 0.5408 d |
| WAIS‐R | 23.51 (9.55) | 24.86 (10.15) | 22.84 (9.22) | 0.1974 a |
| COWAT | 14.33 (7.20) | 14.47 (7.83) | 14.26 (6.88) | 0.8467 a |
| CNT | 17.01 (7.24) | 17.03 (6.63) | 17.00 (7.56) | 0.9790 a |
| FCSRT free recall/48 | 15.13 (7.28) | 13.78 (7.74) | 15.79 (6.98) | 0.0932 a |
| FCSRT total recall (free+cued)/48 | 38.81 (7.94) | 37.02 (8.44) | 39.69 (7.56) | 0.0524 d |
|
FCSRT free+total recall(2*free+cued)/96 |
50.86 (13.53) | 48.81 (13.11) | 53.73 (13.69) | 0.0224 a |
| Cognitive composite score | 0.08 (0.70) | 0.05 (0.70) | 0.09 (0.71) | 0.7454 a |
| plasma p‐tau181(pg/mL) | 19.83 (9.06) | 29.96 (7.63) | 14.64 (3.83) | <0.0001 e |
Note: Data are presented as n (%), or mean (SD).
Abbreviations: ADL, activities of daily living; BMI, body mass index; CDR‐GS, Clinical Dementia Rating–Global Score; CDR‐SoB, Clinical Dementia Rating–Sum of Boxes; CNT, Category Naming Test; COWAT, Controlled Oral Word Association Test; e‐GFR, estimated glomerular filtration rate; FCSRT, Free and Cued Selective Reminding Test; MMSE, Mini‐Mental State Examination; p‐tau181, phosphorylated tau at threonine 181; SD, standard deviation; SPPB, Short Physical Performance Battery; TMT‐A, Trail Making Test A; TMT‐B, Trail Making Test B; WAIS‐R, Wechsler Adult Intelligence Scale–Revised.
Equal variance two sample t test.
Chi‐squared P value.
Fisher exact P value.
Kruskal–Wallis P value.
Unequal variance two‐sample t test.
Table 2 describes the changes from baseline to 2 years in cognitive, functional, and physical measures according to p‐tau181 status. Significant differences in changes from baseline to 2 years were observed between participants with high p‐tau181 levels and those with low or intermediate levels for CDR‐SoB + 0.43 (95% confidence interval [CI] 0.24 to 0.63; P < 0.0001), MMSE −2.09 (−3.17 to −1.02; P = 0.0002), and ADL Index −0.31 (−0.54 to −0.08; P = 0.0080). Figure 2 illustrates the evolution of cognitive and functional outcomes according to p‐tau181 status. Considering physical indicators, significant differences between the two groups were observed for handgrip strength of −2.66 (−4.10 to −1.23; P = 0.0003). Similar results were found when additionally adjusting for cognitive decline, with a significant difference between groups for handgrip strength of −2.17 (−3.62 to −0.72; P = 0.0034). Cognitive decline over 2 years, based on the change in CDR‐GS, was more frequent in participants with higher plasma p‐tau181 levels (66.13% vs. 43.65%; P = 0.0037). Figure 3 depicts the longitudinal changes from baseline in physical indicators according to p‐tau181 status. Considering the neuropsychological assessment (Table S2 in supporting information), no differences in longitudinal evolution were observed between groups except for fluency tests, which declined more markedly in patients with high levels of p‐tau181: COWAT −1.93 (−3.65 to −0.22; P = 0.0271), CNT −3.01 (−4.97 to −1.05; P = 0.0028).
TABLE 2.
