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In a randomized trial, patients with brain amyloid deposition but no dementia who received a β-site amyloid precursor protein–cleaving enzyme 1 inhibitor had no benefit with respect to clinical outcomes and worsening on some measures of cognition and daily function.

It has been proposed that tau aggregation confined to entorhinal cortex and hippocampus, with no or only minimal Aβ deposition, should be considered as a ‘primary age-related tauopathy’ (PART) that is not integral to the continuum of sporadic Alzheimer disease (AD). Here, we examine the evidence that PART has a pathogenic mechanism and a prognosis which differ from those of AD. We contend that no specific property of the entorhinal–hippocampal tau pathology makes it possible to predict either a limited progression or the development of AD, and that biochemical differences await an evidence base. On the other hand, entorhinal–hippocampal tau pathology is an invariant feature of AD and is always associated with its development. Rather than creating a separate disease entity, we recommend the continued use of an analytical approach based on NFT stages and Aβ phases with no inference about hypothetical disease processes.

Is it possible to prevent atrophy of key brain regions related to cognitive decline and Alzheimer’s disease (AD)? One approach is to modify nongenetic risk factors, for instance by lowering elevated plasma homocysteine using B vitamins. In an initial, randomized controlled study on elderly subjects with increased dementia risk (mild cognitive impairment according to 2004 Petersen criteria), we showed that high-dose B-vitamin treatment (folic acid 0.8 mg, vitamin B6 20 mg, vitamin B12 0.5 mg) slowed shrinkage of the whole brain volume over 2 y. Here, we go further by demonstrating that B-vitamin treatment reduces, by as much as seven fold, the cerebral atrophy in those gray matter (GM) regions specifically vulnerable to the AD process, including the medial temporal lobe. In the placebo group, higher homocysteine levels at baseline are associated with faster GM atrophy, but this deleterious effect is largely prevented by B-vitamin treatment. We additionally show that the beneficial effect of B vitamins is confined to participants with high homocysteine (above the median, 11 µmol/L) and that, in these participants, a causal Bayesian network analysis indicates the following chain of events: B vitamins lower homocysteine, which directly leads to a decrease in GM atrophy, thereby slowing cognitive decline. Our results show that B-vitamin supplementation can slow the atrophy of specific brain regions that are a key component of the AD process and that are associated with cognitive decline. Further B-vitamin supplementation trials focusing on elderly subjets with high homocysteine levels are warranted to see if progression to dementia can be prevented.

Studies of patients with major depressive disorder (MDD) have consistently reported reduced hippocampal volumes; however, the exact pattern of these volume changes in specific anatomical subfields and their functional significance is unclear. We sought to clarify the relationship between hippocampal tail volumes and (i) a diagnosis of MDD, and (ii) clinical remission to anti-depressant medications (ADMs). Outpatients with nonpsychotic MDD (n=202) based on DSM-IV criteria and a 17-item Hamilton Rating Scale for Depression (HRSD17) score ⩾16 underwent pretreatment magnetic resonance imaging as part of the international Study to Predict Optimized Treatment for Depression (iSPOT-D). Gender-matched healthy controls (n=68) also underwent MRI scanning. An automated pipeline was used to objectively measure hippocampal subfield and whole brain volumes. Remission was defined as an HRSD17 of ⩽7 following 8 weeks of randomized open-label treatment ADMs: escitalopram, sertraline or venlafaxine-extended release. After controlling for age and total brain volume, hippocampal tail volume was larger in the MDD cohort compared to control subjects. Larger hippocampal tail volume was positively related to clinical remission, independent of total hippocampal volume, total brain volume and age. These data provide convergent evidence of the importance of the hippocampus in the development or treatment of MDD. Hippocampal tail volume is proposed as a potentially useful biomarker of sensitivity to ADM treatment.

