Mechanistic and preclinical evidence supports the investigation of GLP-1-based therapies in AD. Brain insulin resistance, impaired cerebral energy metabolism, synaptic dysfunction, neuroinflammation, mitochondrial dysfunction, and vascular pathology provide multiple potential targets for GLP-1R-mediated effects [21,40,48]. Preclinical studies have reported reductions in amyloid burden, tau phosphorylation, oxidative stress, and cognitive impairment following GLP-1R agonism [17,40,48]. However, negative findings with semaglutide and tirzepatide in amyloid-based mouse models show that this preclinical rationale is not uniformly supported across agents and experimental settings [46,47].

Retatrutide-specific evidence relevant to cognitive outcomes remains preclinical. In streptozotocin-induced diabetic rats [64], treatment preserved overall Morris Water Maze performance relative to untreated diabetic animals and partially attenuated short-term passive avoidance deficits, without consistent normalization across memory measures. These findings were accompanied by a significant reduction in hippocampal TNF-α, a nonsignificant trend toward lower IL-1β, and partial preservation of cortical and hippocampal cytoarchitecture. Retatrutide alone did not improve behavioral performance beyond control levels. Direct central exposure was not established, and the relative contributions of systemic metabolic improvement and direct neural effects remain uncertain. Moreover, this insulin-deficient diabetes model does not reproduce AD-specific pathology, limiting extrapolation to Alzheimer’s disease [64].

Dedicated neurological RCTs have evaluated whether GLP-1R agonism translates into clinical benefit in established AD. In the ELAD study [52], 204 participants without diabetes and with mild-to-moderate AD were randomized to liraglutide or placebo for 52 weeks. The primary endpoint—change in cerebral glucose metabolism—was not significantly different between groups (estimated difference −0.17; 95% CI −0.39 to 0.06; p = 0.14). Exploratory secondary analyses suggested less decline in executive function and reduced gray-matter atrophy, but activities of daily living and global clinical outcomes did not show consistent benefit. Given the negative primary endpoint and the absence of multiplicity adjustment for secondary analyses, these signals were insufficient to confirm clinical efficacy [52].

Similarly, a meta-analysis of three randomized trials involving 278 participants with AD or MCI found no significant improvement in global cognition with liraglutide or exenatide compared with placebo (standardized mean difference −0.21; 95% CI −0.81 to 0.38). Although the small evidence base limits precision, these findings do not support a consistent cognitive benefit in the populations studied [65].

The EVOKE and EVOKE+ randomized trials [24] evaluated oral semaglutide in 3808 participants with early, amyloid-confirmed symptomatic AD. Neither trial demonstrated slower progression on the Clinical Dementia Rating–Sum of Boxes at 104 weeks: the estimated treatment difference was −0.08 (95% CI −0.35 to 0.20; p = 0.57) in EVOKE and 0.10 (95% CI −0.17 to 0.38; p = 0.46) in EVOKE+. Biomarker changes were not accompanied by clinical benefit, underscoring that such changes alone cannot establish disease modification [24].

A subsequent exploratory reanalysis of published aggregate EVOKE/EVOKE+ data identified a nominally significant functional difference at week 130 and trends in selected later outcomes [66]. However, these post hoc comparisons across outcomes and time points do not overturn the negative prespecified primary results or provide confirmatory evidence of disease modification.

Evidence from cardiometabolic RCTs provides a complementary perspective on potential cognitive risk reduction. A meta-analysis [20] reported lower odds of dementia or cognitive impairment among participants receiving GLP-1RAS (odds ratio 0.55; 95% CI 0.35–0.86). However, events were rare, and cognition was generally not a prespecified, systematically adjudicated outcome, limiting conclusions about neurological efficacy [20].

Observational studies have also reported favorable associations. In a propensity-matched electronic-health-record cohort of 60,860 adults with T2DM and obesity, semaglutide or tirzepatide use was associated with lower risks of dementia (hazard ratio 0.63; 95% CI 0.50–0.81), stroke, and mortality compared with the use of other antidiabetic medications; no significant association with PD was observed [59]. A separate large propensity-matched analysis associated GLP-1RA use with lower risks of selected neurodegenerative outcomes [67]. These findings remain hypothesis-generating because residual confounding and differences in prescribing, healthcare contact, and diagnostic ascertainment may influence the associations.