Changes in cognitive, functional, and physical outcomes from baseline to 2 years according to p‐tau181 status.
|
Low/intermediate p‐tau181 * mean [95% CI] |
High p‐tau181 * mean [95% CI] |
High vs. low/intermediate p‐tau181 ** mean [95% CI] P value |
High vs. low/intermediate p‐tau181 ** mean [95% CI] P value |
High vs. low/intermediate p‐tau181 ** mean [95% CI] P value |
|
|---|---|---|---|---|---|
| Outcomes | Not adjusted | Adjusted *** | Adjusted **** | ||
| log(CDR‐SoB) |
0.43 [0.32 to 0.54] |
0.85 [0.68 to 1.01] |
0.42 [0.22 to 0.61] P < 0.0001 |
0.43 [0.24 to 0.63] P < 0.0001 |
|
| MMSE |
−1.51 [−2.13 to −0.89] |
−3.56 [−4.45 to −2.66] |
−2.04 [−3.13 to −0.96] P = 0.0003 |
−2.09 [−3.17 to −1.02] P = 0.0002 |
|
| ADL Index |
−0.20 [−0.32 to ‐0.07] |
−0.51 [−0.70 to ‐0.33] |
−0.31 [−0.54 to ‐0.09] P = 0.0061 |
−0.31 [−0.54 to −0.08] P = 0.0080 |
|
|
Handgrip strength |
−0.43 [−1.23 to 0.37] |
−3.24 [−4.42 to −2.06] |
−2.81 [−4.24 to −1.38] P = 0.0001 |
−2.66 [−4.10 to −1.23] P = 0.0003 |
−2.17 [−3.62 to −0.72] P = 0.0034 |
| Gait speed |
−0.04 [−0.08 to −0.00] |
−0.11 [−0.16 to −0.06] |
−0.07 [−0.13 to −0.00] P = 0.0385 |
−0.06 [−0.12 to 0.00] P = 0.0646 |
−0.03 [−0.10 to 0.03] P = 0.3179 |
| Chair rise time |
0.12 [−0.78 to 1.01] |
1.26 [−0.00 to 2.51] |
1.14 [−0.40 to 2.68] P = 0.1474 |
0.94 [−0.57 to 2.45] P = 0.2222 |
0.80 [−0.76 to 2.36] P = 0.3115 |
| SPPB |
−0.58 [−0.96 to −0.20] |
−1.02 [−1.57 to −0.47] |
−0.44 [−1.11 to 0.22] P = 0.1904 |
−0.42 [−1.08 to 0.23] P = 0.2036 |
−0.25 [−0.91 to 0.42] P = 0.4637 |
Abbreviations: ADL, activities of daily living; CDR‐SoB, Clinical Dementia Rating–Sum Of Boxes; CI, confidence interval; MMSE, Mini‐Mental State Examination; SPPB, Short Physical Performance Battery.
Change from baseline to 2 years.
Difference in change from baseline to 2 years between groups.
Adjusted for age, sex, education level, Charlson Comorbidity Index, body mass index, estimated glomerular filtration rate, and their interactions with time.
Adjusted for age, sex, education level, Charlson Comorbidity Index, body mass index, estimated glomerular filtration rate, cognitive decline, and their interactions with time.
FIGURE 2.
Evolution of cognitive and functional outcomes according to p‐tau181 status. ADL, activities of daily living; CDR‐SoB, Clinical Dementia Rating–Sum of Boxes; MMSE, Mini‐Mental State Examination; p‐tau, phosphorylated tau.
FIGURE 3.
Evolution of physical outcomes according to p‐tau181 status. p‐tau, phosphorylated tau; SPPB, Short Physical Performance Battery.
4. DISCUSSION
In this study, we investigated the association between p‐tau181 levels and the trajectories of cognitive and physical domains in a population of pre‐frail and frail older adults with objective cognitive impairment over a 2‐year follow‐up period. We found that individuals with high plasma p‐tau181 levels (highest tertile of p‐tau181 values distribution) experienced a more marked cognitive decline, as measured by CDR‐SoB and MMSE scores over a 2‐year follow‐up period. Loss of functional independence in activities of daily living was more evident among participants with high p‐tau181 levels. Changes from baseline in physical parameters also varied according to plasma p‐tau181 status, with individuals presenting high p‐tau181 values showing a greater decline in handgrip strength.