Stress and glucocorticoid hormones regulate hippocampal neurogenesis, but the molecular mechanisms mediating these effects are poorly understood. Here we identify the glucocorticoid receptor (GR) target gene, serum- and glucocorticoid-inducible kinase 1 (SGK1), as one such mechanism. Using a human hippocampal progenitor cell line, we found that a small molecule inhibitor for SGK1, GSK650394, counteracted the cortisol-induced reduction in neurogenesis. Moreover, gene expression and pathway analysis showed that inhibition of the neurogenic Hedgehog pathway by cortisol was SGK1-dependent. SGK1 also potentiated and maintained GR activation in the presence of cortisol, and even after cortisol withdrawal, by increasing GR phosphorylation and GR nuclear translocation. Experiments combining the inhibitor for SGK1, GSK650394, with the GR antagonist, RU486, demonstrated that SGK1 was involved in the cortisol-induced reduction in progenitor proliferation both downstream of GR, by regulating relevant target genes, and upstream of GR, by increasing GR function. Corroborating the relevance of these findings in clinical and rodent settings, we also observed a significant increase of SGK1 mRNA in peripheral blood of drug-free depressed patients, as well as in the hippocampus of rats subjected to either unpredictable chronic mild stress or prenatal stress. Our findings identify SGK1 as a mediator for the effects of cortisol on neurogenesis and GR function, with particular relevance to stress and depression.

The central hallmark of Alzheimer's disease (AD) is progressive brain atrophy accompanied by amyloid and tau pathologies. Valiltramiprosate is an oral, small-molecule inhibitor of amyloid oligomer formation in development as a disease-modifying treatment for AD. Whereas APOLLOE4 did not meet the primary endpoint of cognitive slowing in overall Early AD population, valiltramiprosate produced a meaningful improvement (ΔADAS-Cog13 = -2.144, p =0.041) and function (ΔCDR-SB = -0.646, p =0.053) in the prespecified Mild Cognitive Impairment (MCI) subjects. Valiltramiprosate consistently reduced atrophy in hippocampus (-26%, p =0.0042 in MCI) and other brain regions, indicating substantive neuroprotective benefits. We report a subpopulation of early symptomatic super-responders in the APOLLOE4 Phase 3 study that exhibited full prevention of hippocampal atrophy and improved cognition over 78 weeks. The multicenter, randomized, double-blind, placebo-controlled APOLLOE4 Phase 3 trial was conducted in 325 APOE4/4 homozygotes with MCI or Mild AD (MMSE ≥22 and CDR-Global 0.5 - 1.0). The valiltramiprosate dose was 265 mg BID for 78 weeks. The primary outcome was ADAS-Cog13, and volumetric hippocampal volume (HV) MRI was an imaging endpoint. The subpopulation reflects AD subjects with an increased HV at 78 weeks over baseline. Eleven super-responder subjects (MMSE 27.7 ± 0.6; 6 males and 5 females) in the active treatment group and two female placebo subjects (MMSE 28.0 ± 0.0) exhibited a greater HV at 78 weeks than baseline. This represents ∼15% and 6.5% of the active MCI and Mild AD subject populations, respectively. There was an increase of 66.0 ± 20.4 mm (mean ± SEM) HV at 78 weeks vs. baseline in the active super-responders. Also, the active super-responders exhibited a younger age (63.7 ± 2.4 years), higher MMSE, and less baseline hippocampal atrophy (8511.6 ± 348.7 mm ) compared to the overall Early AD population (7045 ± 1002 mm ). The prevention of atrophy by valiltramiprosate treatment corresponded with cognitive and functional benefit (ADAS-Cog13, CDR-SB). Valiltramiprosate demonstrates potential for preventing hippocampal atrophy and stabilization of cognitive and functional decline in earliest symptomatic APOE4/4 AD. The results support a potential disease stabilization benefit of oral valiltramiprosate as a prevention therapy in presymptomatic AD.