Within this observational evidence, a retrospective propensity-matched comparison [60] found lower risks of coded MCI (RR 0.12; 95% CI 0.06–0.22) and dementia (RR 0.15; 95% CI 0.09–0.26) among tirzepatide users than among semaglutide users, whereas the estimate for AD included the null (RR 0.48; 95% CI 0.22–1.01). Absolute MCI risks were low (0.025% versus 0.209%), and mean follow-up differed substantially (255 versus 507 days). Analyses accounting for time to event yielded a less pronounced association for MCI (HR 0.49; 95% CI 0.26–0.93) and nonsignificant associations for dementia and AD [60]. Healthy-adherer effects and treatment channeling by calendar period or access to care are additional potential explanations. Although follow-up began at treatment initiation, only diagnoses occurring at least 12 months later were counted; the handling of earlier events and censoring was insufficiently detailed to exclude selection or time-related bias. These concerns do not demonstrate that bias explains the findings, but they preclude interpreting RR 0.12 as an 88% treatment-induced reduction in MCI risk or evidence of superior neuroprotection [60].

Overall, dedicated AD trials have not demonstrated disease-modifying efficacy of GLP-1RAs [24,52]. Cardiometabolic trials and observational studies suggest a possible role in cognitive risk reduction, but do not establish prevention of AD or treatment of established disease [20,59,60,67]. The observational findings for tirzepatide and preclinical findings for retatrutide discussed here likewise do not demonstrate clinical disease modification or superior neuroprotection [60,64]. Dedicated neurological trials are needed to clarify their potential role in preventing cognitive decline or treating establishedParkinson’s Disease and Related Synucleinopathies

Mechanistic and preclinical evidence supports the investigation of incretin-based therapies in PD, given the contribution of impaired insulin signaling, mitochondrial dysfunction, oxidative stress, neuroinflammation, and synaptic dysfunction to dopaminergic neurodegeneration [18,48]. Preclinical studies have reported neuroprotective effects of GLP-1R agonism in experimental models of PD, but translation into sustained clinical benefit has been inconsistent [18,40,48].

Dedicated neurological RCTs have tested this rationale in PD. In the LIXIPARK trial [54], 156 people with early PD received lixisenatide or placebo for 12 months. Motor disability progressed less in the active-treatment group, with a between-group difference of 3.08 points in MDS-UPDRS part III scores at 12 months (95% CI 0.86–5.30; p = 0.007), but gastrointestinal adverse events were common, and the durability and clinical relevance of the effect require confirmation [54]. Most secondary endpoints did not differ substantially between groups, and the post-washout analysis was not adjusted for multiplicity [54]. Thus, LIXIPARK identified a potential lixisenatide-specific therapeutic signal but did not establish a GLP-1RA class effect.

NLY01, a pegylated exenatide analogue developed for prolonged exposure, did not improve the combined Movement Disorder Society–Unified Parkinson’s Disease Rating Scale parts II and III at 36 weeks in 255 participants with early untreated PD [51]. Neither tested dose separated from placebo, and gastrointestinal adverse events were more frequent [51]. Earlier exenatide studies had suggested persistence of a motor benefit after washout [53], but the larger UK phase 3 trial involving 194 participants did not demonstrate benefit on primary or secondary clinical endpoints over 96 weeks [55].

Interpretation of the phase 3 exenatide findings requires additional caution. In June 2026, The Lancet issued an Expression of Concern regarding the phase 3 exenatide publication [56]. The trial report should therefore be considered alongside this notice; in the absence of sufficient publicly available information regarding its basis and implications, further speculation is unwarranted. Irrespective of this issue, the available clinical trial data do not currently demonstrate replicated efficacy of exenatide in PD.

In MSA, a randomized, open-label proof-of-concept trial involving 50 participants met its primary endpoint, showing less worsening of the Unified Multiple System Atrophy Rating Scale (UMSARS) parts I  +  II combined score at 48 weeks with exenatide than in controls. However, objective clinical measures, sensor-derived gait assessments, imaging, and biomarker findings did not show concordant benefits. Given the open-label design, expectation and observer bias may have contributed to the primary outcome difference. These findings therefore do not establish disease modification [68].