Our findings are consistent with previous longitudinal cohort studies demonstrating the prognostic role of plasma p‐tau181 in cognitive decline among cognitively unimpaired individuals and patients across the MCI/dementia spectrum. 10 , 13 , 14 , 15 , 16 In a sub‐population of the Multidomain Alzheimer Preventive Trial (MAPT) cohort—including individuals at risk for dementia with a median age of 74 years—participants with plasma p‐tau181 levels in the highest tertile exhibited greater cognitive decline over time, whereas those in the lower tertiles remained cognitively stable. 30 Notably, in our study, even individuals with plasma p‐tau181 levels in the lowest tertiles experienced a significant cognitive decline after 2 years of follow‐up compared to baseline. This discrepancy likely reflects baseline differences between the cohorts. While MAPT enrolled younger individuals at risk for cognitive decline, all CogFrail participants had objective cognitive impairment (CDR 0.5 or 1) at baseline and showed higher average plasma p‐tau181 levels. Our findings suggest that biomarker assessment targeting underlying pathophysiological processes may offer greater insight into cognitive trajectories even among older populations with frailty criteria. Measuring plasma p‐tau species may be particularly relevant in the current phase of drug development, as anti‐amyloid treatments are entering clinical practice. 43
Interestingly, we did not observe a significant difference in the evolution of neuropsychological tests assessing memory, most executive function, and attention between patients with high p‐tau181 levels and those with low/intermediate values, except for the fluency tests, which showed a more pronounced decline in the high p‐tau181 group. These results may be partially explained by the limited number of patients who were able to complete the neuropsychological test battery at 24 months, particularly in the high p‐tau181 group and for tests assessing anterograde verbal memory. As a result, only data from individuals with high p‐tau181 levels who showed better performance (i.e., those able to complete the tests) were retained. These findings may question the indication for performing repeated complex neuropsychological assessments in vulnerable populations, as well as their usefulness in predicting the likely etiological origin of cognitive decline.
In our study plasma p‐tau181 levels also appear to be a marker of handgrip strength decline over time. These results persisted after adjusting for cognitive decline, potentially suggesting that the greater decline in handgrip strength observed in participants with higher plasma p‐tau181 levels may not be directly driven by concurrent cognitive decline. The association between plasma p‐tau181 and gait speed impairment observed in the unadjusted model was attenuated after adjusting for confounders, although a trend toward significance persisted. To date, there is limited evidence regarding the relationship between plasma p‐tau181 and physical outcomes, with existing studies involving populations or presenting designs that differ from ours. 17 , 18 , 19 , 20 , 21 A recent analysis from the ongoing Swedish National Study on Aging and Care in Kungsholmen (SNAC‐K), which has followed individuals older than 60 without dementia for 12 years, found that higher concentrations of plasma p‐tau181 were associated with a faster decline in handgrip strength. 21 Similarly, another secondary analysis from the SNAC‐K study found an association between p‐tau181 levels and the risk of development and progression of sarcopenia, defined according to revised European Working Group on Sarcopenia in Older People criteria as a reduction in muscle strength and muscle mass. 44 Contrary to our findings, a secondary analysis from the Memento cohort has reported a longitudinal association between plasma p‐tau181 levels and SPPB values. 20 However, participants in the Memento cohort were mostly cognitively unimpaired, younger, had higher baseline physical performance (mean SPPB score at 10.5), and were followed over a longer period (5 years) than those in the CogFrail study. The age‐related decline in physical performance is a multifactorial process involving metabolic, hormonal, and psychosocial changes, as well as the impact of comorbidities. 45 In this context, the specific mechanisms by which amyloidopathy and associated tauopathy may contribute to physical decline have yet to be elucidated. Brain pathology may impair the transmission of motor signals at the neuromuscular junction, leading to reduced motor unit recruitment and muscle trophism. 46 A potential role for the peripheral effects of proteinopathies may be suggested by the fact that both amyloid and tau are also produced in the peripheral tissues, including skeletal muscle and the peripheral nervous system. 9 In animal models, overexpression of human tau protein has been associated with peripheral neuropathy, 47 muscle weakness, 48 and difficulties in initiating locomotion. 49 In patients with amyotrophic lateral sclerosis, elevated levels of p‐tau181 have been detected in both serum and muscle biopsies, in association with lower motor neuron dysfunction. These findings suggest that plasma p‐tau181 may serve as a potential biomarker of lower motor neuron impairment. 50 However, these potential mechanisms remain speculative, and further studies are needed to confirm and better understand the association between proteinopathies and physical parameters. If physical measures could be integrated as exploratory outcomes in the coming phases of anti‐tau antibody development, these trials could provide an opportunity to understand the effects of anti‐tau drugs on physical function, thereby advancing knowledge in the field.