Three patients had severe ataxia and memory impairment in a phase 1 trial of a fatty acid amide hydrolase inhibitor designed as an analgesic and antiinflammatory drug. One patient became brain dead. MRI of the brain showed lesions in the pons and hippocampi. A decrease in fatty acid amide hydrolase (FAAH) activity increases the levels of endogenous analogues of cannabinoids, or endocannabinoids. 1 FAAH inhibitors have shown analgesic and antiinflammatory activity in animal models, 2 and some have been tested for these purposes in phase 1 and phase 2 studies. 3 Phase 3 studies were not pursued owing to a lack of efficacy. BIA 10-2474, with the chemical name 3-(1-(cyclohexyl(methyl)carbamoyl)-1H-imidazol-4-yl)pyridine 1-oxide, is a new reversible FAAH inhibitor. A phase 1 study was conducted in healthy volunteers to explore the safety profile of BIA 10-2474. Five of the six participants who had received the highest cumulative dose . . .

Valiltramiprosate (ALZ-801), an oral inhibitor of amyloid oligomer formation, was evaluated in a Phase 3 trial in APOE4/4 homozygotes with Early AD (Abushakra, 2024); the topline results being presented at this meeting (Power, 2025). While the primary clinical endpoint was not significant, hippocampal volume (HV, main imaging outcome) showed significant slowing of atrophy. This 78-week placebo-controlled study randomized 325 homozygotes (placebo, 265 mg BID), stratified by MCI/Mild AD. ADAS-Cog13 and CDR-SB were the primary and key secondary outcomes respectively, and DAD (disability assessment for dementia) was a secondary outcome. HV was the main imaging outcome, cortical thickness and whole brain volume (CT, WBV) were secondary. Analyses by disease stage were pre-specified using baseline severity as covariate in the MMRM model; drug-effect correlations utilized Spearman's correlations. The pre-specified MCI subgroup (MMSE 27-30) included 125 subjects (58 placebo, 67 active); with balanced baseline characteristics except for cholinesterase-inhibitors (placebo 31%, active 19%). Imaging population included 54 placebo, 62 active subjects. The MCI subgroup vs placebo showed positive effects on ADAS-cog/DAD (nominal p <0.05), trend on CDR-SB (p =0.053) with significant slowing of HV, CT and WBV atrophy vs placebo (26%, p =0.004; 35% p < 0.0001; 22%, p =0.027). In the active arm, change in HV correlated significantly with change in ADAS-Cog13 (r=-0.40, p <0.005), CDR-SB (r=-0.45, p <0.005), and DAD (r=0.33, p =0.018). For CT, the correlations were also significant: ADAS-Cog13 (r=-0.34, p =0.015), CDR-SB (r=-0.49, p < 0.005), and DAD (r=0.40, p <0.005). WBV treatment effect also correlated with the clinical outcomes (p ≤ 0.01). These strong correlations between structural preservation and clinical benefits of valiltramiprosate at the MCI stage support its efficacy and are consistent with its proposed mechanism of inhibiting amyloid oligomer formation, thereby potentially protecting neurons from synaptic dysfunction and neurodegeneration. Given the accelerated neurodegeneration in APOE4/4 patients, these findings suggest that intervention at the early stages of AD when neuronal reserve is higher, may be critical for valiltramiprosate to exert meaningful clinical effects alongside preservation of brain structure and volume.

