# Misfolded Proteins and Cognitive Decline: Mechanistic Insights into Neurodegenerative Disorders

**Authors:** Elisa Duranti, Chiara Villa

PMC · DOI: 10.3390/neurolint18030048 · Neurology International · 2026-03-02

## TL;DR

This review explores how misfolded proteins contribute to cognitive decline in neurodegenerative diseases like Alzheimer's and Parkinson's.

## Contribution

The paper provides a comprehensive overview of molecular mechanisms linking misfolded proteins to cognitive impairments in neurodegenerative disorders.

## Key findings

- Misfolded protein accumulation is a key driver of neuronal dysfunction and cognitive deterioration in NDs.
- Cognitive deficits in NDs extend beyond motor symptoms to include memory, attention, and executive functions.
- Current diagnostic tools and emerging therapies for mitigating cognitive decline are discussed.

## Abstract

Cognitive decline represents one of the most common clinical manifestations of neurodegenerative diseases (NDs), substantially affecting the quality of life of both patients and their families. Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis are major NDs characterized by a progressive degeneration of the central nervous system, with functional impairments extending beyond motor symptoms to multiple cognitive domains, including memory, attention, language, and executive functions. Increasing evidence highlights misfolded protein accumulation as a key driver of neuronal dysfunction and cognitive deterioration. This narrative review examines the major cognitive deficits associated with these disorders, focusing on the underlying molecular mechanisms, particularly protein aggregation, as well as clinical manifestations and their effects on daily life. Furthermore, current diagnostic tools and emerging therapeutic options for mitigating cognitive decline will be further discussed.

## Linked entities

- **Diseases:** Alzheimer’s disease (MONDO:0004975), Parkinson’s disease (MONDO:0005180), amyotrophic lateral sclerosis (MONDO:0004976)