The main strength of this study lies in the recruitment process and the characteristics of the included population. The CogFrail study provides an accurate representation of a real‐life population of older patients with cognitive decline, as participants were integrated into the study through standard care practices. In most cases, participants were initially referred from primary care or other specialists to the frailty clinic for a comprehensive geriatric assessment. This study provides important new insights into the prognostic role of p‐tau181 in an older population meeting frailty criteria, which is likely to be underrepresented in cohorts that have contributed more knowledge on plasma biomarkers. Other strengths of this study include the simultaneous assessment of two key functions in older adults—cognition and physical function—which are typically evaluated separately, the inclusion of a wide range of physical and cognitive outcomes, and the fact that our analyses were adjusted for relevant clinical variables such as multimorbidity index and kidney function. However, this study has limitations. Due to the higher vulnerability of this population and the burden of the procedures, the study dropout rate was notable, reducing the sample size and potentially creating a potential source of bias, as healthier older adults may have been more likely to complete follow‐up evaluations. Another limitation is that in the CogFrail study, plasma biomarkers, including p‐tau181, were measured from samples collected at the 6‐month visit. Finally, we measured plasma p‐tau181 rather than p‐tau217, which may be a more accurate marker of brain proteinopathy and a better predictor of disease progression, as the latter was not available in this sample.
In conclusion, older frail and pre‐frail individuals with objective cognitive impairment and elevated plasma p‐tau181 levels exhibited greater deterioration in both cognitive and physical functions over a 2‐year period. Age‐related loss of proteostasis, one of the hallmarks of aging, responsible for amyloidopathy and associated tauopathy, may play a role not only in cognitive decline but also in physical decline in older adults, representing a potential target for preventive and therapeutic interventions. Plasma p‐tau181 could help identify patients at higher risk of dual (i.e., physical and cognitive) decline, offering a valuable alternative to more invasive and/or costly biomarker assessment procedures. Our findings deserve to be confirmed in additional studies involving larger sample sizes from diverse populations.
CONFLICT OF INTERESTS STATEMENT
D.A. is an investigator in clinical trials sponsored by Alector, Alzheon, Acadia, Aribio, Biogen, Eisai, Genentech, GSK, Green Valley, Hoffmann‐La Roche, Janssen, Medesis Pharma, Nestlé, Novo Nordisk, Otsuka, Regenlife, and UCB Pharma. He received consulting fees from Novo Nordisk and lecture fees from Eisai. During the past 3 years, J.D. has served as consultant for Roche France in 2020–2022, Eisai France in 2023–2025 and Lilly France in 2024–2025 with personal compensation. He is an investigator in a clinical trial sponsored by Regenlife (NCT05926011) and served as consultant and/or scientific advisory board (SAB) member for Regenlife but received no personal compensation. B.V. is the founding president of IHU HealthAge (ANR‐23‐IAHU‐0011), affiliated with Toulouse University Hospital and Inserm Cerpop. He is also an investigator in clinical trials sponsored by several industry partners. In the past 3 years, he has served as a SAB member for Biogen, Alzheon, Novo Nordisk, Lilly, Eisai, and Roche, JNS without any personal compensation. All other authors report no conflicts of interest.
CONSENT STATEMENT
All human subjects provided informed consent for participation in the CogFrail Study.
AI DISCLOSURE
Artificial intelligence (ChatGPT) was used to improve spelling and grammar.
Supporting information
Supporting information
Supporting information
ACKNOWLEDGMENTS
The CogFrail study has obtained funding from MSDAVENIR. This work was performed into the context of the IHU HealthAge, which has benefted from funding by the Agence Nationale de la Recherche under the France 2030 program (reference number: ANR‐23‐IAHU‐0011).
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