Valiltramiprosate (ALZ-801) is an oral inhibitor of amyloid oligomer formation. Tramiprosate (active agent in ALZ-801) had shown promising efficacy signals with favorable safety in ∼1300 APOE4 carriers with AD, with no observed ARIA-E. This trial evaluated Valiltramiprosate in APOE4/4 homozygotes with Early AD. This 78-week double-blind, placebo-controlled, two-arm trial that randomized 325 homozygotes (162 to placebo, 163 to 265 mg BID), stratified by MCI (MMSE 27-30) or Mild AD (MMSE 22-26). MRI (1.5/3 Tesla) were conducted every 26 weeks and analyzed by Clario Inc. The clinical outcomes were ADAS-Cog13 (primary), CDR-SB (key secondary) and DAD (disability assessment for dementia, secondary). Hippocampal volume (HV) was the main imaging outcome. MMRM was the primary analysis model. Safety population (N =325) was 51% females, 90% Caucasian, mean age 68 years, MMSE 25.6, 39% with MCI (MMSE 27-30) and 30% with baseline microhemorrhages and/or siderosis. In the full analysis set (N =320), the placebo-adjusted least-square mean (LSM) difference in change from baseline (CBL) on ADAS-Cog13 favored drug non-significantly (delta=-0.50; p =0.61, 11% vs placebo CBL); CDR-SB and DAD numerically favored drug by 23% and 29%, but HV favored drug significantly (74 mm , nominal p =0.017, 18% less atrophy). Prespecified Mild AD showed small nonsignificant clinical effects favoring placebo, but showed numerical benefit on HV (51mm , 12% p = 0.115). In prespecified MCI, all outcomes favored drug (nominal p -values): ADAS-Cog13= -2.14 (p =0.041; 52%); CDR-SB= -0.65 (p =0.053, 104%); DAD= 6.09 (p =0.016, 96%); and HV= 108 mm (p = 0.004, 26% less atrophy). Nausea (mostly mild) was the most common adverse event; incidence of ARIA-E was the same as placebo. In the overall population, ADAS-Cog13 did not achieve significance, but the hippocampus showed significant 18% slowing of atrophy. The pre-specified Mild group showed trends to HV atrophy slowing that did not translate to clinical benefits. The pre-specified MCI group showed significant 28% HV atrophy slowing with meaningful cognitive and functional benefits and positive trends on several secondary clinical outcomes. Overall safety was favorable with no increased ARIA. In the high-risk APOE4/4 population, this positive benefit-risk profile supports valiltramiprosate's potential as an oral disease-modifying treatment for APOE4/4 homozygotes with MCI.

Hippocampal hyperactivity is a pathological hallmark of Alzheimer's disease (AD) and a prognostic indicator for AD progression and clinical cognitive worsening in amnestic mild cognitive impairment (aMCI). Extensive data indicate that hippocampal overactivity reflecting an imbalance in inhibitory and excitatory activity is a driver of neurodegeneration and the spread of tau pathology. AGB101 is a proprietary extended-release formulation of low dose levetiracetam in the dose range previously demonstrated to normalize hippocampal activity and improve cognitive performance in aMCI. The HOPE4MCI clinical trial used a 78-week protocol of AGB101 treatment to assess progression in amyloid-positive patients with MCI due to AD. A total of 164 participants who were amyloid positive by PET imaging were randomized to placebo or AGB101 treatment using the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) score as the primary outcome measure. MRI scans obtained in the study at baseline and after 78 weeks were analyzed providing volume measures of key structures of the medial temporal lobe relevant to AD progression. Blood samples collected at 78 weeks in the study were also analyzed for plasma biomarkers in those participants. In a pre-specified subgroup analysis, ApoE-4 carriers, showed no effect of treatment on any measure. However, in ApoE-4 non-carriers, AGB101 treated participants showed a 40% benefit on the CDR-SB score compared to placebo. These results were not significant due to the planned limited sample size. However, in the ApoE-4 non-carriers AGB101 treatment significantly reduced atrophy of the entorhinal cortex. That reduction in atrophy was significantly coupled with the change in CDR-SB and with NFL and GFAP plasma biomarkers of disease. Extensive preclinical and clinical studies show that low dose levetiracetam normalizes aberrant network activity and restores inhibitory and excitatory network balance. The HOPE4MCI clinical trial shows that there is meaningful benefit on the CDR-SB over 18-month AGB101 treatment and a significant reduction in neurodegeneration in the non-carriers of ApoE-4 with MCI due to AD. These findings support the view that reducing hippocampal hyperactivity confers benefit and further testing of AGB101 in patients with MCI due to AD who are non-carriers of ApoE-4 is warranted.