From a translational perspective, these findings highlight the need for future PD and MSA trials to characterize CNS exposure and target engagement, identify potentially responsive metabolic or inflammatory phenotypes, and distinguish symptomatic effects from genuine slowing of neurodegeneration [18,48]. The ongoing MOST-ABLE study, a phase 2 randomized, double-blind, placebo-controlled trial evaluating oral semaglutide in PD, reflects continued clinical investigation of this therapeutic strategy but, as a trial protocol, cannot yet inform efficacy [Multiple Sclerosis, Amyotrophic Lateral Sclerosis, and Huntington’s Disease

Evidence in MS, ALS, and HD is considerably less mature than that available for AD and PD and remains predominantly preclinical [10,70,71,72]. In experimental autoimmune encephalomyelitis, GLP-1R activation reduced neuroinflammatory responses [73]. Liraglutide engaged AMPK/SIRT1 pathways and suppressed NLRP3-associated inflammation [74], while dulaglutide modulated pathogenic Th1/Th17 responses [75]. These mechanisms intersect with metabolic comorbidity and immune dysregulation in MS, but randomized trials evaluating neurological disability, relapse activity, or imaging outcomes have not yet been reported [71]. Accordingly, the present therapeutic relevance of GLP-1R agonism in MS relates primarily to treatment of coexisting metabolic disease and to the development of appropriately designed neurological trials, rather than to established disease modification [10,71].

ALS presents a distinct translational and safety challenge. Weight loss, hypermetabolism, and low body mass are associated with adverse prognosis, so the anorectic and weight-reducing effects that are advantageous in obesity may be undesirable or potentially harmful in metabolically vulnerable patients [70]. Reviews of IGF-1/GLP-1 signaling identify plausible anti-inflammatory, mitochondrial, and trophic mechanisms, but direct therapeutic data in human ALS remain insufficient [72]. Future studies of GLP-1-based therapies should therefore incorporate nutritional status, energy expenditure, body composition, and weight trajectory as major safety and stratification variables rather than secondary metabolic outcomes [70,76].

In HD models, liraglutide or exendin-4 improved neuronal insulin signaling, cognitive or motor phenotypes, pancreatic pathology, and survival [77,78,79]. Liraglutide also attenuated mutant huntingtin-associated neurotoxicity by restoring neuronal insulin signaling, linking impaired insulin regulation more directly to HD pathology [77]. These findings reinforce the relevance of insulin signaling and mitochondrial stress, but translational limitations are considerable: HD is genetically determined, unintended weight loss becomes increasingly prominent during disease progression [80] and no randomized trial has shown that GLP-1-based therapy modifies neurological progression [10].

MS, ALS, and HD therefore illustrate why the neurological effects of incretin-based therapies cannot be extrapolated uniformly across disorders [10]. An agent that is favorable in obesity-associated cognitive risk may be inappropriate in a catabolic motor-neuron disorder [70,72]. Likewise, an anti-inflammatory signal in an MS model may not alter compartmentalized inflammation in progressive MS [71], and restoration of insulin signaling in a toxin or transgenic model may not translate into a meaningful human endpoint [77,78,79]. Disease-specific biology, metabolic phenotype, and nutritional vulnerability should guide candidate selection and trial design rather than metabolic potency alone [10,70,71].

Dedicated trials of selective GLP-1R agonists in AD and PD have yielded mixed or negative clinical results, without establishing a reproducible class-wide disease-modifying effect [24,51,52,53,54,55]. This experience provides a benchmark for evaluating the neurological relevance of dual and triple agonism.

For tirzepatide, observational human data support further investigation but do not demonstrate efficacy in neurodegenerative disease [59,60]. Comparisons with semaglutide remain susceptible to channeling bias, differences in baseline characteristics and access to care, and unequal follow-up [60]. Whether GIPR co-activation confers additional neurological benefit requires evaluation in dedicated randomized trials.

For triple agonists, interpretation requires a clear distinction between experimental peptides and retatrutide [50,61,62]. An experimental GLP-1R/GIPR/GCGR triagonist improved memory and measures of synaptic function, neuronal excitability, and calcium homeostasis in 3xTg-AD mice [49]. Cellular studies also demonstrated neurotrophic, neuroprotective, and anti-inflammatory effects of dual and triple agonists, with some responses exceeding those observed with exendin-4 under the tested conditions [63]. Retatrutide-specific evidence derives from streptozotocin-induced diabetic rats, in which treatment preserved spatial learning performance and partially attenuated behavioral and histological abnormalities, although direct CNS exposure was not demonstrated [64]. Human trials have demonstrated improvements in glycemic control and body weight but were not designed to evaluate disease modification in neurodegenerative disorders [50,61,62].

