Health
Atlas of Alzheimer's Disease Progression
October 29, 2024
At a glance
- Researchers have constructed an atlas of brain cell changes in Alzheimer's disease.
- This discovery reveals two distinct stages of disease progression and suggests potential therapeutic targets.
Alzheimer's disease (AD) is characterized by the accumulation of pathological proteins in the brain. These include amyloid beta (Aβ) plaques and tau tangles. However, which specific cell types in the brain are affected has not been well studied. To improve this, the NIH-funded Seattle Alzheimer's Disease Brain Cell Atlas (SEA-AD) consortium set out to create a high-resolution atlas of the cellular and molecular changes that occur in the brain during Alzheimer's disease.
As part of this effort, a team led by researchers at the Allen Institute and the University of Washington mapped Alzheimer's disease-related changes in a brain region called the middle temporal gyrus. This region is involved in language, memory, and visual processing. This is thought to be a key area in the transition from early to late stages of AD pathology. The research team examined the middle temporal gyrus from the brains of 84 donors with various stages of Alzheimer's disease. All donors were at least 65 years old at death (mean age 88 years). There were more female donors than male donors, which is consistent with the observation that Alzheimer's disease is more prevalent in women.
The researchers assessed each donor for Alzheimer's disease and collected data on gene activity and epigenetic modifications (modifications to the genome that do not affect the DNA sequence itself) in individual cells. Pathology data allowed us to order donors along a continuum of disease progression. They were then able to link the observed cellular or molecular changes to disease progression. Cells were classified by comparing their molecular characteristics to NIH BRAIN Initiative® references. Here are the results: natural neuroscience October 14, 2024.
This analysis revealed that there are two distinct stages in the progression of Alzheimer's disease. At the initial stage, Aβ plaques and tau tangles were sparse and grew slowly. Brain immune cells called microglia had increased activity of inflammatory genes. Other immune cells called astrocytes also showed signs of increased activation. Supporting cells called oligodendrocytes are lost. To compensate, the remaining oligodendrocytes increased their activity. Notably, the number of certain types of inhibitory neurons was reduced. Loss of these neurons can have far-reaching effects on brain function.
At later stages, the number of plaques and tangles increased exponentially. More types of neurons, both excitatory and inhibitory, began to be lost. Astrocytes and microglia remained inflamed, but oligodendrocyte activity decreased.
The research team applied the same analysis to publicly available data from 10 other Alzheimer's disease studies. These comprised over 700 donors spanning a similar range of AD stages. This result confirmed many of the findings from the SEA-AD data.
This finding suggests that early loss of specific inhibitory neurons may drive later AD pathology. Identifying the earliest affected neurons highlights potential new therapeutic targets.
“We can say that we have created a pathology clock that tells us not just what changes are happening in this cortical region, but when they are happening,” said lead author Mariano of the Allen Institute. Dr. Gavitt says: “We now have a framework to organize the sequence of events as Alzheimer's pathology increases over time.”
—Written by Dr. Brian Doctorow
Related links
References: An integrated multimodal cellular atlas of Alzheimer's disease. Gabitto MI, Travaglini KJ, Rachleff VM, Kaplan ES, Long B, Ariza J, Ding Y, Mahoney JT, Dee N, Goldy J, Melief EJ, Agrawal A, Kana O, Zhen X, Barlow ST, Bruner K, Campos J , Fields J, Kerr AJ, Casper T, Chakrabarty R, Clark M, Kuhl J, Daly R, Darvas M, Ding SL, Dolbear T, Egdorf T, Esposito L, Ferrer R, Fleckenstein LE, Gala R, Gary. A, Gelfand E, Groh J, Guilford N, Guzman J, Hirshstein D, Ho W, Hupp M, Jarsky T, Johansen N, Kalmbach BE, Keene LM, Cowand S, Kilgore MD, Kirkland A, Kunst M, Lee BR, Reitze M, McDonald CL, Malone J, Maltzer Z, Martin N, McCue R, McMillen D, Mena G, Meyer-Dix E, Meyers KP, Molenkopf T, Montine M, Nolan AL, Nijhas JK, Olsen PA, Paclev M, Pagan CM, Peña N, Pham T, Pom CA, Postupna N, Remorin C, Ruiz A, Sardi GA, Schantz AM, Shapovalova NV, Sorensen SA, Staats B, Sullivan M, Sankin SM, Thompson C, Tieu M, Ting JT, Torkelson A, Tran T, Varela-Cuevas NJ, Walling-Bell S, Wang MQ, Waters J, Wilson AM, Hsiao M, Hayner D, Gut NM, Jayadev. -S, Mufti S, Ng L, Mukherjee S, Crane PK, Latimer CS, Levi BP, Smith KA, Close JL, Miller JA, Hodge RD, Larson EB, Grabowski TJ, Hollyrich M, Keene. CD, Lane ES. nut neurosi. 2024 10 14. doi: 10.1038/s41593-024-01774-5. Online ahead of print. PMID: 39402379.
Funding: NIH's National Institute on Aging (NIA), National Institute of Neurological Disorders and Stroke (NINDS), and National Institute of Mental Health (NIMH). Nancy and Buster Alvord of the University of Washington establish an endowed fund in neuropathology. Fund to Cure Alzheimer's Disease.
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