## Full-text entities

- **Genes:** IL1B (interleukin 1 beta) [NCBI Gene 3553] {aka IL-1, IL1-BETA, IL1F2, IL1beta}, TNPO1 (transportin 1) [NCBI Gene 3842] {aka IPO2, KPNB2, MIP, MIP1, TRN}, Tardbp (TAR DNA binding protein) [NCBI Gene 230908] {aka 1190002A23Rik, TDP-43, Tdp43}, APP (amyloid beta precursor protein) [NCBI Gene 351] {aka AAA, ABETA, ABPP, AD1, APPI, CTFgamma}, SNAP25 (synaptosome associated protein 25) [NCBI Gene 6616] {aka CMS18, DEE117, RIC-4, RIC4, SEC9, SNAP}, Vhl (von Hippel-Lindau tumor suppressor) [NCBI Gene 22346] {aka Vhlh, pVHL}, HSP90AA1 (heat shock protein 90 alpha family class A member 1) [NCBI Gene 3320] {aka EL52, HEL-S-65p, HSP86, HSP89A, HSP90A, HSP90N}, TARDBP (TAR DNA binding protein) [NCBI Gene 23435] {aka ALS10, TDP-43}, HSPA4 (heat shock protein family A (Hsp70) member 4) [NCBI Gene 3308] {aka APG-2, HEL-S-5a, HS24/P52, HSPH2, RY, hsp70}, SNCA (synuclein alpha) [NCBI Gene 6622] {aka NACP, PARK1, PARK4, PD1}, Crbn (cereblon) [NCBI Gene 58799] {aka 2610203G15Rik, 2900045O07Rik, piL}, Keap1 (kelch-like ECH-associated protein 1) [NCBI Gene 50868] {aka INRF2, mKIAA0132}, SYP (synaptophysin) [NCBI Gene 6855] {aka MRX96, MRXSYP, XLID96}, DBN1 (drebrin 1) [NCBI Gene 1627] {aka D0S117E}, Snca (synuclein, alpha) [NCBI Gene 20617] {aka NACP, alpha-Syn, alphaSYN}, DNAJB6 (DnaJ heat shock protein family (Hsp40) member B6) [NCBI Gene 10049] {aka DJ4, DnaJ, HHDJ1, HSJ-2, HSJ2, LGMD1D}, APOE (apolipoprotein E) [NCBI Gene 348] {aka AD2, APO-E, ApoE4, LDLCQ5, LPG}, GFAP (glial fibrillary acidic protein) [NCBI Gene 2670] {aka ALXDRD}, FUS (FUS RNA binding protein) [NCBI Gene 2521] {aka ALS6, ETM4, FUS1, HNRNPP2, POMP75, TLS}, NRGN (neurogranin) [NCBI Gene 4900] {aka RC3, hng}, DNAJB1P1 (DNAJB1 pseudogene 1) [NCBI Gene 171221] {aka DNAJB1P, HSP40, psiHSP40}, SOD1 (superoxide dismutase 1) [NCBI Gene 6647] {aka ALS, ALS1, HEL-S-44, IPOA, SOD, STAHP}, HMBS (hydroxymethylbilane synthase) [NCBI Gene 3145] {aka ENCEP, LENCEP, PBG-D, PBGD, PORC, UPS}, C9orf72 (C9orf72-SMCR8 complex subunit) [NCBI Gene 203228] {aka ALSFTD, DENND9, DENNL72, FTDALS, FTDALS1}, ACHE (acetylcholinesterase (Yt blood group)) [NCBI Gene 43] {aka ACEE, ARACHE, N-ACHE, YT}, Fus (fused in sarcoma) [NCBI Gene 233908] {aka D430004D17Rik, D930039C12Rik, Fus1, Tls}, MAPT (microtubule associated protein tau) [NCBI Gene 4137] {aka DDPAC, FTD1, FTDP-17, MAPTL, MSTD, MTBT1}, ATHS (atherosclerosis susceptibility (lipoprotein associated)) [NCBI Gene 470] {aka ALP}, RMDN1 (regulator of microtubule dynamics 1) [NCBI Gene 51115] {aka CGI-90, FAM82B, RMD-1, RMD1}, TNF (tumor necrosis factor) [NCBI Gene 7124] {aka DIF, IMD127, TNF-alpha, TNFA, TNFSF2, TNLG1F}, HSPD1 (heat shock protein family D (Hsp60) member 1) [NCBI Gene 3329] {aka CPN60, GROEL, HLD4, HSP-60, HSP60, HSP65}, STMN2 (stathmin 2) [NCBI Gene 11075] {aka SCG10, SCGN10}, IL6 (interleukin 6) [NCBI Gene 3569] {aka BSF-2, BSF2, CDF, HGF, HSF, IFN-beta-2}, UNC13A (unc-13 homolog A) [NCBI Gene 23025] {aka IDDSF, Munc13-1, NEDHES, NEDSMS}, NEFL (neurofilament light chain) [NCBI Gene 4747] {aka CMT1F, CMT2E, CMTDIG, NF-L, NF68, NFL}
- **Diseases:** cytotoxic (MESH:D064420), deficits in (MESH:D009461), muscle weakness (MESH:D018908), amyloid (MESH:C000718787), synaptic dysfunction (MESH:C536122), Lewy bodies (MESH:D020961), frontotemporal degeneration (MESH:D057174), multitasking difficulties (MESH:D051346), balance problems (MESH:D019973), neurotoxic (MESH:D020258), Cognitive decline (MESH:D003072), PQC (MESH:D007174), PD (MESH:D010300), Neuroinflammation (MESH:D000090862), behavioral symptoms (MESH:D001523), ND (MESH:C537849), AD (MESH:D000544), cognitive symptoms (MESH:D019954), FTD (MESH:D057180), ALS (MESH:D000690), Mitochondrial (MESH:D028361), neuronal damage (MESH:D009410), reduced sentence complexity (MESH:D006987), episodic memory impairment (MESH:D008569), motor dysfunction (MESH:D000068079), motor neuron disease (MESH:D016472), fALS (MESH:C531617), Language impairments (MESH:D007806), synapse failure (MESH:D051437), attention deficits (MESH:D001289), tremors (MESH:D014202), FUS/TLS (MESH:D008080), Neurodegenerative Diseases (MESH:D019636), rigidity (MESH:D009127), inflammatory (MESH:D007249), bradykinesia (MESH:D018476), degeneration of the central nervous system (MESH:D002493), mitochondrial defects (MESH:C565376), visuospatial deficits (MESH:D000377), axonal injury (MESH:D001480), neuroaxonal degeneration (MESH:D019150), Synaptic (MESH:D012183), tau disease (MESH:C536599), visual hallucinations (MESH:D006212), injury to (MESH:D014947), dementia (MESH:D003704), decline in episodic memory, (MESH:D060825), NFTs (MESH:D055956), atrophy (MESH:D001284), brain atrophy (MESH:C566985), Dysfunction (MESH:D006331), gait disturbances (MESH:D020233), paralysis (MESH:D010243), function (MESH:D003291), movement disorder (MESH:D009069), personality alterations (MESH:D010554), astrogliosis (MESH:D005911), depression (MESH:D003866), psychotic medications (MESH:D000069279)
- **Chemicals:** oligonucleotide (MESH:D009841), pimavanserin (MESH:C510793), ATP (MESH:D000255), edaravone (MESH:D000077553), Dopaminergic (MESH:D004298), Levodopa (MESH:D007980), glucose (MESH:D005947), calcium (MESH:D002118), donepezil (MESH:D000077265), Tofersen (MESH:C000709090), rivastigmine (MESH:D000068836), PQC (-), riluzole (MESH:D019782), ROS (MESH:D017382), clozapine (MESH:D003024), ALZ-801 (MESH:C000631566), Memantine (MESH:D008559), hydrogen peroxide (MESH:D006861), lecanemab (MESH:C000612089), oxygen (MESH:D010100), glutamate (MESH:D018698), aducanumab (MESH:C000600266), acetylcholine (MESH:D000109), superoxide (MESH:D013481), disulfide (MESH:D004220)
- **Species:** Homo sapiens (human, species) [taxon 9606], Mus musculus (house mouse, species) [taxon 10090]

## Full text

_Full body text omitted from this summary view._ Fetch the complete paper as Markdown: https://tomesphere.com/paper/PMC13029289/full.md

## Figures

2 figures with captions in the complete paper: https://tomesphere.com/paper/PMC13029289/full.md

## References

233 references — full list in the complete paper: https://tomesphere.com/paper/PMC13029289/full.md

---
Source: https://tomesphere.com/paper/PMC13029289