The principal translational question is whether broader receptor engagement can modify disease progression beyond systemic metabolic improvement. Addressing this question requires characterization of CNS exposure where relevant, evidence of receptor or pathway engagement, and concordance between mechanistic biomarkers and clinically meaningful outcomes [48,53]. The relative efficacy of selective, dual, and triple agonists in neurodegenerative disorders remains undetermined.

Table 2 summarizes the principal human studies relevant to the neurological translation of these pharmacological platforms.

Across selective GLP-1R agonists, dual GLP-1R/GIPR agonists, and GLP-1R/GIPR/GCGR triple agonists, a central translational question emerges: to what extent do metabolic efficacy and weight reduction predict neurological benefit? Current evidence suggests that these outcomes should be considered related but biologically distinct. Improvements in body weight, glycemic control, systemic inflammation, and cardiovascular risk may reduce upstream determinants of neurological disease, but they do not establish target engagement within disease-relevant neural or neurovascular compartments or modification of established neurodegenerative pathology [7,18,24].

Weight loss may contribute to brain health by reducing multiple upstream metabolic and vascular risk factors, including insulin resistance, hypertension, dyslipidemia, sleep apnea, systemic inflammation, hepatic metabolic stress, and cerebrovascular risk. Such effects may contribute to lower long-term dementia risk, particularly when obesity, diabetes, and vascular disease coexist [7]. The cardiovascular outcome evidence for semaglutide and the observational dementia and stroke signals are consistent with this prevention model [12,20,59].

The evidence does not support using weight change as a surrogate endpoint for modification of established neurodegeneration. EVOKE and EVOKE+ showed that substantial metabolic efficacy and changes in several biomarkers can occur without slowing clinical progression in early symptomatic AD [24]. PD trials similarly show that belonging to the GLP-1RA class does not predict replicated clinical benefit [51,54,55]. Metabolic improvement and neuroprotection may therefore coexist in some populations, but they should be regarded as biologically and clinically distinct outcomes.

A two-pathway model is therefore most appropriate [18,48]. The indirect pathway runs from metabolic treatment to weight and glycemic improvement, lower inflammatory and vascular burden, and reduced probability of future cognitive or cerebrovascular events. The direct pathway requires drug access to relevant neural or neurovascular targets, engagement of disease-linked signaling, and sustained effects on neurodegenerative biology. The pathways can coexist, but evidence supporting one should not be assumed to establish the other.

The marked weight-reducing efficacy of GLP-1-based therapies requires careful patient selection in neurodegenerative disorders characterized by nutritional vulnerability, where further weight loss may represent a clinical risk rather than a therapeutic objective [12,76,81].

Unintentional weight loss is a clinically meaningful marker of nutritional vulnerability, functional decline, and adverse outcomes, although its relevance varies across disorders and disease stage [76,80,81]. In PD and HD, it may reflect dysphagia, gastrointestinal dysfunction, altered energy expenditure, motor impairment, behavioral changes, or disturbances of hypothalamic and reward-related pathways [80,81].

Nutritional status should therefore be assessed before intentional weight reduction is pursued, particularly in patients with established or anticipated nutritional vulnerability [76,82]. According to the Global Leadership Initiative on Malnutrition (GLIM), the diagnosis of malnutrition requires at least one phenotypic criterion—unintentional weight loss, low body mass index, or reduced muscle mass—and one etiologic criterion, comprising reduced food intake or assimilation or inflammation/disease burden [82].

Accordingly, the decision to use a GLP-1RA, a dual GLP-1R/GIPR agonist, or—within a trial—an investigational triple agonist should consider both the metabolic indication and the nutritional phenotype [10,76]. In patients with neurodegeneration who also have obesity, T2DM, or high cardiovascular risk, an approved agent may remain appropriate for its established metabolic indication when the expected cardiometabolic benefit outweighs the nutritional risk [10,12]. Conversely, further weight reduction may be undesirable in patients with low or rapidly declining body weight, sarcopenia, frailty, dysphagia, hypermetabolism, or an advanced catabolic phenotype, particularly in ALS and in later stages of HD or PD [76,80,81].

When treatment is justified by an established metabolic indication, weight trajectory should be interpreted alongside nutritional and functional status rather than as an isolated marker of therapeutic success [76,81]. Serial assessment of nutritional intake, swallowing and gastrointestinal symptoms, and, where feasible, muscle mass and strength may help identify increasing vulnerability [76,82]. Persistent unintended weight loss, worsening sarcopenia, or functional decline should prompt reassessment of the therapeutic strategy [76].

Preclinical evidence suggests that the neurological response to weight loss may differ from its metabolic effects. In an experimental model of diet-induced obesity, rapid dietary weight loss normalized glucose intolerance without reversing obesity-associated hypothalamic inflammation and was accompanied by further microglial and transcriptomic alterations [83]. Although these findings cannot be directly extrapolated to humans or incretin-based therapies, they illustrate that peripheral metabolic improvement and central neuroinflammatory resolution may follow different trajectories.

The clinical implications of weight reduction in neurodegenerative disorders should be evaluated in relation to baseline adiposity, nutritional status, and disease stage. Therapeutic goals should integrate cardiometabolic risk reduction with preservation of neurological function, maintenance of muscle mass, and patient-reported quality of life [7,12,76,80,81].

The timing of intervention may influence whether metabolic benefits translate into meaningful neurological outcomes. Addressing modifiable metabolic and vascular risk factors, particularly from midlife, offers a rationale for prevention before substantial neurodegenerative pathology develops [7]. Whether GLP-1 receptor agonists, dual agonists, or triple agonists provide additional protection against cognitive decline remains uncertain and requires dedicated prevention trials.

In established neurodegenerative disease, limited neurological efficacy may reflect late intervention, advanced neurodegeneration, or insufficient CNS exposure [18,84]. Species-related differences in GLP-1 receptor distribution may further complicate extrapolation from experimental models [85], while gastrointestinal adverse effects can limit treatment tolerability, as observed in LIXIPARK [54].

Endpoint choice is equally important. Motor scales are sensitive to medication state and symptomatic fluctuation; cognitive composites can be influenced by practice effects, dropout, and comorbidity; MRI volume may reflect fluid or inflammatory changes; and plasma biomarkers may respond to renal, hepatic, or weight-related physiology. Neurological trials should therefore seek convergence across prespecified clinical, imaging, fluid, and, where appropriate, digital outcomes [86]. Adequate multiplicity control and transparent handling of missing data should also be incorporated into trial design and interpretation [87].

The safety profile of these therapies should be interpreted in the context of disease-specific vulnerabilities. Nausea, vomiting, dehydration, gallbladder disease, and loss of lean mass may have greater consequences in older adults with frailty, dysphagia, autonomic failure, or low baseline weight [82]. Nutritional and catabolic vulnerability is particularly relevant in ALS and later-stage PD or HD [76,80,81]. The greater weight-reducing efficacy of dual GLP-1R/GIPR agonists and emerging GLP-1R/GIPR/GCGR triple agonists further emphasizes the importance of monitoring nutritional status and body composition in susceptible neurological populations [58,62].

Potential ocular adverse effects also warrant consideration. Observational studies have raised concerns about a possible association between GLP-1RA use, particularly semaglutide, and non-arteritic anterior ischemic optic neuropathy (NAION) [88,89]. The joint NANOS–AAO consensus statement highlights inconsistent findings, low absolute risk, and limitations related to confounding and diagnostic ascertainment [90]. The available evidence supports individualized benefit–risk assessment and systematic collection of ocular adverse events in neurological trials, but does not establish a uniform risk across selective, dual, and triple agonists.

The neuropsychiatric profile of GLP-1-based therapies is particularly relevant to their evaluation in neurological populations. Regulatory assessments have not identified evidence supporting a causal association between the therapies evaluated and suicidal ideation or behavior [91,92]. In a propensity-score matched cohort of patients with T2DM, semaglutide was not associated with higher 12-month risks of neurological or psychiatric outcomes, including suicidality, compared with other antidiabetic medications [93]. Evidence from randomized trials is similarly reassuring: a meta-analysis found no significant increase in suicide or self-harm events with GLP-1R agonists compared with placebo [94], while a post hoc analysis of the STEP 1, 2, 3, and 5 trials found no increased risk of depressive symptoms or suicidal ideation or behavior with semaglutide in participants without known major psychopathology [95]. Nevertheless, residual confounding in observational studies, limited follow-up, rare events, and selected trial populations constrain interpretation [93,94,95]. Generalizability to patients with neurodegenerative disorders remains uncertain, underscoring the need for dedicated trials with comprehensive neuropsychiatric assessment and longer-term safety monitoring.

Future trials should enroll biologically characterized populations and define whether the therapeutic objective is primary prevention, secondary prevention, symptomatic benefit, or modification of established disease [18]. Metabolic stratification should include diabetes status, insulin resistance, adiposity, vascular burden, recent weight trajectory, and sarcopenia [7,76,81,82]. In populations vulnerable to nutritional decline, phenotyping should extend beyond body weight to include dietary intake, body composition, and measures of muscle mass or function, with disease-specific assessment of swallowing or autonomic dysfunction where clinically relevant [7,76,81,82]. Disease characterization should incorporate established biomarkers where available, including amyloid and tau measures in AD, dopaminergic imaging and α-synuclein-related biomarkers in PD, neurofilament light as a marker of neuroaxonal injury, and disease-appropriate imaging or fluid biomarkers in MS, MSA, ALS, and HD [96,97,98].

Pharmacological exposure should be measured rather than presumed. Trials should incorporate population pharmacokinetics, cerebrospinal-fluid or other disease-relevant compartment exposure where ethically and analytically feasible, receptor- or pathway-engagement markers, and dose–response analyses separated from weight loss [18,48].

Mediation analyses may then help determine the extent to which neurological effects are explained by changes in body weight, glycemia, blood pressure, systemic inflammation, or vascular events, and whether an effect remains compatible with direct neural or neurovascular mechanisms [99].

Treatment benefit should be assessed primarily through changes in cognition, motor function, disability, quality of life, and the time to disease progression. Biomarkers should complement these clinical outcomes, not replace them [18,86]. Multimodal assessment integrating clinical, imaging, fluid, and, where appropriate, digital biomarkers may strengthen disease characterization and treatment-response assessment [86]. Statistical methods, approaches to missing data, and any adjustments for multiplicity should be prespecified and transparently reported [87].

Beyond neurodegenerative diseases, future research may also examine these therapies in syndromes involving persistent neuroinflammation [100], metabolic dysregulation, and cognitive symptoms, including Long COVID [101]. This extension requires disease-specific mechanistic and clinical evidence, as shared features do not imply equivalent pathology or therapeutic response.

A credible claim of neuroprotection would require concordant effects on clinically relevant neurological outcomes and, where feasible, disease-relevant biomarkers of neuroinflammation, axonal injury, synaptic dysfunction, or neurovascular pathology, rather than improvement in body weight, glycemic control, or systemic inflammation alone [18,24]. Replicated benefit across independent, adequately powered trials would be required before selective GLP-1R agonists, dual GLP-1R/GIPR agonists, or GLP-1R/GIPR/GCGR triple agonists could be considered disease-modifying neurological therapies [18,21,87].

 

Selective GLP-1R agonists, dual GLP-1R/GIPR agonists, and GLP-1R/GIPR/GCGR triple agonists provide a pharmacological framework for investigating how metabolic modulation may influence neurodegenerative processes. Selective GLP-1R agonists have the most extensive neurological evidence base, but dedicated trials in AD and PD have yielded mixed or negative results, without demonstrating a reproducible class-wide disease-modifying effect. Neurological evidence for dual and triple agonists remains predominantly observational or preclinical and does not establish superiority over selective agents. Greater metabolic efficacy alone cannot substantiate claims of neuroprotection.

A central unresolved question is whether these therapies influence neurological outcomes through systemic metabolic and vascular improvements, direct neural actions, or both. Weight reduction is not a validated surrogate for neurological benefit, and its clinical implications depend on baseline adiposity, nutritional reserves, and disease stage. In patients with frailty, sarcopenia, or involuntary weight loss, preservation of nutritional status and neurological function deserves particular consideration.

Further progress requires disease-specific randomized trials integrating clinically meaningful outcomes with assessment of pharmacological exposure, target engagement, and metabolic mediation. Such studies should clarify which patients may benefit and whether treatment can prevent cognitive decline or modify established neurodegenerative disease.